Promising bioactivity of curcumin derivatives against malaria: in silico, in vitro and ITC studies

Promising bioactivity of curcumin derivatives against malaria: in silico, in vitro and ITC studies | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Promising bioactivity of curcumin derivatives against malaria: in silico, in vitro and ITC studies Siti Nur Hidayah Jamil, Khairul Azreena Bakar, Amatul Hamizah Ali, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7148737/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Dec, 2025 Read the published version in Scientific Reports → Version 1 posted 16 You are reading this latest preprint version Abstract Curcumin, a natural polyphenolic compound, has been widely studied for its various therapeutic properties. However, its clinical application is constrained by suboptimal pharmacokinetic properties. This study reports on the in silico assessments, comprising molecular docking, molecular dynamics (MD) and density functional theory (DFT) calculations, which revealed the binding interactions and electronic properties of selective curcumin derivatives. Further, we also report the in vitro antiplasmodial effects, haemin binding potential and GSK-3β inhibitory activity of the synthesised curcumin derivatives, to validate the antimalarial efficacy. Ten synthesised compounds from three different types of curcumin derivatives; Knoevenagel condensate, heterocyclic pyrazole and monocarbonyl derivatives, exhibited more effective antiplasmodial activity against both P. falciparum chloroquine-sensitive (CQ-S) 3D7 and chloroquine-resistant (CQ-R) K1 assays, compared to curcumin (EC 50 = 8.32 ± 2.62 µM (3D7) and 30.66 ± 5.44 µM (K1)). We also report, for the first time, the isothermal titration calorimetry (ITC) and in vitro yeast-based assessments to elucidate their multi-targeting potential based on haemin binding activity and immunomodulatory GSK-3β inhibition. Interestingly, some compounds showed multi-targeting potential against haemin and GSK-3β, which also partially influence the effective antimalarial activity. The outcomes from the different analyses incorporating the in vitro assays, ITC assessments and in silico studies, highlighted the promising potential of curcumin derivatives for antimalarial drug research, over the parent curcumin. This study lays the groundwork for further experimental validation and development of curcumin-based compounds as effective and safe antimalarial and anti-inflammatory agents. Physical sciences/Chemistry Biological sciences/Computational biology and bioinformatics Biological sciences/Drug discovery Curcumin derivatives Antimalaria GSK-3β Antiplasmodial Isothermal titration calorimetry DFT calculations Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction The global infection rate of malaria is estimated to have reached 247 million in 2021, covering 84 malaria-endemic countries, with a fatality rate of 14.8 per 100,000 population and an estimated 619,000 deaths [ 1 ]. First identified in 1880, malaria is caused by Plasmodium parasites, mainly P. falciparum and P. vivax , infecting humans. These parasites are transmitted by female Anopheles mosquitoes and can enter the circulatory system within 30 minutes after a bite [ 2 , 3 ]. The parasites first target liver cells and erythrocytes, and if the affected individual remains untreated, the infection could develop into deadly haemorrhagic conditions including severe and cerebral malaria which involve parasite invasion into the brain and immune system. Although much progress has been achieved towards eliminating malaria, the recent rise in malaria cases, particularly in Southeast Asia, is alarming [ 1 , 4 ]. For example, approximately 17,125 cases have been reported in Malaysia over a period of only four years (2017–2021). In addition to the growing number of malaria cases, the resistance of Plasmodium parasites against current antimalarial drugs such as artemisinin and chloroquine is highly concerning. Therefore, the development of effective antimalarial and anti-inflammatory agents is crucial for curbing and eradicating malaria across the globe. The current search for novel antimalarials has mainly revolved around natural compounds, including curcumin. A polyphenol from the rhizomatous perennial plant, Curcuma longa (turmeric), curcumin (Fig. 1 ) is an attractive potential antimalarial owing to its proven effectiveness as a traditional therapeutic. It is acknowledged by the US Food and Drug Administration (FDA) as “generally recognised as safe” (GRAS) and is non-toxic even at high doses [ 5 , 6 , 7 ]. Curcumin has been documented to exhibit a wide array of pharmacological activities, including antimicrobial, antitumour, antioxidant, anti-inflammatory, and antiprotozoal activities by regulating various biological responses in the body [ 8 , 9 ]. Therefore, curcumin has emerged as a desirable lead compound with dual antimalarial and anti-inflammatory properties for the development of new antimalarial agents [ 10 ]. Its antimalarial activity was first reported by Reddy et al. [ 11 ] based on in vitro and in vivo assessments which showed potent growth inhibition of chloroquine-resistant P. falciparum (IC 50 : ~5 µM) and reduction of blood parasitaemia level by 80–90% upon treatment of P. berghei -infected mice with curcumin over three weeks. Nevertheless, the low bioavailability of curcumin due to rapid metabolism, poor oral absorption, and low aqueous solubility is a major limiting factor for its clinical application. Prior studies have explored the use of adjuvants, nanoencapsulation, and structural modifications of curcumin to enhance its pharmacological properties [ 12 , 13 ]. Among these strategies, the synthesis of curcumin derivatives is seen as advantageous, potentially producing analogues with enhanced biological activity whilst maintaining the safety profile. Most prior research on antimalarials have only focused on specific antiparasitic targets. However, the involvement of inflammatory-related proteins in parasitic growth has led to exploring compounds that exert both antiparasitic and anti-inflammatory effects as potential antimalarials. Inhibiting the immunomodulatory human glycogen synthase kinase 3 (GSK-3β), a serine-threonine kinase immunomodulatory protein involved in the host immune response in malarial infection, has been proven to mediate antimalarial effects in humans [ 10 ]. GSK-3β is recognised as a novel target for antimalarial drugs due to its involvement in the dysregulated PI3K/Akt signalling triggered by the invasion of Plasmodium parasites (Fig. 2 ) and it has also been identified as a key evolutionarily conserved Ser/Thr kinase involved in regulating the host immune response, which is essential for managing advanced malarial infections including cerebral and severe malaria [ 14 , 15 ]. The function of GSK-3β is highly dependent on the hinge region containing conserved residues such as Asp133 and Val135 that make up an essential part of the ATP binding pocket [ 16 ]. This facilitates the catalytic activity of GSK-3β, leading to the production of pro-inflammatory cytokines through NF-κB activation. The binding of an inhibitor ligand to GSK-3β will cause conformational change, preventing access of its substrate to the active site [ 17 ], thus suppressing NF-κB and ultimately promoting anti-inflammatory responses [ 14 , 18 ]. Therefore, the role of curcumin and its derivatives as GSK-3β inhibitors in regulating inflammatory cytokine levels complements their antiplasmodial activity and potential as antimalarial agents. Hence, our research explored curcumin derivatives with potential dual antimalarial and anti-inflammatory activities. Specifically, Knoevenagel condensate, heterocyclic pyrazole and monocarbonyl curcumin derivative compounds were screened, in silico , through molecular docking, molecular dynamics and DFT geometry optimisation assessments to explore and overview the binding conformations and electronic properties. An in-silico approach in early-stage drug discovery is favoured for its time- and cost-effectiveness, and helps justify experimental preclinical studies that are often laborious and costly. The molecular docking and MD simulations demonstrated intermolecular interactions between curcumin derivatives and GSK-3β, while DFT calculations provided insights into the molecular and electronic properties of the compounds. Furthermore, selective compounds with excellent in silico profiles were synthesised and investigated for their in vitro antiplasmodial activities against P. falciparum 3D7 and K1 strains, ITC haemin binding and yeast-based GSK-3β inhibition, further validating our computational findings. Throughout, our current study provides groundwork for a deeper understanding of the potential of curcumin derivatives as effective antimalarial and anti-inflammatory agents. Results and discussion Structure-Activity Relationship (SAR) Analysis of Curcumin Derivatives Based on the previously demonstrated antimalarial and anti-inflammatory activities of curcumin [ 10 , 11 ], we initially explored 91 derivatives and analogues of curcumin based on prior SAR analysis[ 19 ] with the objective of enhancing its bioavailability, hence improving its effectiveness as a therapeutic agent, specifically as potential antimalarial and anti-inflammatory agents. Previous studies on Knoevenagel condensate, pyrazole, and monocarbonyl derivatives of curcumin have presented their potential in targeting several proteins involved in malarial infection, including the ATP6 [ 20 ], NF-κβ [ 21 ], Pf GCN5[ 21 ] and Pf DXR[ 22 ] proteins. Different from the previous, we are exploring their potential against specific proteins – plasmodial lactose dehydrogenase (pLDH), GSK-3β and haemin. The presence of the methoxy phenol group is essential for the antimalarial activity of curcumin as supported by the work of Dohutia et al. [ 20 ] who showed that the in vitro IC 50 of a dimethoxy-substituted phenyl was two-fold higher than that of curcumin, indicating the decreased potency of the derivative. We previously discussed that the design of curcumin derivatives is focused on the modification of methylene and dicarbonyl groups as they are the most reactive, hence unstable, sites of curcumin [ 19 ]. The design of the Knoevenagel condensate, monocarbonyl, and pyrazole derivatives focused mainly on improving the antimalarial activity of curcumin rather than its potential as an anti-inflammatory agent (Fig. 3 ). Hence, among the 91 initially selected derivatives, 21 of them were screened and relisted as derivatives with good SAR (Fig. 4 ) for further molecular docking studies with GSK-3β as the target. ADMET Assessments The pharmacokinetic properties of these compounds, characterised by their predicted ADMET profiles, are presented in Table 1 . The in-silico assessment included selective parameters such as the topological polar surface area (TPSA), pan-assay interference compounds (PAINS), water solubility, intestinal absorption, blood-brain-barrier (BBB) and central nervous system (CNS) permeability, total clearance, and toxicity. The TPSA values for all the assessed compounds remained below 140 Å, which suggested good cell permeability [ 20 , 23 ]. In addition, PAINS moieties were also assessed to identify compounds that tend to be false positives based on structures that appeared promiscuous [ 24 ]. Two of the derivatives, 21 and 22 showed an alert for PAINS, which may suggest that these compounds are associated with potential false positive results. Furthermore, achieving adequate bioavailability is crucial for effective pharmacological action [ 25 , 26 ]. With the exception of derivative 20 , the predicted water solubility for all derivatives was, however, lower than curcumin. Hence, these derivatives might have a lower rate of dissolution and absorption into the bloodstream. Nevertheless, the derivatives were predicted to have favourable intestinal absorption with values above 70%. Thus, sufficient concentrations of these compounds are expected to reach the systemic circulation to exert therapeutic effect. With regard to the blood-brain barrier (BBB) and central nervous system (CNS) permeabilities of the derivatives, there appeared to be no major changes upon structural modifications to the parent curcumin. Despite variations in the values of log BB and log PS, all the tested compounds were classified as unable to readily cross the BBB and penetrate into the CNS. Hence, it is expected that the derivatives would not cause neurologically related side effects. Another factor limiting curcumin’s bioavailability is its rapid excretion, which reduces its effective duration of action. As shown in Table 1 , the total clearance of the Knoevenagel condensate derivatives was lower than that of curcumin, signifying potentially slower excretion and longer in vivo availability. Finally, the toxicity predictions performed include Ames toxicity (mutagenicity), hepatotoxicity (liver-associated side effects), and cytotoxicity (cell disruptability). Non- or low toxicity is a critical requirement in ensuring the safety of a drug candidate to mitigate potential risks of adverse effects. Thus, it should be noted that derivatives 4 , and 18 exhibited potential toxicity which should be taken into consideration for further drug development. Table 1 Predicted ADMET profiles of curcumin and its derivatives. Compound Curcumin 2 3 4 6 10 17 18 20 21 22 Molecular weight, g/mol 368.38 456.49 472.49 502.51 472.49 501.48 485.49 509.38 326.34 352.38 366.41 H-bond acceptor 6 6 7 8 7 8 7 5 5 5 5 H-bond donor 2 2 3 3 3 2 2 2 2 2 2 Log P, log(mol/L) -4.356 -6.247 -5.159 -5.440 -4.897 -5.721 -4.889 -5.380 -4.137 -4.480 -4.643 TPSA, aÅ 93.06 93.06 113.29 122.52 113.29 138.88 122.56 76.74 75.99 75.99 75.99 PAINS alert 0 0 0 0 0 0 0 0 0 1 1 ABSORPTION a Log S, log(mol/L) -4.450 -6.570 -5.980 -6.080 -5.980 -5.900 -6.460 -8.290 -4.120 -5.090 -5.370 Intestinal absorption, % 75.494 84.347 76.07 70.186 76.137 81.145 97.636 88.885 93.613 92.748 92.114 DISTRIBUTION BBB permeability, log(mol/L) -0.528 -0.606 -1.024 -1.316 -1.14 -1.128 -1.098 -0.957 -0.221 -0.158 -0.152 CNS permeability, log(mol/L) -2.964 -2.975 -2.937 -3.096 -2.976 -2.968 -2.208 -1.759 -2.377 -2.078 -1.984 METABOLISM b CYP2D6/CYP3A4 substrate No/Yes No/Yes No/Yes No/Yes No/Yes No/Yes No/Yes No/Yes No/No No/No No/No CYP2D6/CYP3A4 inhibitor No/Yes No/Yes No/Yes No/Yes No/Yes No/Yes No/Yes No/Yes No/Yes No/Yes No/Yes CYP1A2 inhibitor No No No No No No No No Yes Yes Yes CYP2C19/CYP2C9 inhibitor Yes/Yes Yes/Yes Yes/Yes Yes/Yes Yes/Yes No/Yes Yes/Yes Yes/Yes Yes/Yes Yes/Yes Yes/Yes EXCRETION Total Clearance, log(mL/min/kg) 0.071 0.042 0.002 0.016 0.020 0.070 0.209 0.222 0.091 0.114 0.122 Renal OCT2 substrate No No No No No No No No No No No TOXICITY AMES toxicity No No No No No No No No No No No Hepatotoxicity No No No No No No No Yes No No No Cytotoxicity No No No Yes No No No No No No No a Intestinal absorption: good if > 30% b Being a non-substrate and inhibitor means slower metabolism Docking of Curcumin Derivatives to GSK-3β In searching for and designing compounds with potential inhibitory action against a target protein, molecular docking simulations are helpful in elucidating the interaction between the designed compounds and the amino acids of the target protein. Here, docking simulations were employed to establish an understanding of the anti-inflammatory effect of curcumin derivatives through their interaction with GSK-3β. Inhibiting GSK-3β has been proven to mediate antimalarial effects in humans [ 10 ]. GSK-3β is recognized as a novel target for antimalarial drugs due to its involvement in the dysregulated PI3K/Akt signalling triggered by the invasion of Plasmodium parasites. The function of GSK-3β is highly dependent on the hinge region containing conserved residues such as Asp133 and Val135 that make up an essential part of the ATP binding pocket [ 16 ]. This facilitates the catalytic activity of GSK-3β, leading to the production of pro-inflammatory cytokines through NF-κB activation. The binding of an inhibitor ligand to the GSK-3β will cause conformational change preventing access of its substrate to the active site [ 17 ], thus suppressing NF-κB and ultimately promoting anti-inflammatory responses [ 14 , 18 ]. The ligand originally bound to the 1Q5K crystal structure of GSK-3β, TMU1 (AR-A014418), is a potent and selective GSK-3β inhibitor that attenuates the inflammatory response [ 27 , 28 ]. Hence, TMU1 was re-docked for docking-site validation [ 29 , 28 ]. The cross-docking validated the docking cavity and coordinates used for the molecular docking simulation based on the obtained binding energy at -6.451 kcal/mol and RMSD value of less than 1 Å (0.491 Å). Further, the binding cavity of GSK-3β was defined based on the residues involved in the TMU1–GSK-3β binding: Ile62, Val70, Ala83, Tyr134, and Val135, as illustrated in Fig. 5 . Curcumin and its derivatives were hypothesised to bind to the same binding site as TMU1. Indeed, as shown in Table 2 and depicted in Supporting Information S1 – S2 , curcumin exhibited favourable affinity towards GSK-3β and was docked to the same binding pocket as TMU1 based on the residues involved in the interaction. In contrast to TMU1, curcumin formed a more extensive network of hydrogen bonding involving five residues: Asp133, Tyr134, Arg141, Asn186, and Cys199, resulting in a stronger binding energy of -7.437 kcal/mol. The docking simulations were repeated with the aforementioned 21 curcumin derivatives, out of which ten derivatives showed better binding profiles compared to curcumin (Table 2 and S1–S5). All derivatives potentially showed stronger inhibition with more negative binding energies compared to curcumin. For some of the compounds (derivatives 10 , 17 and 18 ), the interactions not only involved hydrogen bonds and hydrophobic interactions, but also featured a pi-cation electrostatic interaction involving Arg141. These differences in binding characteristics likely contributed to the enhanced affinity of these compounds towards GSK-3β. Similarly, derivatives 3 and 6 also showed better interactions with GSK-3β than the parent curcumin based on their binding energies of -9.424 and − 9.079 kcal/mol, respectively. Notably, these derivatives probably benefited from stronger hydrophobic interactions involving six residues, compared to only five for curcumin. As for the heterocyclic pyrazole derivatives, compounds 17 and 18 also possessed relatively higher binding energies than curcumin (-8.728 and − 8.093 kcal/mol, respectively). These derivatives revealed the significant contribution of hydrophobic interactions, in addition to the hydrogen bonds, in stabilizing their complexation with GSK-3β. Likewise, the monocarbonyl derivatives 20 , 21 and 22 were identified to bind more favourably to GSK-3β than curcumin (binding energy: -8.161, -8.100 and − 8.970 kcal/mol, respectively). Our comparative molecular docking revealed that all three derivatisation strategies produced compounds with better binding profiles over curcumin towards GSK-3β and thus, potentially higher inhibitory activity against the protein. Therefore, the ten derivatives listed in were selected for DFT calculations, and MD simulations. Table 2 Curcumin derivatives categorised according to the type of structural modification and the affinity towards GSK-3β. Compound No Binding Energy, kcal/mol Type of Interaction Amino Acid Residues Involved in Binding TMU1 - -6.451 Hydrogen bonds Val135 Hydrophobic interactions Ile62, Val70, Ala83, Tyr134 Curcumin 1 -7.437 Hydrogen bonds Asp133, Tyr134, Arg141, Asn186, Cys199 Hydrophobic interactions Ile62, Val70, Ala83, Leu188 Knoevenagel condensate derivatives 2 -8.772 Hydrogen bonds Ile62, Val135, Arg141, Cys199 Hydrophobic interactions Ile62, Val70, Ala83, Lys85, Val110, Leu132 3 -9.424 Hydrogen bonds Ile62, Asp133, Tyr134, Pro136, Arg144. Cys199 Hydrophobic interactions Ile62, Val70, Ala83, Lys85, Lys183, Leu188, Cys199 4 -9.070 Hydrogen bonds Val62, Arg141, Asp133 Hydrophobic interactions Ile62, Gly63, Val70, Ala83, Leu132, Leu188, Cys199 6 -9.079 Hydrogen bonds Ile62, Lys85, Tyr134, Val135, Arg141, Cys199 Hydrophobic interactions Ile62, Val70, Ala83, Lys85, Val110, Leu132, Tyr134 10 -10.310 Hydrogen bonds Asp133, Tyr134, Val135, Arg141, Arg144 Hydrophobic interactions Ile62, Val70, Ala83, Tyr143, Leu188 Electrostatic interactions Arg141 Pyrazole derivatives 17 -8.728 Hydrogen bonds Val61, Tyr134, Arg144, Asp200 Hydrophobic interactions Ile62, Ala83, Lys85, Val110, Leu132, Leu188, Cys199 Electrostatic interactions Arg141 18 -8.093 Hydrogen bonds Cys199, Asp200 Hydrophobic interactions Ile62, Gly63, Val70, Lys85, Val110, Leu132, Leu188 Electrostatic interactions Arg141 Monocarbonyl derivatives 20 -8.161 Hydrogen bonds Tyr134, Val135, Arg141, Asn186 Hydrophobic interactions Ile62, Val70, Lys85, Cys199 21 -8.100 Hydrogen bonds Ile62, Arg141 Val135, Asp200 Hydrophobic interactions Ile62, Val70, Ala83, Val110, Leu132, Leu188, Cys199 22 -8.970 Hydrogen bonds Ile62, Try134, Arg144, Asp200 Hydrophobic interactions Ile62, Val70, Ala83, Val110, Leu132, Leu188, Cys199 MD Analysis MD simulations allow a deeper understanding of the stability, structural and conformational fluctuations, and kinetic behaviour of ligands and proteins upon their binding. The simulation creates a dynamic environment in which molecular interactions would happen as in the cellular milieu. The conformational changes of the ligand-protein complexes can be observed and analysed for a particular time scale to compare the stability of the different complexes. The environment of the system mimics the biological system for the behaviour and stability of the bounded ligand and protein, while allowing conformational changes of the ligand within the active site of the protein [ 30 ]. In this study, MD simulations of the binding of curcumin and the eleven derivatives to GSK-3β were carried out over 100 ns to generate information on root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (R g ), and hydrogen bond interactions. To highlight and validate the docking results, which converged to derivative 10 as the top hit ligand with the highest binding affinity, the plots of the generated information are obtained as depicted in Fig. 6. RMSD information (Fig. 6, 1 (a), 1(b), 1(a)-ligand and 1(b)-ligand) presents the stability of a compound to stay within its docked confirmation and maintain its binding throughout the simulation time [ 30 ]. The RMSD of the complexes for curcumin started at 0.1 nm and stabilised within the range 0.4–0.7 nm after 10 ns, while 10 started at 0.1 nm and stabilised within 0.3–0.4 nm after 25 ns through the whole simulation period, in which the conformational change is less deviated than curcumin. In addition, based on the plots of ligand-RMSD as presented in Fig. 6, 1 (a)-ligand and 1(b)-ligand, the same graph trend is observed compared to the complexes. This shows that the detected movement of the complexes throughout the simulation is based on the movement of both ligand and protein, with RMSD of derivative 10 is showing less deviated range of RMSD (0.25–0.35 nm) after it stabilised at 5 ns (1(b)-ligand) compared to curcumin with larger RMSD range (0.15–0.45 nm). Hence, this validates the stability of the ligand, specifically derivative 10, to retain its docked configuration within the binding cavity of GSK-3β. The RMSF plots (Fig. 6, 2 (a) and 2(b)), which express the flexibility and fluctuations of particular residues during the simulations [ 31 ], show that curcumin, with RMSF values ranging between 0.05 and 0.40 nm, fluctuates more than 10 , with RMSF ranging between 0.05 and 0.35 nm. These fluctuations could be influenced by the conformational changes adopted by the residues, to facilitate and involve in binding with the ligand [ 31 ]. Notably, there are fluctuations observed involving the Ile62, Val70, and Ala83 which signifies the hydrophobic interactions (Table 2 ), and residues Asp133, Tyr134, and Val135 which reasoned the hydrogen bonding interactions. Additionally, the highest fluctuation at 0.35 nm RMSF is observed at residue Ser219, which is one of the catalytic residues that might also influence significant dynamics of the protein. Further, the hydrogen bonds involving Asp133, Tyr134, Val135, Arg141, Arg144 residues are also maintained (Fig. 6, 3 (b)) as the observed number of hydrogen bonds were retained between two to four throughout the MD simulation for the 10 -GSK-3β complex, which is more than that observed for the curcumin-GSK-3β complex. This suggests that derivative 10 is more stable while maintaining the hydrogen bonds and, hence holds stronger interactions with GSK-3β. The gyration plots (Fig. 6, 4 (a) and 4(b)) explain the spatial distribution or compactness of the complexes. The gyration for curcumin projected highly variable and fluctuating trends on the plots with values ranging from 2.112 to 2.185 gyration, compared to the 10 , which maintains a consistent and stable range of gyration between 2.115 and 2.180. Hence, this could be explained that the structure of the 10 -GSK-3β complex is more compact than curcumin. Based on these, derivative 10 is justified as the top-hit compound with the highest probability for binding and dynamically stable in maintaining its ligand-protein structure, hence potentially inhibiting GSK-3β, better than curcumin. Geometry Optimisation by Quantum DFT Calculations DFT calculations revealed that the derivatives generally maintained a stable molecular structure and possessed improved molecular and electronic properties, suggesting increased chemical reactivity and stability. It has been suggested that the geometry and charge distribution of a molecule, comprising the molecular orbital (MO) descriptors including molecular structure energy E, HOMO, LUMO, and dipole moment (Table 3 and S6–S8), are important factors that affect the biological activities of a compound [ 32 , 33 ]. In addition, the DFT results also provide the reactivity analysis based on the global reactivity parameters including ionisation potential IP, electron affinity EA, chemical potential µ, electronegativity ꭓ, chemical hardness η and electrophilicity index ω [ 34 , 35 , 36 , 37 ], in which the corresponding information is presented in Table 3 . To specifically understand the reactivity of the derivative compounds as potential drug candidates with optimal pharmacokinetics and bioavailability [ 38 ], these parameters are investigated in comparison with the parent curcumin. Applying DFT calculations to identify the lowest energy geometry of curcumin derivatives rationalises their ability to form molecular interactions with GSK-3β. Table 3 Molecular structure energy E, dipole moment, molecular orbital energy gap and the global reactivity parameters of curcumin and selected derivatives obtained from DFT calculations. Compound E, a.u. Energy gap, eV Dipole moment, Debye IP, eV EA, eV µ, eV η, eV ꭓ, eV ω, eV Curcumin -1263.64 3.5990 6.0792 5.9947 2.3957 -4.1952 1.7995 4.1952 4.8901 2 -1532.81 3.6186 3.9073 5.9329 2.3143 -4.1236 1.8093 4.1236 4.6991 3 -1608.03 3.6145 4.8004 5.8926 2.2781 -4.0854 1.8072 4.0854 4.6176 4 -1722.55 3.3984 5.4908 5.7898 2.3913 -4.0906 1.6992 4.0906 4.9236 6 -1608.03 3.6107 5.2226 5.9781 2.3674 -4.1727 1.8053 4.1727 4.8223 10 -1683.26 3.1916 6.6906 6.1465 2.9549 -4.5507 1.5958 4.5507 6.4885 17 -2373.50 1.9813 1.9154 3.7535 1.7723 -2.7629 0.9906 2.7629 3.8529 18 -1553.53 2.4977 3.7980 5.4850 2.9873 -4.2361 1.2489 4.2361 7.1844 20 -1111.00 3.4175 7.6197 5.8262 2.4088 -4.1175 1.7087 4.1175 4.9609 21 -1187.20 3.3046 4.6716 5.4398 2.1353 -3.7876 1.6523 3.7876 4.3412 22 -1227.74 3.4556 4.9924 5.6861 2.2305 -3.9583 1.7278 3.9583 4.5342 Based on our DFT analysis of geometry optimisation, the Knoevenagel condensate and heterocyclic pyrazole derivatives, particularly derivatives 4 , 10 , and 17 , possessed favourably more negative molecular structure energy compared to curcumin (Table 3 ), indicating that these specific derivatives are more structurally stable than curcumin and the monocarbonyl derivatives. Similarly for IP and EA, except for derivative 17 , the values are very comparable to curcumin which signifies the effectiveness and degradability, where these compounds are expected to be quite stable against oxidation processes. The frontier MO analysis based on the HOMO-LUMO energy gap allows for the evaluation of the chemical reactivity of a compound. As shown in Table 3 and S6, derivatives 10 and 17 have smaller energy gaps with values lower than 3.2 eV and higher electrophilicity index ω, suggesting that these compounds would possess higher binding potential and more readily interact with target proteins. Further, a slightly more negative value of chemical potential µ, specifically for derivatives 10 , and comparable values for most of the other derivatives, signifies for the electron and charge distribution of these compounds. Compounds with more negative µ are expected to potentially have better molecular interactions and binding, hence better affinity with the target protein. Additionally, the HOMOs and LUMOs also interpret the electrophilicity of the C and O atoms of the dicarbonyl groups. Based on the HOMOs, the orbitals do not participate in the electron donation, while the LUMOs show that the orbitals are able to accept electrons [ 38 ]. This verifies that the carbonyl group is non-nucleophilic but highly electrophilic, hence supporting the rationale of targeting the carbonyl group as the reactive site of curcumin to synthesise new derivatives [ 19 , 38 ]. Further, the dipole moment, as measured in Debye, explains the overall charge distribution in a molecule. This parameter correlates to polarity, deformability and electronegativity, where a higher dipole moment reflects a more polar and deformable structure, allowing for greater cellular interactions. Among the compounds, only derivatives 10 and 20 have higher dipole moment than curcumin, and hence, higher polarity and solubility, thus resulting in potentially enhanced bioavailability. However, the electronegativity data showed that all derivatives possessed similar values to curcumin except for derivative 17 , suggesting that these compounds have very comparable polarity with curcumin. In addition, the previous ADMET assessment predicted that only derivative 20 had better aqueous solubility than curcumin. Accordingly, this necessitates further experimental validation to determine the solubility profile of the derivatives. Further, DFT results also allow to simulate the shelf stability and thermodynamic stability of the compounds based on the chemical hardness parameter, η. Most compounds, specifically the Knoevenagel condensate and monocarbonyl derivatives have similar η values with curcumin, representing that these compounds are expected to have good stability and not easily degraded which benefits for development of drug with convenient oral dosage form and better shelf-life. Throughout, most derivative compounds generally showed favourable electronic and reactivity profiles, however, comparable to curcumin. These observations urge for the necessity to experimentally validate the results and further derivatise these compounds. Synthesis of curcumin derivatives The synthesis strategy of the compounds is relatively straightforward, whereby the Knoevenagel condensate derivatives 2 – 4 , 6 and 10 were synthesised through modified reaction conditions of the procedure adapted from the previously reported work [ 39 , 40 ]. The condition was modified to the optimised reaction conditions including the amount of solvent, conditions/temperature of the reaction, catalysts, and reaction time, affording a good percentage yield of all desired Knoevenagel condensate curcumin derivatives. The synthesis was performed in one step by reacting curcumin and an excess of respective R-benzaldehyde in dimethylformamide (DMF), in the presence of acetic acid and piperidine, at room temperature for 48 hours, to successfully obtained derivatives 2 – 4 , 6 and 10 in good yields between 63–79%. The presence of both acid and base catalysts facilitates the reaction by protonating the aldehyde making it more electrophilic and deprotonating the highly acidic methylene hydrogen of curcumin making it more nucleophilic. Despites most published Knoevenagel condensation reaction used methanol as solvent and higher temperature (> 70℃, reflux), the use of DMF as solvent allows the reaction to proceed at higher concentration, lower temperature and safer conditions. The next series of derivatives were synthesised to obtain the heterocyclic pyrazole derivatives 17 and 18 , based on the published procedures [ 21 , 41 ]. The synthesis was achieved in one-step procedure by reacting curcumin with an excess of respective R-phenylhydrazine hydrochloride in acid-catalysed ethanolic reaction, at 85℃ (reflux) overnight. The presence of acetic acid catalyst protonates the carbonyl group of curcumin making it more susceptible for nucleophilic attack by the hydrazine, forming a hydrazone intermediate, and proceeded to intramolecular cyclisation eliminating water and generating the aromatic pyrazole ring, to afford the desired compounds in a good yield of 65–70%. The monocarbonyl curcumin derivatives 20–22 were successfully synthesised based on the procedure described by Deck et al.[ 42 ] and Du et al.[ 43 ] by total synthesis through aldol reaction between two mole equivalent of aldehyde and one mole equivalent of ketone. Vanillin was reacted with an appropriate ketone in glacial acetic acid saturated with anhydrous concentrated hydrochloric acid, at 30℃ for 2 hours to obtain the desired compounds in a good yield of 61–71%. The structures of all synthesised compounds were characterised and validated by comparing the published with the measured 1 H NMR, presented in the S10 – S19 . This concluded the synthesis works of ten curcumin derivative compounds to be assessed for their antiplasmodial and antimalarial activities. Biological activities In vitro pLDH antiplasmodial activity and cytotoxicity The results detailed the antiplasmodial activity of curcumin derivatives against P. falciparum 3D7 (chloroquine-sensitive) and K1 (multi-drug-resistant) strains, evaluated based on the EC 50 (effective concentration for 50% inhibition), CC 50 (cytotoxicity to WRL-68 human cells), and Selectivity Index (SI) as presented in Table 4 and S20–S32. The EC 50 obtained against both strains suggest the potential inhibition of parasite metabolism, particularly through the interference of pLDH, a crucial enzyme involved in the glycolytic pathway of the parasite. Chloroquine, the reference compound, showed exceptional potency (EC 50 = 0.008 µM for 3D7) and high selectivity (SI = 12352 fo r 3D7). The parent compound, curcumin, was moderately active (EC 50 = 8.32 µM for 3D7 ) and non-toxic to human cells (CC 50 > 99 µM) with moderate selectivity (SI = 11.99). Among the derivatives, monocarbonyl derivatives 20 – 22 exceptionally exhibited better and more potent activities against 3D7 (EC 50 = 0.15–0.25 µM) and K1 (EC 50 = 1.30–2.53 µM), than curcumin. However, the cytotoxicity and SI analysis revealed that most derivative compounds exhibit potential cytotoxicity whereby pure compounds are classified as toxic to normal mammalian cells when CC 50 value is less than 10 µM or 4 µg/mL [ 44 , 45 ]. Notably, derivative 3 with EC 50 = 0.82 µM (3D7) and 16.70 µM (K1) is the only Knoevenagel condensate compound that showed no toxicity (CC 50 > 99) and SI of 22.76 (3D7) and 7.43 (K1). This reinforces the safety profile of derivative 3 suggesting its promising potential. Meanwhile, pyrazole derivative 17 is also demonstrated significant antiplasmodial activity based on EC 50 = 0.82 µM (3D7) and 16.70 µM (K1), CC 50 > 99 µM, with the highest SI of 120.73 (3D7) and 5.93 (K1). This highlights that 17 exhibit the most notable inhibition, non-toxic and therapeutically more potent antimalarial agent than curcumin and other derivative compounds. Overall, all derivatives also shown lower EC 50 values against 3D7 compared to K1, and higher resistance index value (RI > 1), implying a potential resistance factor in CQ-resistant parasites. This warrants further assessment into the mechanism of action. Throughout, the in vitro evaluation of all synthesised derivative compounds demonstrated promising antiplasmodial activity based on the observed effective concentration EC 50 values against both 3D7 and K1 strains which indicate that all synthesised compounds exhibit significantly better potency, surpassing the parent compound, curcumin. Specifically, monocarbonyl derivatives 20 – 22 which have smaller MW are observed to be much more potent than the other derivatives. Overall, these findings highlight the potential of curcumin derivatives for further development as selective antiplasmodial drugs. Further structural optimisation of those compounds lacking in antiplasmodial potency and cytotoxicity may be needed to improve their therapeutic potential and safety profile. Table 4 Anti-plasmodial activities of curcumin derivatives against Plasmodium falciparum 3D7 (CQ-sensitive strain) and Plasmodium falciparum K1 (multi-drug-resistant strain), and cytotoxic evaluation against WRL-68 human cells. Compound 3D7 EC 50 ± SD, µM K1 EC 50 ± SD, µM WRL-68 CC 50 ± SD, µM 3D7 Selectivity Index (SI) a K1 Selectivity Index (SI) a Resistance Index (RI) b Chloroquine 0.008 ± 0.003 0.53 ± 0.12 98.82 ± 0.2 12352.50 186.45 66.25 Curcumin 8.32 ± 2.62 30.66 ± 5.44 > 99 11.90 3.23 3.69 2 3.79 ± 0.88 17.09 ± 2.33 0.10 ± 0.02 0.03 0.01 4.51 3 4.35 ± 2.43 13.33 ± 7.23 > 99 22.76 7.43 3.06 4 1.79 ± 0.35 18.84 ± 0.78 0.31 ± 0.11 0.17 0.02 10.53 6 1.15 ± 0.26 11.01 ± 2.67 0.19 ± 0.07 0.17 0.02 9.57 10 2.77 ± 0.56 9.10 ± 1.04 0.53 ± 0.14 0.19 0.06 3.29 17 0.82 ± 0.37 16.70 ± 5.76 > 99 120.73 5.93 20.37 18 3.29 ± 0.70 25.90 ± 0.79 > 99 30.09 3.82 7.87 20 0.15 ± 0.03 2.53 ± 1.06 3.93 ± 0.95 26.20 1.55 16.87 21 0.25 ± 0.11 1.47 ± 0.36 2.16 ± 0.59 8.64 1.47 5.88 22 0.20 ± 0.09 1.30 ± 0.37 6.71 ± 1.82 33.55 5.16 6.50 a Selectivity Index (SI) = CC 50 MTT / EC 50 pLDH b Resistance Index (RI) = EC 50 K1 / EC 50 3D7 ITC haemin binding activity The potential of binding to haem, an essential intermediate in the haem detoxification pathway of Plasmodium , is one of the mechanism of actions of antimalarial drugs such as chloroquine and artemisinin. The haem released from haemoglobin hydrolysis by the malaria parasite is detoxified into inert hemozoin; interference with this process leads to toxic haem accumulation and death of the parasite [ 46 , 47 ]. A strong binding of compounds to free haem can inhibit its detoxification and serves as a validated antimalarial mechanism of action, as exemplified by chloroquine. Therefore, the binding characteristics of the synthesised compounds with haem were accessed using ITC experiment, elucidating key parameters including association constants ( K a ), binding ratio ( n ), and variations in enthalpy (Δ H ), entropy (Δ S ), and Gibbs free energy (Δ G ), thereby facilitating a direct comparison with the reference compounds curcumin and chloroquine (Table 5 and S33–S34). Among the assessed compounds, derivative 3 showed the highest binding affinity to hemin with a binding constant of (7.44 ± 3.48) × 10⁶ M⁻¹, approximately 1.8 times higher than curcumin (4.08 ± 2.64) × 10⁶ M⁻¹. Meanwhile, binding affinities of derivatives 17 , 18 and 21 were comparable to curcumin, reflecting favourable interaction strengths. Although derivatives 2 , 4 , and 10 showed considerably lower K a compared to other derivative compounds, but their binding affinities were close to chloroquine (10⁵ M⁻¹). Overall, derivatives 3 , 17 , 18 , and 21 have significant haem-binding affinities, which means they can possibly disrupt the formation of hemozoin. This would interfere with the detoxification process of the parasite and make them promising candidates for antimalarial drugs. The nature of the interaction forces involved was determined by further analysis the thermodynamic parameters of synthesised compound-haem interactions, which are shown in Table 5 . All examined compounds, including references, exhibited negative entropy (Δ S ) values and strongly exothermic interactions. A negative ΔS value suggests that the system becomes more ordered upon binding, resulting in a complex with restricted mobility during the interaction. At the same time, the exothermic binding is indicative of the release of heat to the environment, which is likely facilitated by hydrogen bonding and van der Waals forces rather than hydrophobic effects. Furthermore, all derivatives have negative Δ G values when bound to haem suggest that binding is both spontaneous and thermodynamically favourable. Overall, our findings support the haemin binding potential of curcumin derivative compounds, particularly derivatives 3 , 17 and 18 which are superiorly more potent than curcumin and chloroquine, as potential multi-targeting antimalarial agents. This suggests that these derivatives with more favourable aqueous solubility and stearic accessibility are selectively more effective disruptors of the haem detoxification pathways. Table 5 Thermodynamic properties from the binding of curcumin derivative compounds with haemin from ITC experiments Compound K a × 10 6 , M -1 Δ H , kJ/mol Δ S , J/mol⋅K Δ G , kJ/mol Chloroquine 0.14 ± 0.35 −37.71 ± 1.12 −23.34 ± 0.76 −30.48 ± 0.88 Curcumin 4.08 ± 2.64 −99.76 ± 0.11 −196.05 ± 5.44 −38.95 ± 1.80 2 0.23 ± 0.14 −99.45 ± 0.55 −219.00 ± 7.21 −31.52 ± 1.68 3 7.44 ± 3.48 −98.57 ± 1.34 −186.75 ± 8.41 −40.65 ± 1.26 4 0.35 ± 0.27 −94.80 ± 1.56 −200.85 ± 1.91 −32.52 ± 2.16 6 2.79 ± 1.17 −98.08 ± 1.31 −212.47 ± 7.56 −32.19 ± 1.06 10 0.49 ± 0.32 −98.74 ± 0.57 −210.50 ± 7.78 −33.45 ± 1.85 17 5.44 ± 4.87 −99.90 ± 0.08 −195.30 ± 9.05 −39.34 ± 2.72 18 3.16 ± 1.90 −99.11 ± 0.82 −196.40 ± 3.70 −38.19 ± 1.90 20 1.77 ± 0.73 −99.77 ± 0.13 −202.45 ± 4.03 −36.98 ± 1.10 21 3.27 ± 2.31 −98.54 ± 2.06 −194.20 ± 0.14 −38.31 ± 2.00 22 2.22 ± 2.62 −99.42 ± 0.28 −199.10 ± 1.83 −37.67 ± 0.31 Yeast-based in vitro GSK-3β inhibition The study paved further to evaluate the multi-targeting potential of these derivatives based on the anti-inflammatory effect through their interaction with GSK-3β. The inhibition of GSK-3β by curcumin was only recently shown experimentally by Ali et. al. [ 10 , 18 ], but was earlier suggested through preliminary computational simulations [ 48 ]. While all derivative compounds exhibited more effective inhibition against the pLDH assays (Table 4 ), the GSK-3β inhibition was only observed for monocarbonyl derivative 20 , selectively at 0.02 M, despite in silico findings demonstrated potential inhibition across all derivative compounds (Table 6 and S35). This discrepancy underscores the complexity of target specificity in the complex biological environment, where factors such as molecular weight, solubility and stability, which are beyond the molecular docking and MD scores, should be taken into consideration. Smaller molecular size/weight and better lipophilicity (logP) of derivative 20 might be influencing the efficacy for better passive diffusion to penetrate the yeast cell membrane [ 49 ]. Curcumin and all other derivative compounds with higher molecular weight and lower log P may struggle to penetrate to effectively interact with GSK-3β within the yeast system, hence no inhibitory activities were observed. Table 6 Inhibition of GSK-3β at 28 ℃ and 37 ℃ inhibition zones from the yeast-based assay. Compound Concentration, M Zone of inhibition, mm Remarks 28 ℃ 37 ℃ Curcumin 0.0002–0.5 - - No activity 2 0.0002–0.5 - - No activity 3 0.0002–0.5 - - No activity 4 0.0002–0.5 - - No activity 6 0.0002–0.5 - - No activity 10 0.0002–0.5 - - No activity 18 0.0002–0.5 - - No activity 19 0.0002–0.5 - - No activity 20 0.5 7.50 ± 0.71 8.00 ± 0.00 Selective inhibition of GSK-3β at 0.02 M 0.05 7.00 ± 0.00 8.00 ± 0.00 0.02 - 7.00 ± 0.00 0.002 - - No activity 0.0002 - - No activity 21 0.0002–0.5 - - No activity 22 0.0002–0.5 - - No activity TDZD-8 a 0.02 16.67 ± 1.41 18.00 ± 1.66 Non-selective inhibition of GSK-3β DMSO b – - - No activity a positive control b blank sample Experimental In silico Assessments ADMET studies The predicted ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of curcumin, which we have previously obtained from the SwissADME (http://www.swissadme.ch/index.php), pkCSM (http://biosig.unimelb.edu.au/pkcsm/), and proTox-II (https://tox.charite.de/protox_II) web servers, were compared to those of the derivatives [19, 50, 51, 52]. The ADMET information predicts the overall pharmacological behaviour of potential drug candidates in the body including the blood, tissues, and organs, thus providing an alternative pathway for screening a long list of compounds. Molecular docking The 3D X-ray crystallographic structure of GSK-3β was retrieved from the Protein Data Bank (PDB ID: 1Q5K, resolution 1.94 Å, https://www.rcsb.org) [29]. It was prepared for molecular docking by removing water molecules and adding polar hydrogen as well as Kollman charges, before saved as a .pdbqt file [53]. The docking analysis was performed to screen curcumin derivatives that bind best to GSK-3β while determining the optimal energy geometry of the docked compounds. Based on the previously validated active site of the protein, the docking simulation was performed with a defined grid box dimension of 40×30×30 Å centred at x=23.9226, y=21.6961, and z=9.76081 [53, 54]. The active site of the protein is specified as the cavity that binds specific ligands (curcumin derivatives) resulting in potential inhibition of its activity. The other docking parameters were set to default [54]. Analysis of the docking results revealed the binding affinity, the type of molecular interactions and the amino acids involved in the binding. BIOVIA Discovery Studio Visualizer [55] and Ligplot+ [56] were utilised to map the interactions and visualise the position and distance of the amino acid residues interacting with the ligands. MD simulations MD simulations were performed to analyse the dynamics of ligand-protein complexation and to validate the docking results. In a MD simulation, the environment of the system mimics the biological system for the behaviour and stability of the bounded ligand and protein, while allowing conformational changes of the ligand within the active site of the protein [30]. The simulations were carried out over 100 ns using the GROMACS 2020.6 software package [57] running on a Ubuntu -2020.6-2 operating system to generate information on root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (R g ), and hydrogen bond interactions. The temperature and pressure for the experimental conditions were set at 300 K and 1 atm, respectively, to imitate the physiological [58]. DFT calculations DFT calculations were performed using GaussView 6.0.16 [59] at the B3LYP/6-311G++(d,p) level, which was adopted from the previously reported method by Hazarika and Kalita [38]. The DFT analysis provide critical information on energy minimisation for bonding, dipole moment, molecular orbital energy profile and the global reactivity parameters from geometry optimisation calculations. Theoretically, it enables geometry optimisation of a chemical structure in order to find its stable geometry using a quantum chemical technique [60]. Materials Curcumin was purchased from Sigma Aldrich Co. (USA) (>80% purity) and Tokyo Chemical Industry (TCI) (Japan) (synthetic, >97% purity). Other chemicals were purchased: R-benzaldehyde and R-phenylhydrazine hydrochloride from Sigma Aldrich Co. (USA), solvents from Merck (Germany) and other commercial sources. All purchased reagents and chemicals were used without further purification. Solvents were dried according to the previously established procedure from the literature [61]. TLC plates (Kieselgel 60 F254) from Merck (Germany) were used and visualised with ultraviolet (UV) light at 254 nm or by heating after treatment with a solution of anisaldehyde in ethanol. Flash column chromatography for purification was performed with Merck silica gel 60 (0.04–0.063 mm), and reverse phase column chromatography was performed using Waters Sep-Pak® Vac 35cc C 18 10g (Waters Corporation, Milford, MA, USA). Instrumentations and compound characterisations All the synthesised compounds were characterised and identified by Nuclear Magnetic Resonance (NMR) 1 H and 13 C NMR spectroscopy. Samples were dissolved in deuterated chloroform, CDCl 3 , measured using Bruker Fourier Transform FT-NMR (Karlsruhe, Germany) and JEOL FT-NMR (Japan), both operating at 400 MHz, and analysed using ACD/Labs NMR Processor software. NMR data were analysed, and all spectra were matched with the previously reported information. Characterisation details of all synthesised compounds including 1 H and 13 C NMR spectroscopy, can be found in the Supporting Information. General procedure for the synthesis of curcumin derivative compounds General procedure A: Synthesis of Knoevenagel condensate derivatives The synthesis strategy of the compounds is relatively straightforward, with modifications on the reaction conditions. The five Knoevenagel condensate derivatives ( 2 – 4 , 6 and 10 ) were synthesised through the modified reaction conditions from the previously reported general procedure by Zuo et al. and Pedersen et al. [39, 40]. The procedure was modified to the optimised reaction conditions: i) amount of solvent, ii) conditions/temperature of the reaction, iii) catalysts, and iv) reaction time. The synthesis was conducted according to Scheme 1 by reacting curcumin (0.543 mmol, 1.0 eq.) with appropriate R-benzaldehyde (0.706 mmol, 1.3 eq.) in 1.00 mL dry dimethylformamide (DMF), catalysed by piperidine (0.543 mmol, 1.0 eq.) and acetic acid (0.706 mmol, 1.3 eq.) at room temperature for 48 hours. On completion (monitored through TLC), the reaction mixture was diluted with ethyl acetate and washed with water followed by brine. Purified yield was obtained by column chromatography using a gradient eluent system (Hexane:EtOAc = 100:0 → 60:40, v/v) and dried in vacuo . Heterocyclic pyrazole curcumin derivatives The procedure for the synthesis of heterocyclic pyrazole derivatives 17 – 18 was referred from the published methodology by Sagnou et al. [41] and Mishra et al. [62]. The synthesis was conducted according to Scheme 2 , by reacting curcumin (0.271 mmol, 1.00 eq.) with R-phenylhydrazine hydrochloride (0.407 mmol, 1.50 eq.) in 4.00 mL ethanol, catalysed by acetic acid (5.24 mmol), reflux at 85 °C, for 15 hours. On completion (monitored through TLC), the crude was dried in vacuo followed by a treatment with ethyl acetate. Solid precipitate was filtered and washed with cold water. Final yield was left drying in a desiccator for 24 hours to obtain the purified yield. Monocarbonyl curcumin derivatives The monocarbonyl derivatives 20 – 22 were synthesised according to Scheme 3 based on the procedure described by Deck et al. [42] and Du et al. [43]. A mixture of vanillin (0.657 mmol, 2.00 eq.) and an appropriate ketone (0.328 mmol, 1.00 eq.) was reacted in 1.00 mL acetic acid, catalysed by concentrated hydrochloric acid cat. (0.328 mmol, 1.00 eq.) at 30 °C for 2 hours. After completion (monitored through TLC), the reaction mixture was left standing for 24 hours before the crude was filtered and washed with cold water. The product was redissolved with ethyl acetate and extracted from water. The organic layer was collected and purified yield was dried in vacuo . Biological Assessments In vitro P. falciparum 3D7 and K1 assays The antiplasmodial activities of curcumin and the synthesised curcumin derivative compounds were assessed using the P. falciparum chloroquine-sensitive (CQ-S) 3D7 and chloroquine-resistant (CQ-R) K1 strains, obtained from the Malaria Research and Reference Reagent Resource Center (MR4), Manassas, Virginia. The parasites were revived from cryopreservation and cultured at 1% haematocrit using purified O+ human erythrocytes in RPMI 1640 medium supplemented with 0.5% Albumax I (GIBCO, Life Technologies, USA), 25 mM HEPES, 100 μM hypoxanthine, 12.5 μg/mL gentamicin, and 1.77 mM sodium bicarbonate. Cultures were maintained at 37°C in a 5% CO₂ atmosphere. Parasitaemia was assessed by microscopic examination of field-stained thin blood smears. Parasite sensitivity to curcumin was evaluated using the parasite lactate dehydrogenase (pLDH) assay, as described by Makler et al. [63], in flat-bottom 96-well microtiter plates. Prior to the assay, parasite cultures were synchronised using 5% D-sorbitol and plated at 2% haematocrit and 2% parasitaemia, predominantly in the ring stage. Curcumin derivatives were added at predetermined concentrations. Following a one-hour incubation at room temperature in the dark, colour development was measured at 655 nm using a Fluostar Optima microplate reader. Data were analysed via non-linear regression using GraphPad Prism 5 (GraphPad Software, Inc., San Diego, CA) to determine the 50% inhibitory concentration (EC₅₀). Cytotoxicity The human normal liver cell line WRL-68 (ATCC: CL-48) was obtained from the American Type Culture Collection (ATCC), USA. Cytotoxicity of curcumin derivatives was assessed using the MTT assay, as described by Mosmann [64]. Briefly, 100 µL of WRL-68 cells (2 × 10⁴ cells/mL) in complete medium supplemented with 10% fetal bovine serum (FBS) was seeded into 96-well flat-bottom microtiter plates. Cells were incubated with or without curcumin derivatives for 48 hours at 37°C in a 5% CO₂ atmosphere. After incubation, confluent cells were treated with curcumin derivatives at concentrations ranging from 10 to 0.01 µg/mL. Wells containing untreated cells served as positive controls for cell viability. Following treatment, 5 mg/mL MTT solution in phosphate-buffered saline (MTT-PBS) was added to each well, and the plates were incubated for an additional 3 hours under the same conditions. The medium was then removed and replaced with 100 µL of dimethyl sulfoxide (DMSO) per well to solubilise the formazan crystals, followed by a 10-minute incubation at 37°C in a CO₂ incubator. Absorbance was measured at 540 nm using a Fluorostar OPTIMA microplate reader. The 50% cytotoxic concentration (CC₅₀) of the curcumin derivatives was determined from three independent experiments. Percentage growth inhibition and CC₅₀ values were calculated by non-linear regression analysis using GraphPad Prism. Cytotoxicity was reported as the concentration required to inhibit 50% of cell growth. Selectivity Index (SI) and Resistance Index (RI) The selectivity index (SI) was calculated as the ratio of the 50% cytotoxic concentration (CC₅₀) to the 50% inhibitory concentration (IC₅₀) of antimalarial activity (SI = CC₅₀/IC₅₀), based on data from MTT and pLDH assays. Compounds with SI values greater than 100 (SI > 100) were considered strong and selective antiplasmodial agents, as described by Sarr et al. [65]. Additionally, the resistance index (RI) was determined by calculating the ratio of IC₅₀ values obtained from the resistant strain (K1) to those from the sensitive strain (3D7) (RI = IC₅₀ K1 / IC₅₀ 3D7). A higher RI indicates reduced sensitivity of the resistant strain to the test compound. ITC assessment An ITC microcalorimeter (TA Instruments, New Castle, DE, USA) was utilised to assess the interaction of the synthesised curcumin derivative compounds with haemin at 37 °C as described by Feroz et al. [66]. Curcumin and chloroquine were used as reference compounds to enable comparative analysis of binding affinities and thermodynamic parameters. The synthesised compounds were dissolved in acetone at concentrations ranging from 1 to 1.5 mg/mL to prepare stock solutions, while haemin stock solution (0.5 mg/mL) was prepared by dissolving hemin in 0.5 M NaOH. The stock solutions were subsequently diluted with 10 mM sodium phosphate buffer (pH 7.4), resulting in the final samples containing 0.5 M NaOH and about 3% acetone. All samples were vacuum-degassed for 10 minutes before the titration experiments. For the titration, 20 µM hemin was placed in the sample cell, with the reference cell containing deionised water. The hybrid compound (100 µM) was loaded into a 250 µL syringe and introduced into the microcalorimeter for injection. The titration required 16 consecutive 15 µL injections into the sample cell, spaced each 400 s, with stirring kept at 200 rpm to ensure adequate mixing. In the data analysis, the heat effects from solution mixing and dilution were manually corrected. An independent binding model was employed to process and analyse the data using NanoAnalyze software (v3.3.0). The results are presented as the average ± standard deviation of the selected replicates showing the best consistency. In vitro yeast-based GSK-3β assay The GSK3β-inhibitory activity of test compounds was assessed using an in vivo yeast-based assay as described by Andoh et al. [67]. In this system, mammalian GSK3β was inserted and expressed in a temperature-sensitive gsk-3 null mutant yeast strain (pKT10-GSK3β) with the genotype MATa his3 leu2 ura3 trp1 ade2 mck1::TRP1 mds1::HIS3 mrk1 yol128c::LEU2, thereby restoring the original phenotype. For screening, a loopful of a three-day-old yeast culture was inoculated into 5.0 mL of synthetic complete medium lacking uracil (SC-Ura) and incubated in a water bath at 37°C with shaking at 150 rpm for 48 hours. Subsequently, 400 μL of the yeast culture was mixed with 100 mL of SC-Ura agar, poured into six plates, and allowed to solidify at room temperature. The disc diffusion technique was employed by applying 20 μL of 100 mg/mL test samples onto sterile paper discs, which were then placed on the SC-Ura agar plates. Plates were incubated at both 28°C (permissive temperature) and 37°C (restrictive temperature) for 120 hours, and yeast growth was monitored over five days. All assays were conducted in triplicate. Inhibition of yeast growth at 37°C indicated GSK3β-inhibitory activity of the test compounds [53, 68]. Conclusion The incorporation of multi-faceted approach integrating in silico , synthesis and biological assessment highlight the intricacy of multi-targeting strategies in the discovery and development of antimalarial drug based on the groundwork exploration of curcumin derivatives. While all the assessed curcumin derivative compounds demonstrated favourable physiochemical properties based on the ADMET profiles and in silico inhibitory potential, experimental assessments revealed promising antimalarial activities with selective compounds demonstrated multi-targeting potential as prospective antimalarial agents. This suggested that parameters beyond docking scores and in silico parameters would also strongly influence the inhibitory activities within the biological systems, reinforcing the necessity of experimental validations. The pLDH assay confirmed that all derivatives demonstrated more potent antiplasmodial activity than curcumin, as suggested from the in silico assessments, with derivative 20 being the most potent. Interestingly, only derivative 3 and 17 exhibited higher potential haemin binding affinity than curcumin and chloroquine from the ITC experiment, and derivative 20 selectively showed inhibition of GSK-3β based on the yeast-based assay. These discrepancies suggest that compounds with specific pharmacological profiles are selectively more promising as multi-targeting antimalarial agents over the other derivative compounds – Knoevenagel condensate 3 with the least stearic and better solubility (log P and log S), heterocyclic pyrazole derivative 17 with more favourable electronic and reactivity profiles (DFT calculations) and monocarbonyl derivative 20 with smaller MW, better solubility (log P and log S) and metabolism. The potential haemin binding and GSK-3β inhibition of these selective derivatives are observed to be influencing the antimalarial potential based on the selectively smaller and potent EC 50 for derivative 17 and 20 . The diverging computational explorations and experimental assessments, however, also presents the limitations of independent structure-based modelling, emphasising the importance of biological validations. Further investigations employing scaffold derivatisations, in vivo assessments, experimental pharmacokinetic validations and target-specific mechanism studies would allow in-depth understanding of the antimalarial potential of curcumin derivative compounds, which is cost-effectively sourced, to streamline the complexity of effective antimalarial drug discovery and development. Declarations Ethics approval and consent to participate Clinical trial number: not applicable. Consent for publication Not applicable Competing interests The authors declare that they have no competing interests Funding This study was supported by the South Asia Research Hub, Foreign, Commonwealth & Development Office (FCDO), Government of the United Kingdom [ST-2024-001]. Author Contribution SNH.J. contributed to conceptualisation, methodology planning, data curation, formal analysis, writing, reviewing and editing the original draft. KA.B., AH.A., NFN.M. and F.S. were involved in conceptualisation, methodology planning, writing, reviewing and editing the original draft. F.M., SD.L. and SR.F. were involved in conceptualisation, methodology planning, reviewing and editing the draft, providing resources and access to software, supervising the progress, and data validation. N.O. provided supervision, reviewing and editing the manuscript. Y.Z., MI.M., R.M. and U.S. provided access to resources and supervise the progress. J.L. contributed to funding acquisition, project administration, access to resources, and overall supervision. All authors reviewed the manuscript. Acknowledgement This study was supported by the South Asia Research Hub, Foreign, Commonwealth & Development Office (FCDO), Government of the United Kingdom [ST-2024-001]. The views expressed in this report, however, do not necessarily reflect the official policies of the Government of the United Kingdom. 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Yeast glycogen synthase kinase-3beta pathway inhibitors from an organic extract of. J. Nat. Prod. 72 , 1520–1523. 10.1021/np900163f (2009). Schemes Schemes 1 to 3 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files SC1.png Scheme 1. Synthesis of Knoevenagel condensate derivatives (2–4, 6 and 10). R-benzaldehyde: benzaldehyde (2), 4-hydroxybenzaldehyde (3), 4-hydroxy-3-methoxybenzaldehyde (4), 3-hydroxybenzaldehyde (6) and 4-nitrobenzaldehyde (10). SC2.png Scheme 2. Synthesis of heterocyclic pyrazole derivative (17–18). R-phenylhydrazine hydrochloride: 3-nitrophenylhydrazine hydrochloride (17) and 2,4-dichlorophenylhydrazine hydrochloride (18). SC3.png Scheme 3. Synthesis of monocarbonyl curcumin derivatives 20–22. 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11:53:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7148737/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7148737/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-32346-7","type":"published","date":"2025-12-15T15:57:09+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":88627983,"identity":"866346da-0ad0-41b7-8f1a-fbde6da43823","added_by":"auto","created_at":"2025-08-08 13:18:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":47902,"visible":true,"origin":"","legend":"\u003cp\u003e2D and geometry optimised 3D structures of the keto-isomer of curcumin.\u003c/p\u003e\n\u003cp\u003eIts antimalarial activity was first reported by Reddy et al. [11] based on \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein vivo\u003c/em\u003e assessments which showed potent growth inhibition of chloroquine-resistant \u003cem\u003eP. falciparum\u003c/em\u003e (IC\u003csub\u003e50\u003c/sub\u003e: ~5 µM) and reduction of blood parasitaemia level by 80–90% upon treatment of \u003cem\u003eP. berghei\u003c/em\u003e-infected mice with curcumin over three weeks. Nevertheless, the low bioavailability of curcumin due to rapid metabolism, poor oral absorption, and low aqueous solubility is a major limiting factor for its clinical application. Prior studies have explored the use of adjuvants, nanoencapsulation, and structural modifications of curcumin to enhance its pharmacological properties [12, 13]. Among these strategies, the synthesis of curcumin derivatives is seen as advantageous, potentially producing analogues with enhanced biological activity whilst maintaining the safety profile.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7148737/v1/d117d6e1c1337af205ee84c2.png"},{"id":88629003,"identity":"31d91eb2-b95f-482c-9348-d805a661c6e3","added_by":"auto","created_at":"2025-08-08 13:26:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":240612,"visible":true,"origin":"","legend":"\u003cp\u003eSignalling pathway involved in the mechanism of action of curcumin and its derivatives which inhibit GSK-3β, leading to the regulation of pro- and anti-inflammatory cytokine levels.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7148737/v1/fb515582e5780ab5c821b17d.png"},{"id":88627985,"identity":"60384354-2e90-45ba-965b-69ebb708350a","added_by":"auto","created_at":"2025-08-08 13:18:03","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":32871,"visible":true,"origin":"","legend":"\u003cp\u003eStructural identity of curcumin showing the modification sites, followed by the three different approaches for designing curcumin derivatives.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7148737/v1/88ce3e4b1b0569620f6dd19d.png"},{"id":88627991,"identity":"e0518343-3e39-41c1-a99a-7e77ea6849ef","added_by":"auto","created_at":"2025-08-08 13:18:03","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":177208,"visible":true,"origin":"","legend":"\u003cp\u003eStructures of screened curcumin derivatives with good SAR.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7148737/v1/a049849ea85ac5684822977c.png"},{"id":88629004,"identity":"2527b315-c2f1-4202-a9c1-a944db9179fc","added_by":"auto","created_at":"2025-08-08 13:26:03","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":213720,"visible":true,"origin":"","legend":"\u003cp\u003eComparison between the co-crystallised and the re-docked TMU1 within the binding site of GSK-3β showing similar conformation and docked position with a favourably low RMSD (0.491 Å).\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7148737/v1/6b468ab8664eafdbea05c49f.png"},{"id":88627994,"identity":"9d72e78d-1ed2-4424-bb07-7cd5b01ef69f","added_by":"auto","created_at":"2025-08-08 13:18:03","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1254171,"visible":true,"origin":"","legend":"\u003cp\u003eAnalysis of MD simulations of ligand-GSK-3β complexation involving (a) curcumin and (b) derivative \u003cstrong\u003e10\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7148737/v1/c02a8203b1be21568acdcbc2.png"},{"id":98814054,"identity":"b279ba3c-cf84-42d3-8495-827ee6ba4c9b","added_by":"auto","created_at":"2025-12-22 16:10:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4186164,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7148737/v1/207ac613-eeb9-43df-b8d0-212be4ae70d4.pdf"},{"id":88629002,"identity":"b0edc914-f2f5-4990-9143-376d479c8c7f","added_by":"auto","created_at":"2025-08-08 13:26:03","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14961,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 1\u003c/strong\u003e. Synthesis of Knoevenagel condensate derivatives (\u003cstrong\u003e2\u003c/strong\u003e–\u003cstrong\u003e4\u003c/strong\u003e, \u003cstrong\u003e6\u003c/strong\u003e and \u003cstrong\u003e10\u003c/strong\u003e). R-benzaldehyde: benzaldehyde (\u003cstrong\u003e2\u003c/strong\u003e), 4-hydroxybenzaldehyde (3), 4-hydroxy-3-methoxybenzaldehyde (\u003cstrong\u003e4\u003c/strong\u003e), 3-hydroxybenzaldehyde (\u003cstrong\u003e6\u003c/strong\u003e) and 4-nitrobenzaldehyde\u003cstrong\u003e \u003c/strong\u003e(\u003cstrong\u003e10\u003c/strong\u003e).\u003c/p\u003e","description":"","filename":"SC1.png","url":"https://assets-eu.researchsquare.com/files/rs-7148737/v1/637bb101ed8e90dcef11341a.png"},{"id":88629001,"identity":"ac74affb-3d5c-44df-aac9-65071490a591","added_by":"auto","created_at":"2025-08-08 13:26:03","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":13895,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 2\u003c/strong\u003e. Synthesis of heterocyclic pyrazole derivative (\u003cstrong\u003e17\u003c/strong\u003e–\u003cstrong\u003e18\u003c/strong\u003e). R-phenylhydrazine hydrochloride: 3-nitrophenylhydrazine hydrochloride (\u003cstrong\u003e17\u003c/strong\u003e) and 2,4-dichlorophenylhydrazine hydrochloride (\u003cstrong\u003e18\u003c/strong\u003e).\u003c/p\u003e","description":"","filename":"SC2.png","url":"https://assets-eu.researchsquare.com/files/rs-7148737/v1/de6d1f277a6aa3a313aadbe4.png"},{"id":88627988,"identity":"de68b93f-7002-4ada-8bc1-1dfa405050de","added_by":"auto","created_at":"2025-08-08 13:18:03","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":14014,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 3\u003c/strong\u003e. Synthesis of monocarbonyl curcumin derivatives \u003cstrong\u003e20\u003c/strong\u003e–\u003cstrong\u003e22\u003c/strong\u003e. Ketone: acetone (\u003cstrong\u003e20\u003c/strong\u003e), cyclopentanone (\u003cstrong\u003e21\u003c/strong\u003e) and cyclohexanone (\u003cstrong\u003e22\u003c/strong\u003e).\u003c/p\u003e","description":"","filename":"SC3.png","url":"https://assets-eu.researchsquare.com/files/rs-7148737/v1/0d1874966ea36214c95161a5.png"},{"id":88628021,"identity":"98ffd3fc-9b77-47d0-b341-caeced550b61","added_by":"auto","created_at":"2025-08-08 13:18:04","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":13066090,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"20250704SupportingInformationManuscript2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7148737/v1/2a75538bf947dc2c888edbee.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Promising bioactivity of curcumin derivatives against malaria: in silico, in vitro and ITC studies","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe global infection rate of malaria is estimated to have reached 247\u0026nbsp;million in 2021, covering 84 malaria-endemic countries, with a fatality rate of 14.8 per 100,000 population and an estimated 619,000 deaths [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. First identified in 1880, malaria is caused by \u003cem\u003ePlasmodium\u003c/em\u003e parasites, mainly \u003cem\u003eP. falciparum\u003c/em\u003e and \u003cem\u003eP. vivax\u003c/em\u003e, infecting humans. These parasites are transmitted by female \u003cem\u003eAnopheles\u003c/em\u003e mosquitoes and can enter the circulatory system within 30 minutes after a bite [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The parasites first target liver cells and erythrocytes, and if the affected individual remains untreated, the infection could develop into deadly haemorrhagic conditions including severe and cerebral malaria which involve parasite invasion into the brain and immune system.\u003c/p\u003e\u003cp\u003eAlthough much progress has been achieved towards eliminating malaria, the recent rise in malaria cases, particularly in Southeast Asia, is alarming [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. For example, approximately 17,125 cases have been reported in Malaysia over a period of only four years (2017\u0026ndash;2021). In addition to the growing number of malaria cases, the resistance of \u003cem\u003ePlasmodium\u003c/em\u003e parasites against current antimalarial drugs such as artemisinin and chloroquine is highly concerning. Therefore, the development of effective antimalarial and anti-inflammatory agents is crucial for curbing and eradicating malaria across the globe.\u003c/p\u003e\u003cp\u003eThe current search for novel antimalarials has mainly revolved around natural compounds, including curcumin. A polyphenol from the rhizomatous perennial plant, \u003cem\u003eCurcuma longa\u003c/em\u003e (turmeric), curcumin (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) is an attractive potential antimalarial owing to its proven effectiveness as a traditional therapeutic. It is acknowledged by the US Food and Drug Administration (FDA) as \u0026ldquo;generally recognised as safe\u0026rdquo; (GRAS) and is non-toxic even at high doses [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Curcumin has been documented to exhibit a wide array of pharmacological activities, including antimicrobial, antitumour, antioxidant, anti-inflammatory, and antiprotozoal activities by regulating various biological responses in the body [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Therefore, curcumin has emerged as a desirable lead compound with dual antimalarial and anti-inflammatory properties for the development of new antimalarial agents [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIts antimalarial activity was first reported by Reddy et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] based on \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein vivo\u003c/em\u003e assessments which showed potent growth inhibition of chloroquine-resistant \u003cem\u003eP. falciparum\u003c/em\u003e (IC\u003csub\u003e50\u003c/sub\u003e: ~5 \u0026micro;M) and reduction of blood parasitaemia level by 80\u0026ndash;90% upon treatment of \u003cem\u003eP. berghei\u003c/em\u003e-infected mice with curcumin over three weeks. Nevertheless, the low bioavailability of curcumin due to rapid metabolism, poor oral absorption, and low aqueous solubility is a major limiting factor for its clinical application. Prior studies have explored the use of adjuvants, nanoencapsulation, and structural modifications of curcumin to enhance its pharmacological properties [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Among these strategies, the synthesis of curcumin derivatives is seen as advantageous, potentially producing analogues with enhanced biological activity whilst maintaining the safety profile.\u003c/p\u003e\u003cp\u003eMost prior research on antimalarials have only focused on specific antiparasitic targets. However, the involvement of inflammatory-related proteins in parasitic growth has led to exploring compounds that exert both antiparasitic and anti-inflammatory effects as potential antimalarials. Inhibiting the immunomodulatory human glycogen synthase kinase 3 (GSK-3β), a serine-threonine kinase immunomodulatory protein involved in the host immune response in malarial infection, has been proven to mediate antimalarial effects in humans [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. GSK-3β is recognised as a novel target for antimalarial drugs due to its involvement in the dysregulated PI3K/Akt signalling triggered by the invasion of \u003cem\u003ePlasmodium\u003c/em\u003e parasites (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) and it has also been identified as a key evolutionarily conserved Ser/Thr kinase involved in regulating the host immune response, which is essential for managing advanced malarial infections including cerebral and severe malaria [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The function of GSK-3β is highly dependent on the hinge region containing conserved residues such as Asp133 and Val135 that make up an essential part of the ATP binding pocket [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This facilitates the catalytic activity of GSK-3β, leading to the production of pro-inflammatory cytokines through NF-κB activation. The binding of an inhibitor ligand to GSK-3β will cause conformational change, preventing access of its substrate to the active site [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], thus suppressing NF-κB and ultimately promoting anti-inflammatory responses [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Therefore, the role of curcumin and its derivatives as GSK-3β inhibitors in regulating inflammatory cytokine levels complements their antiplasmodial activity and potential as antimalarial agents.\u003c/p\u003e\u003cp\u003eHence, our research explored curcumin derivatives with potential dual antimalarial and anti-inflammatory activities. Specifically, Knoevenagel condensate, heterocyclic pyrazole and monocarbonyl curcumin derivative compounds were screened, \u003cem\u003ein silico\u003c/em\u003e, through molecular docking, molecular dynamics and DFT geometry optimisation assessments to explore and overview the binding conformations and electronic properties. An \u003cem\u003ein-silico\u003c/em\u003e approach in early-stage drug discovery is favoured for its time- and cost-effectiveness, and helps justify experimental preclinical studies that are often laborious and costly. The molecular docking and MD simulations demonstrated intermolecular interactions between curcumin derivatives and GSK-3β, while DFT calculations provided insights into the molecular and electronic properties of the compounds. Furthermore, selective compounds with excellent \u003cem\u003ein silico\u003c/em\u003e profiles were synthesised and investigated for their \u003cem\u003ein vitro\u003c/em\u003e antiplasmodial activities against \u003cem\u003eP. falciparum\u003c/em\u003e 3D7 and K1 strains, ITC haemin binding and yeast-based GSK-3β inhibition, further validating our computational findings. Throughout, our current study provides groundwork for a deeper understanding of the potential of curcumin derivatives as effective antimalarial and anti-inflammatory agents.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Results and discussion","content":"\u003cp\u003e\u003cstrong\u003eStructure-Activity Relationship (SAR) Analysis of Curcumin Derivatives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on the previously demonstrated antimalarial and anti-inflammatory activities of curcumin [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e], we initially explored 91 derivatives and analogues of curcumin based on prior SAR analysis[\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e] with the objective of enhancing its bioavailability, hence improving its effectiveness as a therapeutic agent, specifically as potential antimalarial and anti-inflammatory agents. Previous studies on Knoevenagel condensate, pyrazole, and monocarbonyl derivatives of curcumin have presented their potential in targeting several proteins involved in malarial infection, including the ATP6 [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e], NF-\u0026kappa;\u0026beta; [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e], \u003cem\u003ePf\u003c/em\u003eGCN5[\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e] and \u003cem\u003ePf\u003c/em\u003eDXR[\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e] proteins. Different from the previous, we are exploring their potential against specific proteins \u0026ndash; \u003cem\u003eplasmodial\u003c/em\u003e lactose dehydrogenase (pLDH), GSK-3\u0026beta; and haemin.\u003c/p\u003e\n\u003cp\u003eThe presence of the methoxy phenol group is essential for the antimalarial activity of curcumin as supported by the work of Dohutia et al. [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e] who showed that the \u003cem\u003ein vitro\u003c/em\u003e IC\u003csub\u003e50\u003c/sub\u003e of a dimethoxy-substituted phenyl was two-fold higher than that of curcumin, indicating the decreased potency of the derivative. We previously discussed that the design of curcumin derivatives is focused on the modification of methylene and dicarbonyl groups as they are the most reactive, hence unstable, sites of curcumin [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]. The design of the Knoevenagel condensate, monocarbonyl, and pyrazole derivatives focused mainly on improving the antimalarial activity of curcumin rather than its potential as an anti-inflammatory agent (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Hence, among the 91 initially selected derivatives, 21 of them were screened and relisted as derivatives with good SAR (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e) for further molecular docking studies with GSK-3\u0026beta; as the target.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eADMET Assessments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe pharmacokinetic properties of these compounds, characterised by their predicted ADMET profiles, are presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The \u003cem\u003ein-silico\u003c/em\u003e assessment included selective parameters such as the topological polar surface area (TPSA), pan-assay interference compounds (PAINS), water solubility, intestinal absorption, blood-brain-barrier (BBB) and central nervous system (CNS) permeability, total clearance, and toxicity.\u003c/p\u003e\n\u003cp\u003eThe TPSA values for all the assessed compounds remained below 140 \u0026Aring;, which suggested good cell permeability [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]. In addition, PAINS moieties were also assessed to identify compounds that tend to be false positives based on structures that appeared promiscuous [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e]. Two of the derivatives, \u003cstrong\u003e21\u003c/strong\u003e and \u003cstrong\u003e22\u003c/strong\u003e showed an alert for PAINS, which may suggest that these compounds are associated with potential false positive results. Furthermore, achieving adequate bioavailability is crucial for effective pharmacological action [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]. With the exception of derivative \u003cstrong\u003e20\u003c/strong\u003e, the predicted water solubility for all derivatives was, however, lower than curcumin. Hence, these derivatives might have a lower rate of dissolution and absorption into the bloodstream. Nevertheless, the derivatives were predicted to have favourable intestinal absorption with values above 70%. Thus, sufficient concentrations of these compounds are expected to reach the systemic circulation to exert therapeutic effect. With regard to the blood-brain barrier (BBB) and central nervous system (CNS) permeabilities of the derivatives, there appeared to be no major changes upon structural modifications to the parent curcumin. Despite variations in the values of log BB and log PS, all the tested compounds were classified as unable to readily cross the BBB and penetrate into the CNS. Hence, it is expected that the derivatives would not cause neurologically related side effects. Another factor limiting curcumin\u0026rsquo;s bioavailability is its rapid excretion, which reduces its effective duration of action. As shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, the total clearance of the Knoevenagel condensate derivatives was lower than that of curcumin, signifying potentially slower excretion and longer \u003cem\u003ein vivo\u003c/em\u003e availability. Finally, the toxicity predictions performed include Ames toxicity (mutagenicity), hepatotoxicity (liver-associated side effects), and cytotoxicity (cell disruptability). Non- or low toxicity is a critical requirement in ensuring the safety of a drug candidate to mitigate potential risks of adverse effects. Thus, it should be noted that derivatives \u003cstrong\u003e4\u003c/strong\u003e, and \u003cstrong\u003e18\u003c/strong\u003e exhibited potential toxicity which should be taken into consideration for further drug development.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePredicted ADMET profiles of curcumin and its derivatives.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003cth style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eCompound\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eCurcumin\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMolecular weight, g/mol\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e368.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e456.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e472.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e502.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e472.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e501.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e485.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e509.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e326.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e352.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e366.41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eH-bond acceptor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eH-bond donor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLog P, log(mol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-4.356\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-6.247\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-5.159\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-5.440\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-4.897\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-5.721\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-4.889\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-5.380\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-4.137\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-4.480\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-4.643\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTPSA, a\u0026Aring;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e93.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e93.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e113.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e122.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e113.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e138.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e122.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e76.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e75.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e75.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e75.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePAINS alert\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 37px;\"\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eABSORPTION\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003ea\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLog S, log(mol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-4.450\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-6.570\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-5.980\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-6.080\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-5.980\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-5.900\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-6.460\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-8.290\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-4.120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-5.090\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-5.370\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntestinal absorption, %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e75.494\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e84.347\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e76.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e70.186\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e76.137\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e81.145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e97.636\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e88.885\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e93.613\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e92.748\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e92.114\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDISTRIBUTION\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBBB permeability, log(mol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-0.528\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-0.606\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-1.024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-1.316\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-1.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-1.128\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-1.098\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-0.957\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-0.221\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-0.158\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-0.152\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCNS permeability, log(mol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-2.964\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-2.975\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-2.937\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-3.096\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-2.976\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-2.968\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-2.208\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-1.759\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-2.377\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-2.078\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e-1.984\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 37px;\"\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMETABOLISM\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eb\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 37px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCYP2D6/CYP3A4 substrate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/No\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCYP2D6/CYP3A4 inhibitor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCYP1A2 inhibitor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCYP2C19/CYP2C9 inhibitor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eYes/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eYes/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eYes/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eYes/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eYes/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eYes/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eYes/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eYes/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eYes/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eYes/Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eEXCRETION\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal Clearance, log(mL/min/kg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0.071\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0.042\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0.016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0.020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0.070\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0.209\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0.222\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0.091\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0.114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e0.122\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRenal OCT2 substrate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTOXICITY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAMES toxicity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHepatotoxicity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 35px;\"\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCytotoxicity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr style=\"height: 15px;\"\u003e\n \u003ctd style=\"height: 15px;\" colspan=\"12\"\u003e\u003csup\u003ea\u003c/sup\u003e Intestinal absorption: good if\u0026thinsp;\u0026gt;\u0026thinsp;30%\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr style=\"height: 15px;\"\u003e\n \u003ctd style=\"height: 15px;\" colspan=\"12\"\u003e\u003csup\u003eb\u003c/sup\u003e Being a non-substrate and inhibitor means slower metabolism\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eDocking of Curcumin Derivatives to GSK-3\u0026beta;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn searching for and designing compounds with potential inhibitory action against a target protein, molecular docking simulations are helpful in elucidating the interaction between the designed compounds and the amino acids of the target protein. Here, docking simulations were employed to establish an understanding of the anti-inflammatory effect of curcumin derivatives through their interaction with GSK-3\u0026beta;. Inhibiting GSK-3\u0026beta; has been proven to mediate antimalarial effects in humans [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]. GSK-3\u0026beta; is recognized as a novel target for antimalarial drugs due to its involvement in the dysregulated PI3K/Akt signalling triggered by the invasion of \u003cem\u003ePlasmodium\u003c/em\u003e parasites. The function of GSK-3\u0026beta; is highly dependent on the hinge region containing conserved residues such as Asp133 and Val135 that make up an essential part of the ATP binding pocket [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]. This facilitates the catalytic activity of GSK-3\u0026beta;, leading to the production of pro-inflammatory cytokines through NF-\u0026kappa;B activation. The binding of an inhibitor ligand to the GSK-3\u0026beta; will cause conformational change preventing access of its substrate to the active site [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e], thus suppressing NF-\u0026kappa;B and ultimately promoting anti-inflammatory responses [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eThe ligand originally bound to the 1Q5K crystal structure of GSK-3\u0026beta;, TMU1 (AR-A014418), is a potent and selective GSK-3\u0026beta; inhibitor that attenuates the inflammatory response [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. Hence, TMU1 was re-docked for docking-site validation [\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. The cross-docking validated the docking cavity and coordinates used for the molecular docking simulation based on the obtained binding energy at -6.451 kcal/mol and RMSD value of less than 1 \u0026Aring; (0.491 \u0026Aring;). Further, the binding cavity of GSK-3\u0026beta; was defined based on the residues involved in the TMU1\u0026ndash;GSK-3\u0026beta; binding: Ile62, Val70, Ala83, Tyr134, and Val135, as illustrated in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eCurcumin and its derivatives were hypothesised to bind to the same binding site as TMU1. Indeed, as shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and depicted in Supporting Information \u003cstrong\u003eS1\u003c/strong\u003e\u0026ndash;\u003cstrong\u003eS2\u003c/strong\u003e, curcumin exhibited favourable affinity towards GSK-3\u0026beta; and was docked to the same binding pocket as TMU1 based on the residues involved in the interaction. In contrast to TMU1, curcumin formed a more extensive network of hydrogen bonding involving five residues: Asp133, Tyr134, Arg141, Asn186, and Cys199, resulting in a stronger binding energy of -7.437 kcal/mol.\u003c/p\u003e\n\u003cp\u003eThe docking simulations were repeated with the aforementioned 21 curcumin derivatives, out of which ten derivatives showed better binding profiles compared to curcumin (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and S1\u0026ndash;S5). All derivatives potentially showed stronger inhibition with more negative binding energies compared to curcumin. For some of the compounds (derivatives \u003cstrong\u003e10\u003c/strong\u003e, \u003cstrong\u003e17\u003c/strong\u003e and \u003cstrong\u003e18\u003c/strong\u003e), the interactions not only involved hydrogen bonds and hydrophobic interactions, but also featured a pi-cation electrostatic interaction involving Arg141. These differences in binding characteristics likely contributed to the enhanced affinity of these compounds towards GSK-3\u0026beta;. Similarly, derivatives \u003cstrong\u003e3\u003c/strong\u003e and \u003cstrong\u003e6\u003c/strong\u003e also showed better interactions with GSK-3\u0026beta; than the parent curcumin based on their binding energies of -9.424 and \u0026minus;\u0026thinsp;9.079 kcal/mol, respectively. Notably, these derivatives probably benefited from stronger hydrophobic interactions involving six residues, compared to only five for curcumin. As for the heterocyclic pyrazole derivatives, compounds \u003cstrong\u003e17\u003c/strong\u003e and \u003cstrong\u003e18\u003c/strong\u003e also possessed relatively higher binding energies than curcumin (-8.728 and \u0026minus;\u0026thinsp;8.093 kcal/mol, respectively). These derivatives revealed the significant contribution of hydrophobic interactions, in addition to the hydrogen bonds, in stabilizing their complexation with GSK-3\u0026beta;. Likewise, the monocarbonyl derivatives \u003cstrong\u003e20\u003c/strong\u003e, \u003cstrong\u003e21\u003c/strong\u003e and \u003cstrong\u003e22\u003c/strong\u003e were identified to bind more favourably to GSK-3\u0026beta; than curcumin (binding energy: -8.161, -8.100 and \u0026minus;\u0026thinsp;8.970 kcal/mol, respectively). Our comparative molecular docking revealed that all three derivatisation strategies produced compounds with better binding profiles over curcumin towards GSK-3\u0026beta; and thus, potentially higher inhibitory activity against the protein. Therefore, the ten derivatives listed in were selected for DFT calculations, and MD simulations.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCurcumin derivatives categorised according to the type of structural modification and the affinity towards GSK-3\u0026beta;.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCompound\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBinding Energy, kcal/mol\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eType of Interaction\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAmino Acid Residues Involved in Binding\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eTMU1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" align=\"char\"\u003e\n \u003cp\u003e-6.451\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrogen bonds\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVal135\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrophobic interactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIle62, Val70, Ala83, Tyr134\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eCurcumin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" align=\"char\"\u003e\n \u003cp\u003e-7.437\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrogen bonds\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAsp133, Tyr134, Arg141, Asn186, Cys199\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrophobic interactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIle62, Val70, Ala83, Leu188\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"11\" align=\"left\"\u003e\n \u003cp\u003eKnoevenagel condensate derivatives\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" align=\"char\"\u003e\n \u003cp\u003e-8.772\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrogen bonds\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIle62, Val135, Arg141, Cys199\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrophobic interactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIle62, Val70, Ala83, Lys85, Val110, Leu132\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" align=\"char\"\u003e\n \u003cp\u003e-9.424\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrogen bonds\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIle62, Asp133, Tyr134, Pro136, Arg144. Cys199\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrophobic interactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIle62, Val70, Ala83, Lys85, Lys183, Leu188, Cys199\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" align=\"char\"\u003e\n \u003cp\u003e-9.070\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrogen bonds\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVal62, Arg141, Asp133\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrophobic interactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIle62, Gly63, Val70, Ala83, Leu132, Leu188, Cys199\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" align=\"char\"\u003e\n \u003cp\u003e-9.079\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrogen bonds\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIle62, Lys85, Tyr134, Val135, Arg141, Cys199\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrophobic interactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIle62, Val70, Ala83, Lys85, Val110, Leu132, Tyr134\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" align=\"char\"\u003e\n \u003cp\u003e-10.310\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrogen bonds\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAsp133, Tyr134, Val135, Arg141, Arg144\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrophobic interactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIle62, Val70, Ala83, Tyr143, Leu188\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eElectrostatic interactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eArg141\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" align=\"left\"\u003e\n \u003cp\u003ePyrazole derivatives\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" align=\"char\"\u003e\n \u003cp\u003e-8.728\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrogen bonds\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVal61, Tyr134, Arg144, Asp200\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrophobic interactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIle62, Ala83, Lys85, Val110, Leu132, Leu188, Cys199\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eElectrostatic interactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eArg141\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" align=\"char\"\u003e\n \u003cp\u003e-8.093\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrogen bonds\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCys199, Asp200\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrophobic interactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIle62, Gly63, Val70, Lys85, Val110, Leu132, Leu188\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eElectrostatic interactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eArg141\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" align=\"left\"\u003e\n \u003cp\u003eMonocarbonyl derivatives\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" align=\"char\"\u003e\n \u003cp\u003e-8.161\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrogen bonds\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTyr134, Val135, Arg141, Asn186\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrophobic interactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIle62, Val70, Lys85, Cys199\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" align=\"char\"\u003e\n \u003cp\u003e-8.100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrogen bonds\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIle62, Arg141 Val135, Asp200\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrophobic interactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIle62, Val70, Ala83, Val110, Leu132, Leu188, Cys199\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" align=\"char\"\u003e\n \u003cp\u003e-8.970\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrogen bonds\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIle62, Try134, Arg144, Asp200\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrophobic interactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIle62, Val70, Ala83, Val110, Leu132, Leu188, Cys199\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eMD Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMD simulations allow a deeper understanding of the stability, structural and conformational fluctuations, and kinetic behaviour of ligands and proteins upon their binding. The simulation creates a dynamic environment in which molecular interactions would happen as in the cellular milieu. The conformational changes of the ligand-protein complexes can be observed and analysed for a particular time scale to compare the stability of the different complexes. The environment of the system mimics the biological system for the behaviour and stability of the bounded ligand and protein, while allowing conformational changes of the ligand within the active site of the protein [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]. In this study, MD simulations of the binding of curcumin and the eleven derivatives to GSK-3\u0026beta; were carried out over 100 ns to generate information on root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (R\u003csub\u003eg\u003c/sub\u003e), and hydrogen bond interactions.\u003c/p\u003e\n\u003cp\u003eTo highlight and validate the docking results, which converged to derivative 10 as the top hit ligand with the highest binding affinity, the plots of the generated information are obtained as depicted in Fig.\u0026nbsp;6. RMSD information (Fig.\u0026nbsp;6, \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e(a), 1(b), 1(a)-ligand and 1(b)-ligand) presents the stability of a compound to stay within its docked confirmation and maintain its binding throughout the simulation time [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]. The RMSD of the complexes for curcumin started at 0.1 nm and stabilised within the range 0.4\u0026ndash;0.7 nm after 10 ns, while 10 started at 0.1 nm and stabilised within 0.3\u0026ndash;0.4 nm after 25 ns through the whole simulation period, in which the conformational change is less deviated than curcumin. In addition, based on the plots of ligand-RMSD as presented in Fig.\u0026nbsp;6, \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e(a)-ligand and 1(b)-ligand, the same graph trend is observed compared to the complexes. This shows that the detected movement of the complexes throughout the simulation is based on the movement of both ligand and protein, with RMSD of derivative 10 is showing less deviated range of RMSD (0.25\u0026ndash;0.35 nm) after it stabilised at 5 ns (1(b)-ligand) compared to curcumin with larger RMSD range (0.15\u0026ndash;0.45 nm). Hence, this validates the stability of the ligand, specifically derivative 10, to retain its docked configuration within the binding cavity of GSK-3\u0026beta;.\u003c/p\u003e\n\u003cp\u003eThe RMSF plots (Fig.\u0026nbsp;6, \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e(a) and 2(b)), which express the flexibility and fluctuations of particular residues during the simulations [\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e], show that curcumin, with RMSF values ranging between 0.05 and 0.40 nm, fluctuates more than \u003cstrong\u003e10\u003c/strong\u003e, with RMSF ranging between 0.05 and 0.35 nm. These fluctuations could be influenced by the conformational changes adopted by the residues, to facilitate and involve in binding with the ligand [\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]. Notably, there are fluctuations observed involving the Ile62, Val70, and Ala83 which signifies the hydrophobic interactions (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), and residues Asp133, Tyr134, and Val135 which reasoned the hydrogen bonding interactions. Additionally, the highest fluctuation at 0.35 nm RMSF is observed at residue Ser219, which is one of the catalytic residues that might also influence significant dynamics of the protein.\u003c/p\u003e\n\u003cp\u003eFurther, the hydrogen bonds involving Asp133, Tyr134, Val135, Arg141, Arg144 residues are also maintained (Fig.\u0026nbsp;6, \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e(b)) as the observed number of hydrogen bonds were retained between two to four throughout the MD simulation for the \u003cstrong\u003e10\u003c/strong\u003e-GSK-3\u0026beta; complex, which is more than that observed for the curcumin-GSK-3\u0026beta; complex. This suggests that derivative \u003cstrong\u003e10\u003c/strong\u003e is more stable while maintaining the hydrogen bonds and, hence holds stronger interactions with GSK-3\u0026beta;.\u003c/p\u003e\n\u003cp\u003eThe gyration plots (Fig.\u0026nbsp;6, \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e(a) and 4(b)) explain the spatial distribution or compactness of the complexes. The gyration for curcumin projected highly variable and fluctuating trends on the plots with values ranging from 2.112 to 2.185 gyration, compared to the \u003cstrong\u003e10\u003c/strong\u003e, which maintains a consistent and stable range of gyration between 2.115 and 2.180. Hence, this could be explained that the structure of the \u003cstrong\u003e10\u003c/strong\u003e-GSK-3\u0026beta; complex is more compact than curcumin.\u003c/p\u003e\n\u003cp\u003eBased on these, derivative \u003cstrong\u003e10\u003c/strong\u003e is justified as the top-hit compound with the highest probability for binding and dynamically stable in maintaining its ligand-protein structure, hence potentially inhibiting GSK-3\u0026beta;, better than curcumin.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGeometry Optimisation by Quantum DFT Calculations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDFT calculations revealed that the derivatives generally maintained a stable molecular structure and possessed improved molecular and electronic properties, suggesting increased chemical reactivity and stability. It has been suggested that the geometry and charge distribution of a molecule, comprising the molecular orbital (MO) descriptors including molecular structure energy E, HOMO, LUMO, and dipole moment (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e and S6\u0026ndash;S8), are important factors that affect the biological activities of a compound [\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e]. In addition, the DFT results also provide the reactivity analysis based on the global reactivity parameters including ionisation potential IP, electron affinity EA, chemical potential \u0026micro;, electronegativity ꭓ, chemical hardness \u0026eta; and electrophilicity index \u0026omega; [\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e], in which the corresponding information is presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. To specifically understand the reactivity of the derivative compounds as potential drug candidates with optimal pharmacokinetics and bioavailability [\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e], these parameters are investigated in comparison with the parent curcumin. Applying DFT calculations to identify the lowest energy geometry of curcumin derivatives rationalises their ability to form molecular interactions with GSK-3\u0026beta;.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMolecular structure energy E, dipole moment, molecular orbital energy gap and the global reactivity parameters of curcumin and selected derivatives obtained from DFT calculations.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCompound\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eE, a.u.\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEnergy gap, eV\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDipole moment, Debye\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIP, eV\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEA, eV\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026micro;, eV\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026eta;, eV\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eꭓ, eV\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026omega;, eV\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCurcumin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1263.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.5990\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.0792\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.9947\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.3957\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-4.1952\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.7995\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.1952\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.8901\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1532.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.6186\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.9073\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.9329\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.3143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-4.1236\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.8093\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.1236\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.6991\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1608.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.6145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.8004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.8926\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.2781\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-4.0854\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.8072\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.0854\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.6176\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1722.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.3984\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.4908\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.7898\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.3913\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-4.0906\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.6992\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.0906\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.9236\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1608.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.6107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.2226\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.9781\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.3674\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-4.1727\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.8053\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.1727\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.8223\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1683.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.1916\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.6906\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.1465\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.9549\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-4.5507\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.5958\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.5507\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.4885\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e17\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-2373.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.9813\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.9154\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.7535\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.7723\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-2.7629\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.9906\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.7629\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.8529\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1553.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.4977\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.7980\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.4850\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.9873\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-4.2361\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.2489\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.2361\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.1844\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e20\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1111.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.4175\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.6197\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.8262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.4088\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-4.1175\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.7087\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.1175\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.9609\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e21\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1187.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.3046\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.6716\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.4398\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.1353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-3.7876\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.6523\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.7876\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.3412\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e22\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1227.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.4556\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.9924\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.6861\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.2305\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-3.9583\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.7278\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.9583\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.5342\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eBased on our DFT analysis of geometry optimisation, the Knoevenagel condensate and heterocyclic pyrazole derivatives, particularly derivatives \u003cstrong\u003e4\u003c/strong\u003e, \u003cstrong\u003e10\u003c/strong\u003e, and \u003cstrong\u003e17\u003c/strong\u003e, possessed favourably more negative molecular structure energy compared to curcumin (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e), indicating that these specific derivatives are more structurally stable than curcumin and the monocarbonyl derivatives. Similarly for IP and EA, except for derivative \u003cstrong\u003e17\u003c/strong\u003e, the values are very comparable to curcumin which signifies the effectiveness and degradability, where these compounds are expected to be quite stable against oxidation processes.\u003c/p\u003e\n\u003cp\u003eThe frontier MO analysis based on the HOMO-LUMO energy gap allows for the evaluation of the chemical reactivity of a compound. As shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e and S6, derivatives \u003cstrong\u003e10\u003c/strong\u003e and \u003cstrong\u003e17\u003c/strong\u003e have smaller energy gaps with values lower than 3.2 eV and higher electrophilicity index \u0026omega;, suggesting that these compounds would possess higher binding potential and more readily interact with target proteins. Further, a slightly more negative value of chemical potential \u0026micro;, specifically for derivatives \u003cstrong\u003e10\u003c/strong\u003e, and comparable values for most of the other derivatives, signifies for the electron and charge distribution of these compounds. Compounds with more negative \u0026micro; are expected to potentially have better molecular interactions and binding, hence better affinity with the target protein.\u003c/p\u003e\n\u003cp\u003eAdditionally, the HOMOs and LUMOs also interpret the electrophilicity of the C and O atoms of the dicarbonyl groups. Based on the HOMOs, the orbitals do not participate in the electron donation, while the LUMOs show that the orbitals are able to accept electrons [\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e]. This verifies that the carbonyl group is non-nucleophilic but highly electrophilic, hence supporting the rationale of targeting the carbonyl group as the reactive site of curcumin to synthesise new derivatives [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eFurther, the dipole moment, as measured in Debye, explains the overall charge distribution in a molecule. This parameter correlates to polarity, deformability and electronegativity, where a higher dipole moment reflects a more polar and deformable structure, allowing for greater cellular interactions. Among the compounds, only derivatives \u003cstrong\u003e10\u003c/strong\u003e and \u003cstrong\u003e20\u003c/strong\u003e have higher dipole moment than curcumin, and hence, higher polarity and solubility, thus resulting in potentially enhanced bioavailability. However, the electronegativity data showed that all derivatives possessed similar values to curcumin except for derivative \u003cstrong\u003e17\u003c/strong\u003e, suggesting that these compounds have very comparable polarity with curcumin. In addition, the previous ADMET assessment predicted that only derivative \u003cstrong\u003e20\u003c/strong\u003e had better aqueous solubility than curcumin. Accordingly, this necessitates further experimental validation to determine the solubility profile of the derivatives.\u003c/p\u003e\n\u003cp\u003eFurther, DFT results also allow to simulate the shelf stability and thermodynamic stability of the compounds based on the chemical hardness parameter, \u0026eta;. Most compounds, specifically the Knoevenagel condensate and monocarbonyl derivatives have similar \u0026eta; values with curcumin, representing that these compounds are expected to have good stability and not easily degraded which benefits for development of drug with convenient oral dosage form and better shelf-life. Throughout, most derivative compounds generally showed favourable electronic and reactivity profiles, however, comparable to curcumin. These observations urge for the necessity to experimentally validate the results and further derivatise these compounds.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSynthesis of curcumin derivatives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe synthesis strategy of the compounds is relatively straightforward, whereby the Knoevenagel condensate derivatives \u003cstrong\u003e2\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e4\u003c/strong\u003e, \u003cstrong\u003e6\u003c/strong\u003e and \u003cstrong\u003e10\u003c/strong\u003e were synthesised through modified reaction conditions of the procedure adapted from the previously reported work [\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e]. The condition was modified to the optimised reaction conditions including the amount of solvent, conditions/temperature of the reaction, catalysts, and reaction time, affording a good percentage yield of all desired Knoevenagel condensate curcumin derivatives.\u003c/p\u003e\n\u003cp\u003eThe synthesis was performed in one step by reacting curcumin and an excess of respective R-benzaldehyde in dimethylformamide (DMF), in the presence of acetic acid and piperidine, at room temperature for 48 hours, to successfully obtained derivatives \u003cstrong\u003e2\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e4\u003c/strong\u003e, \u003cstrong\u003e6\u003c/strong\u003e and \u003cstrong\u003e10\u003c/strong\u003e in good yields between 63\u0026ndash;79%. The presence of both acid and base catalysts facilitates the reaction by protonating the aldehyde making it more electrophilic and deprotonating the highly acidic methylene hydrogen of curcumin making it more nucleophilic. Despites most published Knoevenagel condensation reaction used methanol as solvent and higher temperature (\u0026gt;\u0026thinsp;70℃, reflux), the use of DMF as solvent allows the reaction to proceed at higher concentration, lower temperature and safer conditions.\u003c/p\u003e\n\u003cp\u003eThe next series of derivatives were synthesised to obtain the heterocyclic pyrazole derivatives \u003cstrong\u003e17\u003c/strong\u003e and \u003cstrong\u003e18\u003c/strong\u003e, based on the published procedures [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e]. The synthesis was achieved in one-step procedure by reacting curcumin with an excess of respective R-phenylhydrazine hydrochloride in acid-catalysed ethanolic reaction, at 85℃ (reflux) overnight. The presence of acetic acid catalyst protonates the carbonyl group of curcumin making it more susceptible for nucleophilic attack by the hydrazine, forming a hydrazone intermediate, and proceeded to intramolecular cyclisation eliminating water and generating the aromatic pyrazole ring, to afford the desired compounds in a good yield of 65\u0026ndash;70%.\u003c/p\u003e\n\u003cp\u003eThe monocarbonyl curcumin derivatives \u003cstrong\u003e20\u0026ndash;22\u003c/strong\u003e were successfully synthesised based on the procedure described by Deck et al.[\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e] and Du et al.[\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e] by total synthesis through aldol reaction between two mole equivalent of aldehyde and one mole equivalent of ketone. Vanillin was reacted with an appropriate ketone in glacial acetic acid saturated with anhydrous concentrated hydrochloric acid, at 30℃ for 2 hours to obtain the desired compounds in a good yield of 61\u0026ndash;71%.\u003c/p\u003e\n\u003cp\u003eThe structures of all synthesised compounds were characterised and validated by comparing the published with the measured \u003csup\u003e1\u003c/sup\u003eH NMR, presented in the \u003cstrong\u003eS10\u003c/strong\u003e \u0026ndash; \u003cstrong\u003eS19\u003c/strong\u003e. This concluded the synthesis works of ten curcumin derivative compounds to be assessed for their antiplasmodial and antimalarial activities.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBiological activities\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIn vitro\u003c/strong\u003e \u003cstrong\u003epLDH antiplasmodial activity and cytotoxicity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results detailed the antiplasmodial activity of curcumin derivatives against \u003cem\u003eP. falciparum\u003c/em\u003e 3D7 (chloroquine-sensitive) and K1 (multi-drug-resistant) strains, evaluated based on the EC\u003csub\u003e50\u003c/sub\u003e (effective concentration for 50% inhibition), CC\u003csub\u003e50\u003c/sub\u003e (cytotoxicity to WRL-68 human cells), and Selectivity Index (SI) as presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e and S20\u0026ndash;S32. The EC\u003csub\u003e50\u003c/sub\u003e obtained against both strains suggest the potential inhibition of parasite metabolism, particularly through the interference of pLDH, a crucial enzyme involved in the glycolytic pathway of the parasite. Chloroquine, the reference compound, showed exceptional potency (EC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.008 \u0026micro;M for 3D7) and high selectivity (SI\u0026thinsp;=\u0026thinsp;12352 fo\u003cem\u003er\u003c/em\u003e 3D7). The parent compound, curcumin, was moderately active (EC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;8.32 \u0026micro;M for 3D7\u003cem\u003e)\u003c/em\u003e and non-toxic to human cells (CC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;99 \u0026micro;M) with moderate selectivity (SI\u0026thinsp;=\u0026thinsp;11.99).\u003c/p\u003e\n\u003cp\u003eAmong the derivatives, monocarbonyl derivatives \u003cstrong\u003e20\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e22\u003c/strong\u003e exceptionally exhibited better and more potent activities against 3D7 (EC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.15\u0026ndash;0.25 \u0026micro;M) and K1 (EC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.30\u0026ndash;2.53 \u0026micro;M), than curcumin. However, the cytotoxicity and SI analysis revealed that most derivative compounds exhibit potential cytotoxicity whereby pure compounds are classified as toxic to normal mammalian cells when CC\u003csub\u003e50\u003c/sub\u003e value is less than 10 \u0026micro;M or 4 \u0026micro;g/mL [\u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e]. Notably, derivative \u003cstrong\u003e3\u003c/strong\u003e with EC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.82 \u0026micro;M (3D7) and 16.70 \u0026micro;M (K1) is the only Knoevenagel condensate compound that showed no toxicity (CC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;99) and SI of 22.76 (3D7) and 7.43 (K1). This reinforces the safety profile of derivative \u003cstrong\u003e3\u003c/strong\u003e suggesting its promising potential. Meanwhile, pyrazole derivative \u003cstrong\u003e17\u003c/strong\u003e is also demonstrated significant antiplasmodial activity based on EC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.82 \u0026micro;M (3D7) and 16.70 \u0026micro;M (K1), CC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;99 \u0026micro;M, with the highest SI of 120.73 (3D7) and 5.93 (K1). This highlights that \u003cstrong\u003e17\u003c/strong\u003e exhibit the most notable inhibition, non-toxic and therapeutically more potent antimalarial agent than curcumin and other derivative compounds.\u003c/p\u003e\n\u003cp\u003eOverall, all derivatives also shown lower EC\u003csub\u003e50\u003c/sub\u003e values against 3D7 compared to K1, and higher resistance index value (RI\u0026thinsp;\u0026gt;\u0026thinsp;1), implying a potential resistance factor in CQ-resistant parasites. This warrants further assessment into the mechanism of action. Throughout, the \u003cem\u003ein vitro\u003c/em\u003e evaluation of all synthesised derivative compounds demonstrated promising antiplasmodial activity based on the observed effective concentration EC\u003csub\u003e50\u003c/sub\u003e values against both 3D7 and K1 strains which indicate that all synthesised compounds exhibit significantly better potency, surpassing the parent compound, curcumin. Specifically, monocarbonyl derivatives \u003cstrong\u003e20\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e22\u003c/strong\u003e which have smaller MW are observed to be much more potent than the other derivatives. Overall, these findings highlight the potential of curcumin derivatives for further development as selective antiplasmodial drugs. Further structural optimisation of those compounds lacking in antiplasmodial potency and cytotoxicity may be needed to improve their therapeutic potential and safety profile.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eAnti-plasmodial activities of curcumin derivatives against Plasmodium falciparum 3D7 (CQ-sensitive strain) \u003cem\u003eand\u003c/em\u003e Plasmodium falciparum K1 (multi-drug-resistant strain), and cytotoxic evaluation against WRL-68 human cells.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCompound\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e3D7 EC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, \u0026micro;M\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eK1 EC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, \u0026micro;M\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eWRL-68 CC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, \u0026micro;M\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e3D7\u003c/p\u003e\n \u003cp\u003eSelectivity Index (SI)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eK1\u003c/p\u003e\n \u003cp\u003eSelectivity Index (SI)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eResistance Index (RI)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eChloroquine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.008\u0026thinsp;\u0026plusmn;\u0026thinsp;0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.53\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e98.82\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12352.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e186.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e66.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCurcumin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.32\u0026thinsp;\u0026plusmn;\u0026thinsp;2.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30.66\u0026thinsp;\u0026plusmn;\u0026thinsp;5.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.69\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.79\u0026thinsp;\u0026plusmn;\u0026thinsp;0.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17.09\u0026thinsp;\u0026plusmn;\u0026thinsp;2.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.35\u0026thinsp;\u0026plusmn;\u0026thinsp;2.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13.33\u0026thinsp;\u0026plusmn;\u0026thinsp;7.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.79\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18.84\u0026thinsp;\u0026plusmn;\u0026thinsp;0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.31\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10.53\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11.01\u0026thinsp;\u0026plusmn;\u0026thinsp;2.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.19\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.77\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.10\u0026thinsp;\u0026plusmn;\u0026thinsp;1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.53\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e17\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.82\u0026thinsp;\u0026plusmn;\u0026thinsp;0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16.70\u0026thinsp;\u0026plusmn;\u0026thinsp;5.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e120.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20.37\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.29\u0026thinsp;\u0026plusmn;\u0026thinsp;0.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.87\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e20\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.53\u0026thinsp;\u0026plusmn;\u0026thinsp;1.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.93\u0026thinsp;\u0026plusmn;\u0026thinsp;0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16.87\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e21\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e22\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.30\u0026thinsp;\u0026plusmn;\u0026thinsp;0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.71\u0026thinsp;\u0026plusmn;\u0026thinsp;1.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003e\u003csup\u003ea\u003c/sup\u003e Selectivity Index (SI)\u0026thinsp;=\u0026thinsp;CC\u003csub\u003e50\u003c/sub\u003e MTT / EC\u003csub\u003e50\u003c/sub\u003e pLDH\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003e\u003csup\u003eb\u003c/sup\u003e Resistance Index (RI)\u0026thinsp;=\u0026thinsp;EC\u003csub\u003e50\u003c/sub\u003e K1 / EC\u003csub\u003e50\u003c/sub\u003e 3D7\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eITC haemin binding activity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe potential of binding to haem, an essential intermediate in the haem detoxification pathway of \u003cem\u003ePlasmodium\u003c/em\u003e, is one of the mechanism of actions of antimalarial drugs such as chloroquine and artemisinin. The haem released from haemoglobin hydrolysis by the malaria parasite is detoxified into inert hemozoin; interference with this process leads to toxic haem accumulation and death of the parasite [\u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e]. A strong binding of compounds to free haem can inhibit its detoxification and serves as a validated antimalarial mechanism of action, as exemplified by chloroquine. Therefore, the binding characteristics of the synthesised compounds with haem were accessed using ITC experiment, elucidating key parameters including association constants (\u003cem\u003eK\u003c/em\u003e\u003csub\u003ea\u003c/sub\u003e), binding ratio (\u003cem\u003en\u003c/em\u003e), and variations in enthalpy (\u0026Delta;\u003cem\u003eH\u003c/em\u003e), entropy (\u0026Delta;\u003cem\u003eS\u003c/em\u003e), and Gibbs free energy (\u0026Delta;\u003cem\u003eG\u003c/em\u003e), thereby facilitating a direct comparison with the reference compounds curcumin and chloroquine (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e and S33\u0026ndash;S34).\u003c/p\u003e\n\u003cp\u003eAmong the assessed compounds, derivative \u003cstrong\u003e3\u003c/strong\u003e showed the highest binding affinity to hemin with a binding constant of (7.44\u0026thinsp;\u0026plusmn;\u0026thinsp;3.48) \u0026times; 10⁶ M⁻\u0026sup1;, approximately 1.8 times higher than curcumin (4.08\u0026thinsp;\u0026plusmn;\u0026thinsp;2.64) \u0026times; 10⁶ M⁻\u0026sup1;. Meanwhile, binding affinities of derivatives \u003cstrong\u003e17\u003c/strong\u003e, \u003cstrong\u003e18\u003c/strong\u003e and \u003cstrong\u003e21\u003c/strong\u003e were comparable to curcumin, reflecting favourable interaction strengths. Although derivatives \u003cstrong\u003e2\u003c/strong\u003e, \u003cstrong\u003e4\u003c/strong\u003e, and \u003cstrong\u003e10\u003c/strong\u003e showed considerably lower \u003cem\u003eK\u003c/em\u003e\u003csub\u003ea\u003c/sub\u003e compared to other derivative compounds, but their binding affinities were close to chloroquine (10⁵ M⁻\u0026sup1;). Overall, derivatives \u003cstrong\u003e3\u003c/strong\u003e, \u003cstrong\u003e17\u003c/strong\u003e, \u003cstrong\u003e18\u003c/strong\u003e, and \u003cstrong\u003e21\u003c/strong\u003e have significant haem-binding affinities, which means they can possibly disrupt the formation of hemozoin. This would interfere with the detoxification process of the parasite and make them promising candidates for antimalarial drugs.\u003c/p\u003e\n\u003cp\u003eThe nature of the interaction forces involved was determined by further analysis the thermodynamic parameters of synthesised compound-haem interactions, which are shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e. All examined compounds, including references, exhibited negative entropy (\u0026Delta;\u003cem\u003eS\u003c/em\u003e) values and strongly exothermic interactions. A negative \u0026Delta;S value suggests that the system becomes more ordered upon binding, resulting in a complex with restricted mobility during the interaction. At the same time, the exothermic binding is indicative of the release of heat to the environment, which is likely facilitated by hydrogen bonding and van der Waals forces rather than hydrophobic effects. Furthermore, all derivatives have negative \u0026Delta;\u003cem\u003eG\u003c/em\u003e values when bound to haem suggest that binding is both spontaneous and thermodynamically favourable.\u003c/p\u003e\n\u003cp\u003eOverall, our findings support the haemin binding potential of curcumin derivative compounds, particularly derivatives \u003cstrong\u003e3\u003c/strong\u003e, \u003cstrong\u003e17\u003c/strong\u003e and \u003cstrong\u003e18\u003c/strong\u003e which are superiorly more potent than curcumin and chloroquine, as potential multi-targeting antimalarial agents. This suggests that these derivatives with more favourable aqueous solubility and stearic accessibility are selectively more effective disruptors of the haem detoxification pathways.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab5\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eThermodynamic properties from the binding of curcumin derivative compounds with haemin from ITC experiments\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCompound\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eK\u003c/em\u003e\u003csub\u003ea\u003c/sub\u003e \u0026times; 10\u003csup\u003e6\u003c/sup\u003e, M\u003csup\u003e-1\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026Delta;\u003cem\u003eH\u003c/em\u003e, kJ/mol\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026Delta;\u003cem\u003eS\u003c/em\u003e, J/mol\u0026sdot;K\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026Delta;\u003cem\u003eG\u003c/em\u003e, kJ/mol\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eChloroquine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;37.71\u0026thinsp;\u0026plusmn;\u0026thinsp;1.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;23.34\u0026thinsp;\u0026plusmn;\u0026thinsp;0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;30.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCurcumin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.08\u0026thinsp;\u0026plusmn;\u0026thinsp;2.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;99.76\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;196.05\u0026thinsp;\u0026plusmn;\u0026thinsp;5.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;38.95\u0026thinsp;\u0026plusmn;\u0026thinsp;1.80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;99.45\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;219.00\u0026thinsp;\u0026plusmn;\u0026thinsp;7.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;31.52\u0026thinsp;\u0026plusmn;\u0026thinsp;1.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.44\u0026thinsp;\u0026plusmn;\u0026thinsp;3.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;98.57\u0026thinsp;\u0026plusmn;\u0026thinsp;1.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;186.75\u0026thinsp;\u0026plusmn;\u0026thinsp;8.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;40.65\u0026thinsp;\u0026plusmn;\u0026thinsp;1.26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;94.80\u0026thinsp;\u0026plusmn;\u0026thinsp;1.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;200.85\u0026thinsp;\u0026plusmn;\u0026thinsp;1.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;32.52\u0026thinsp;\u0026plusmn;\u0026thinsp;2.16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.79\u0026thinsp;\u0026plusmn;\u0026thinsp;1.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;98.08\u0026thinsp;\u0026plusmn;\u0026thinsp;1.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;212.47\u0026thinsp;\u0026plusmn;\u0026thinsp;7.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;32.19\u0026thinsp;\u0026plusmn;\u0026thinsp;1.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;98.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;210.50\u0026thinsp;\u0026plusmn;\u0026thinsp;7.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;33.45\u0026thinsp;\u0026plusmn;\u0026thinsp;1.85\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e17\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.44\u0026thinsp;\u0026plusmn;\u0026thinsp;4.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;99.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;195.30\u0026thinsp;\u0026plusmn;\u0026thinsp;9.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;39.34\u0026thinsp;\u0026plusmn;\u0026thinsp;2.72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.16\u0026thinsp;\u0026plusmn;\u0026thinsp;1.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;99.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;196.40\u0026thinsp;\u0026plusmn;\u0026thinsp;3.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;38.19\u0026thinsp;\u0026plusmn;\u0026thinsp;1.90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e20\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.77\u0026thinsp;\u0026plusmn;\u0026thinsp;0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;99.77\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;202.45\u0026thinsp;\u0026plusmn;\u0026thinsp;4.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;36.98\u0026thinsp;\u0026plusmn;\u0026thinsp;1.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e21\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.27\u0026thinsp;\u0026plusmn;\u0026thinsp;2.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;98.54\u0026thinsp;\u0026plusmn;\u0026thinsp;2.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;194.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;38.31\u0026thinsp;\u0026plusmn;\u0026thinsp;2.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e22\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.22\u0026thinsp;\u0026plusmn;\u0026thinsp;2.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;99.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;199.10\u0026thinsp;\u0026plusmn;\u0026thinsp;1.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026minus;37.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eYeast-based\u003c/strong\u003e \u003cstrong\u003ein vitro\u003c/strong\u003e \u003cstrong\u003eGSK-3\u0026beta; inhibition\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study paved further to evaluate the multi-targeting potential of these derivatives based on the anti-inflammatory effect through their interaction with GSK-3\u0026beta;. The inhibition of GSK-3\u0026beta; by curcumin was only recently shown experimentally by Ali et. al. [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e], but was earlier suggested through preliminary computational simulations [\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e]. While all derivative compounds exhibited more effective inhibition against the pLDH assays (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e), the GSK-3\u0026beta; inhibition was only observed for monocarbonyl derivative \u003cstrong\u003e20\u003c/strong\u003e, selectively at 0.02 M, despite \u003cem\u003ein silico\u003c/em\u003e findings demonstrated potential inhibition across all derivative compounds (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e and S35). This discrepancy underscores the complexity of target specificity in the complex biological environment, where factors such as molecular weight, solubility and stability, which are beyond the molecular docking and MD scores, should be taken into consideration. Smaller molecular size/weight and better lipophilicity (logP) of derivative \u003cstrong\u003e20\u003c/strong\u003e might be influencing the efficacy for better passive diffusion to penetrate the yeast cell membrane [\u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e]. Curcumin and all other derivative compounds with higher molecular weight and lower log P may struggle to penetrate to effectively interact with GSK-3\u0026beta; within the yeast system, hence no inhibitory activities were observed.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab6\" border=\"1\" class=\"fr-table-selection-hover\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eInhibition of GSK-3\u0026beta; at 28 ℃ and 37 ℃ inhibition zones from the yeast-based assay.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eCompound\u003c/p\u003e\n \u003c/th\u003e\n \u003cth rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eConcentration, M\u003c/p\u003e\n \u003c/th\u003e\n \u003cth colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eZone of inhibition, mm\u003c/p\u003e\n \u003c/th\u003e\n \u003cth rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eRemarks\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e28 ℃\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e37 ℃\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCurcumin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0002\u0026ndash;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo activity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0002\u0026ndash;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo activity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0002\u0026ndash;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo activity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0002\u0026ndash;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo activity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0002\u0026ndash;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo activity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0002\u0026ndash;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo activity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0002\u0026ndash;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo activity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e19\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0002\u0026ndash;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo activity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e20\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003cimg 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\" 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\" style=\"width: 113px;\"\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" align=\"left\"\u003e\n \u003cp\u003eSelective inhibition of GSK-3\u0026beta; at 0.02 M\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo activity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo activity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e21\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0002\u0026ndash;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo activity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e22\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0002\u0026ndash;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo activity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTDZD-8\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003ea\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.67\u0026thinsp;\u0026plusmn;\u0026thinsp;1.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.00\u0026thinsp;\u0026plusmn;\u0026thinsp;1.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon-selective inhibition of GSK-3\u0026beta;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDMSO\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eb\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo activity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003e positive control\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003e\u003csup\u003eb\u003c/sup\u003e blank sample\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Experimental ","content":"\u003cp\u003e\u003cstrong\u003eIn silico Assessments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eADMET studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe predicted ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of curcumin, which we have previously obtained from the SwissADME (http://www.swissadme.ch/index.php), pkCSM (http://biosig.unimelb.edu.au/pkcsm/), and proTox-II (https://tox.charite.de/protox_II) web servers, were compared to those of the derivatives [19, 50, 51, 52]. The ADMET information predicts the overall pharmacological behaviour of potential drug candidates in the body including the blood, tissues, and organs, thus providing an alternative pathway for screening a long list of compounds.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMolecular docking \u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe 3D X-ray crystallographic structure of GSK-3\u0026beta; was retrieved from the Protein Data Bank (PDB ID: 1Q5K, resolution 1.94 \u0026Aring;, https://www.rcsb.org) [29]. It was prepared for molecular docking by removing water molecules and adding polar hydrogen as well as Kollman charges, before saved as a .pdbqt file [53]. The docking analysis was performed to screen curcumin derivatives that bind best to GSK-3\u0026beta; while determining the optimal energy geometry of the docked compounds. Based on the previously validated active site of the protein, the docking simulation was performed with a defined grid box dimension of 40\u0026times;30\u0026times;30 \u0026Aring; centred at x=23.9226, y=21.6961, and z=9.76081 [53, 54]. The active site of the protein is specified as the cavity that binds specific ligands (curcumin derivatives) resulting in potential inhibition of its activity. The other docking parameters were set to default [54]. Analysis of the docking results revealed the binding affinity, the type of molecular interactions and the amino acids involved in the binding. BIOVIA Discovery Studio Visualizer [55] and Ligplot+ [56] were utilised to map the interactions and visualise the position and distance of the amino acid residues interacting with the ligands.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMD simulations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMD simulations were performed to analyse the dynamics of ligand-protein complexation and to validate the docking results. In a MD simulation, the environment of the system mimics the biological system for the behaviour and stability of the bounded ligand and protein, while allowing conformational changes of the ligand within the active site of the protein [30]. The simulations were carried out over 100 ns using the GROMACS 2020.6 software package [57] running on a Ubuntu -2020.6-2 operating system to generate information on root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (R\u003csub\u003eg\u003c/sub\u003e), and hydrogen bond interactions. The temperature and pressure for the experimental conditions were set at 300 K and 1 atm, respectively, to imitate the physiological\u0026nbsp;[58].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDFT calculations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDFT calculations were performed using GaussView 6.0.16 [59] at the B3LYP/6-311G++(d,p) level, which was adopted from the previously reported method by Hazarika and Kalita [38]. The DFT analysis provide critical information on energy minimisation for bonding, dipole moment, molecular orbital energy profile and the global reactivity parameters from geometry optimisation calculations. Theoretically, it enables geometry optimisation of a chemical structure in order to find its stable geometry using a quantum chemical technique [60].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCurcumin was purchased from Sigma Aldrich Co. (USA) (\u0026gt;80% purity) and Tokyo Chemical Industry (TCI) (Japan) (synthetic, \u0026gt;97% purity). Other chemicals were purchased: R-benzaldehyde and R-phenylhydrazine hydrochloride from Sigma Aldrich Co. (USA), solvents from Merck (Germany) and other commercial sources. All purchased reagents and chemicals were used without further purification. Solvents were dried according to the previously established procedure from the literature [61]. TLC plates (Kieselgel 60 F254) from Merck (Germany) were used and visualised with ultraviolet (UV) light at 254 nm or by heating after treatment with a solution of anisaldehyde in ethanol. Flash column chromatography for purification was performed with Merck silica gel 60 (0.04\u0026ndash;0.063 mm), and reverse phase column chromatography was performed using Waters Sep-Pak\u0026reg; Vac 35cc C\u003csub\u003e18\u003c/sub\u003e 10g (Waters Corporation, Milford, MA, USA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstrumentations and compound characterisations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the synthesised compounds were characterised and identified by Nuclear Magnetic Resonance (NMR) \u003csup\u003e1\u003c/sup\u003eH and\u003csup\u003e13\u003c/sup\u003eC NMR spectroscopy. Samples were dissolved in deuterated chloroform, CDCl\u003csub\u003e3\u003c/sub\u003e, measured using Bruker Fourier Transform FT-NMR (Karlsruhe, Germany) and JEOL FT-NMR (Japan), both operating at 400 MHz, and analysed using ACD/Labs NMR Processor software. NMR data were analysed, and all spectra were matched with the previously reported information. Characterisation details of all synthesised compounds including \u003csup\u003e1\u003c/sup\u003eH and\u003csup\u003e13\u003c/sup\u003eC NMR spectroscopy, can be found in the Supporting Information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGeneral procedure for the synthesis of curcumin derivative compounds\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGeneral procedure A: Synthesis of Knoevenagel condensate derivatives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe synthesis strategy of the compounds is relatively straightforward, with modifications on the reaction conditions. The five Knoevenagel condensate derivatives (\u003cstrong\u003e2\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e4\u003c/strong\u003e, \u003cstrong\u003e6\u003c/strong\u003e and \u003cstrong\u003e10\u003c/strong\u003e) were synthesised through the modified reaction conditions from the previously reported general procedure by Zuo et al. and Pedersen et al. [39, 40]. The procedure was modified to the optimised reaction conditions: i) amount of solvent, ii) conditions/temperature of the reaction, iii) catalysts, and iv) reaction time. The synthesis was conducted according to \u003cstrong\u003eScheme 1\u003c/strong\u003e by reacting curcumin (0.543 mmol, 1.0 eq.) with appropriate R-benzaldehyde (0.706 mmol, 1.3 eq.) in 1.00 mL dry dimethylformamide (DMF), catalysed by piperidine (0.543 mmol, 1.0 eq.) and acetic acid (0.706 mmol, 1.3 eq.) at room temperature for 48 hours. On completion (monitored through TLC), the reaction mixture was diluted with ethyl acetate and washed with water followed by brine. Purified yield was obtained by column chromatography using a gradient eluent system (Hexane:EtOAc = 100:0 \u0026rarr; 60:40, v/v) and dried \u003cem\u003ein vacuo\u003c/em\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHeterocyclic pyrazole curcumin derivatives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe procedure for the synthesis of heterocyclic pyrazole derivatives \u003cstrong\u003e17\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e18\u003c/strong\u003e was referred from the published methodology by Sagnou et al. [41] and Mishra et al. [62]. The synthesis was conducted according to \u003cstrong\u003eScheme 2\u003c/strong\u003e, by reacting curcumin (0.271 mmol, 1.00 eq.) with R-phenylhydrazine hydrochloride (0.407 mmol, 1.50 eq.) in 4.00 mL ethanol, catalysed by acetic acid (5.24 mmol), reflux at 85 \u0026deg;C, for 15 hours. On completion (monitored through TLC), the crude was dried \u003cem\u003ein vacuo\u003c/em\u003e followed by a treatment with ethyl acetate. Solid precipitate was filtered and washed with cold water. Final yield was left drying in a desiccator for 24 hours to obtain the purified yield.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMonocarbonyl curcumin derivatives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe monocarbonyl derivatives \u003cstrong\u003e20\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e22\u003c/strong\u003e were synthesised according to \u003cstrong\u003eScheme 3\u003c/strong\u003e based on the procedure described by Deck et al. [42] and Du et al. [43]. A mixture of vanillin (0.657 mmol, 2.00 eq.) and an appropriate ketone (0.328 mmol, 1.00 eq.) was reacted in 1.00 mL acetic acid, catalysed by concentrated hydrochloric acid cat. (0.328 mmol, 1.00 eq.) at 30 \u0026deg;C for 2 hours. After completion (monitored through TLC), the reaction mixture was left standing for 24 hours before the crude was filtered and washed with cold water. The product was redissolved with ethyl acetate and extracted from water. The organic layer was collected and purified yield was dried \u003cem\u003ein vacuo\u003c/em\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBiological Assessments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eIn vitro\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eP. falciparum\u003c/em\u003e 3D7 and K1 assays\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe antiplasmodial activities of curcumin and the synthesised curcumin derivative compounds were assessed using the \u003cem\u003eP. falciparum\u003c/em\u003e chloroquine-sensitive (CQ-S) 3D7 and chloroquine-resistant (CQ-R) K1 strains, obtained from the Malaria Research and Reference Reagent Resource Center (MR4), Manassas, Virginia. The parasites were revived from cryopreservation and cultured at 1% haematocrit using purified O+ human erythrocytes in RPMI 1640 medium supplemented with 0.5% Albumax I (GIBCO, Life Technologies, USA), 25 mM HEPES, 100 \u0026mu;M hypoxanthine, 12.5 \u0026mu;g/mL gentamicin, and 1.77 mM sodium bicarbonate. Cultures were maintained at 37\u0026deg;C in a 5% CO₂ atmosphere. Parasitaemia was assessed by microscopic examination of field-stained thin blood smears. Parasite sensitivity to curcumin was evaluated using the parasite lactate dehydrogenase (pLDH) assay, as described by Makler et al. [63], in flat-bottom 96-well microtiter plates. Prior to the assay, parasite cultures were synchronised using 5% D-sorbitol and plated at 2% haematocrit and 2% parasitaemia, predominantly in the ring stage. Curcumin derivatives were added at predetermined concentrations. Following a one-hour incubation at room temperature in the dark, colour development was measured at 655 nm using a Fluostar Optima microplate reader. Data were analysed via non-linear regression using GraphPad Prism 5 (GraphPad Software, Inc., San Diego, CA) to determine the 50% inhibitory concentration (EC₅₀).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCytotoxicity \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe human normal liver cell line WRL-68 (ATCC: CL-48) was obtained from the American Type Culture Collection (ATCC), USA. Cytotoxicity of curcumin derivatives was assessed using the MTT assay, as described by Mosmann [64]. Briefly, 100 \u0026micro;L of WRL-68 cells (2 \u0026times; 10⁴ cells/mL) in complete medium supplemented with 10% fetal bovine serum (FBS) was seeded into 96-well flat-bottom microtiter plates. Cells were incubated with or without curcumin derivatives for 48 hours at 37\u0026deg;C in a 5% CO₂ atmosphere. After incubation, confluent cells were treated with curcumin derivatives at concentrations ranging from 10 to 0.01 \u0026micro;g/mL. Wells containing untreated cells served as positive controls for cell viability.\u003c/p\u003e\n\u003cp\u003eFollowing treatment, 5 mg/mL MTT solution in phosphate-buffered saline (MTT-PBS) was added to each well, and the plates were incubated for an additional 3 hours under the same conditions. The medium was then removed and replaced with 100 \u0026micro;L of dimethyl sulfoxide (DMSO) per well to solubilise the formazan crystals, followed by a 10-minute incubation at 37\u0026deg;C in a CO₂ incubator. Absorbance was measured at 540 nm using a Fluorostar OPTIMA microplate reader. The 50% cytotoxic concentration (CC₅₀) of the curcumin derivatives was determined from three independent experiments. Percentage growth inhibition and CC₅₀ values were calculated by non-linear regression analysis using GraphPad Prism. Cytotoxicity was reported as the concentration required to inhibit 50% of cell growth.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSelectivity Index (SI) and Resistance Index (RI)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe selectivity index (SI) was calculated as the ratio of the 50% cytotoxic concentration (CC₅₀) to the 50% inhibitory concentration (IC₅₀) of antimalarial activity (SI = CC₅₀/IC₅₀), based on data from MTT and pLDH assays. Compounds with SI values greater than 100 (SI \u0026gt; 100) were considered strong and selective antiplasmodial agents, as described by Sarr et al. [65]. Additionally, the resistance index (RI) was determined by calculating the ratio of IC₅₀ values obtained from the resistant strain (K1) to those from the sensitive strain (3D7) (RI = IC₅₀ K1 / IC₅₀ 3D7). A higher RI indicates reduced sensitivity of the resistant strain to the test compound.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eITC assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn ITC microcalorimeter (TA Instruments, New Castle, DE, USA) was utilised to assess the interaction of the synthesised curcumin derivative compounds with haemin at 37 \u0026deg;C as described by Feroz et al. [66]. Curcumin and chloroquine were used as reference compounds to enable comparative analysis of binding affinities and thermodynamic parameters. The synthesised compounds were dissolved in acetone at concentrations ranging from 1 to 1.5 mg/mL to prepare stock solutions, while haemin stock solution (0.5 mg/mL) was prepared by dissolving hemin in 0.5 M NaOH. The stock solutions were subsequently diluted with 10 mM sodium phosphate buffer (pH 7.4), resulting in the final samples containing 0.5 M NaOH and about 3% acetone. All samples were vacuum-degassed for 10 minutes before the titration experiments. For the titration, 20 \u0026micro;M hemin was placed in the sample cell, with the reference cell containing deionised water. The hybrid compound (100 \u0026micro;M) was loaded into a 250 \u0026micro;L syringe and introduced into the microcalorimeter for injection. The titration required 16 consecutive 15 \u0026micro;L injections into the sample cell, spaced each 400 s, with stirring kept at 200 rpm to ensure adequate mixing. In the data analysis, the heat effects from solution mixing and dilution were manually corrected. An independent binding model was employed to process and analyse the data using NanoAnalyze software (v3.3.0). The results are presented as the average \u0026plusmn; standard deviation of the selected replicates showing the best\u0026nbsp;consistency.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eIn vitro\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e yeast-based GSK-3\u0026beta; assay\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe GSK3\u0026beta;-inhibitory activity of test compounds was assessed using an \u003cem\u003ein vivo\u003c/em\u003e yeast-based assay as described by Andoh et al. [67]. In this system, mammalian GSK3\u0026beta; was inserted and expressed in a temperature-sensitive \u003cem\u003egsk-3\u003c/em\u003e null mutant yeast strain (pKT10-GSK3\u0026beta;) with the genotype MATa his3 leu2 ura3 trp1 ade2 mck1::TRP1 mds1::HIS3 mrk1 yol128c::LEU2, thereby restoring the original phenotype. For screening, a loopful of a three-day-old yeast culture was inoculated into 5.0 mL of synthetic complete medium lacking uracil (SC-Ura) and incubated in a water bath at 37\u0026deg;C with shaking at 150 rpm for 48 hours.\u003c/p\u003e\n\u003cp\u003eSubsequently, 400 \u0026mu;L of the yeast culture was mixed with 100 mL of SC-Ura agar, poured into six plates, and allowed to solidify at room temperature. The disc diffusion technique was employed by applying 20 \u0026mu;L of 100 mg/mL test samples onto sterile paper discs, which were then placed on the SC-Ura agar plates. Plates were incubated at both 28\u0026deg;C (permissive temperature) and 37\u0026deg;C (restrictive temperature) for 120 hours, and yeast growth was monitored over five days. All assays were conducted in triplicate. Inhibition of yeast growth at 37\u0026deg;C indicated GSK3\u0026beta;-inhibitory activity of the test compounds [53, 68].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe incorporation of multi-faceted approach integrating \u003cem\u003ein silico\u003c/em\u003e, synthesis and biological assessment highlight the intricacy of multi-targeting strategies in the discovery and development of antimalarial drug based on the groundwork exploration of curcumin derivatives. While all the assessed curcumin derivative compounds demonstrated favourable physiochemical properties based on the ADMET profiles and \u003cem\u003ein silico\u003c/em\u003e inhibitory potential, experimental assessments revealed promising antimalarial activities with selective compounds demonstrated multi-targeting potential as prospective antimalarial agents. This suggested that parameters beyond docking scores and \u003cem\u003ein silico\u003c/em\u003e parameters would also strongly influence the inhibitory activities within the biological systems, reinforcing the necessity of experimental validations. The pLDH assay confirmed that all derivatives demonstrated more potent antiplasmodial activity than curcumin, as suggested from the \u003cem\u003ein silico\u003c/em\u003e assessments, with derivative \u003cb\u003e20\u003c/b\u003e being the most potent. Interestingly, only derivative \u003cb\u003e3\u003c/b\u003e and \u003cb\u003e17\u003c/b\u003e exhibited higher potential haemin binding affinity than curcumin and chloroquine from the ITC experiment, and derivative \u003cb\u003e20\u003c/b\u003e selectively showed inhibition of GSK-3β based on the yeast-based assay. These discrepancies suggest that compounds with specific pharmacological profiles are selectively more promising as multi-targeting antimalarial agents over the other derivative compounds \u0026ndash; Knoevenagel condensate \u003cb\u003e3\u003c/b\u003e with the least stearic and better solubility (log P and log S), heterocyclic pyrazole derivative \u003cb\u003e17\u003c/b\u003e with more favourable electronic and reactivity profiles (DFT calculations) and monocarbonyl derivative \u003cb\u003e20\u003c/b\u003e with smaller MW, better solubility (log P and log S) and metabolism. The potential haemin binding and GSK-3β inhibition of these selective derivatives are observed to be influencing the antimalarial potential based on the selectively smaller and potent EC\u003csub\u003e50\u003c/sub\u003e for derivative \u003cb\u003e17\u003c/b\u003e and \u003cb\u003e20\u003c/b\u003e. The diverging computational explorations and experimental assessments, however, also presents the limitations of independent structure-based modelling, emphasising the importance of biological validations. Further investigations employing scaffold derivatisations, \u003cem\u003ein vivo\u003c/em\u003e assessments, experimental pharmacokinetic validations and target-specific mechanism studies would allow in-depth understanding of the antimalarial potential of curcumin derivative compounds, which is cost-effectively sourced, to streamline the complexity of effective antimalarial drug discovery and development.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cp\u003eClinical trial number: not applicable.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003eNot applicable\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis study was supported by the South Asia Research Hub, Foreign, Commonwealth \u0026amp; Development Office (FCDO), Government of the United Kingdom [ST-2024-001].\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eSNH.J. contributed to conceptualisation, methodology planning, data curation, formal analysis, writing, reviewing and editing the original draft. KA.B., AH.A., NFN.M. and F.S. were involved in conceptualisation, methodology planning, writing, reviewing and editing the original draft. F.M., SD.L. and SR.F. were involved in conceptualisation, methodology planning, reviewing and editing the draft, providing resources and access to software, supervising the progress, and data validation. N.O. provided supervision, reviewing and editing the manuscript. Y.Z., MI.M., R.M. and U.S. provided access to resources and supervise the progress. J.L. contributed to funding acquisition, project administration, access to resources, and overall supervision. All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThis study was supported by the South Asia Research Hub, Foreign, Commonwealth \u0026amp; Development Office (FCDO), Government of the United Kingdom [ST-2024-001]. The views expressed in this report, however, do not necessarily reflect the official policies of the Government of the United Kingdom.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData is provided within the manuscript and supplementary information files.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWorld Malaria Report. World Health Organization, Geneva, 2025. (2024). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2024\u003c/span\u003e\u003cspan address=\"https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2024\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 21 Mar 2025.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e2023 17th Annual Report to Congress. Centers for Disease Control and Prevention (CDC). 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Prod.\u003c/em\u003e \u003cb\u003e72\u003c/b\u003e, 1520\u0026ndash;1523. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1021/np900163f\u003c/span\u003e\u003cspan address=\"10.1021/np900163f\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2009).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Schemes","content":"\u003cp\u003eSchemes 1 to 3 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Curcumin derivatives, Antimalaria, GSK-3β, Antiplasmodial, Isothermal titration calorimetry, DFT calculations","lastPublishedDoi":"10.21203/rs.3.rs-7148737/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7148737/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCurcumin, a natural polyphenolic compound, has been widely studied for its various therapeutic properties. However, its clinical application is constrained by suboptimal pharmacokinetic properties. This study reports on the \u003cem\u003ein silico\u003c/em\u003e assessments, comprising molecular docking, molecular dynamics (MD) and density functional theory (DFT) calculations, which revealed the binding interactions and electronic properties of selective curcumin derivatives. Further, we also report the \u003cem\u003ein vitro\u003c/em\u003e antiplasmodial effects, haemin binding potential and GSK-3β inhibitory activity of the synthesised curcumin derivatives, to validate the antimalarial efficacy. Ten synthesised compounds from three different types of curcumin derivatives; Knoevenagel condensate, heterocyclic pyrazole and monocarbonyl derivatives, exhibited more effective antiplasmodial activity against both \u003cem\u003eP. falciparum\u003c/em\u003e chloroquine-sensitive (CQ-S) 3D7 and chloroquine-resistant (CQ-R) K1 assays, compared to curcumin (EC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;8.32\u0026thinsp;\u0026plusmn;\u0026thinsp;2.62 \u0026micro;M (3D7) and 30.66\u0026thinsp;\u0026plusmn;\u0026thinsp;5.44 \u0026micro;M (K1)). We also report, for the first time, the isothermal titration calorimetry (ITC) and \u003cem\u003ein vitro\u003c/em\u003e yeast-based assessments to elucidate their multi-targeting potential based on haemin binding activity and immunomodulatory GSK-3β inhibition. Interestingly, some compounds showed multi-targeting potential against haemin and GSK-3β, which also partially influence the effective antimalarial activity. The outcomes from the different analyses incorporating the \u003cem\u003ein vitro\u003c/em\u003e assays, ITC assessments and \u003cem\u003ein silico\u003c/em\u003e studies, highlighted the promising potential of curcumin derivatives for antimalarial drug research, over the parent curcumin. This study lays the groundwork for further experimental validation and development of curcumin-based compounds as effective and safe antimalarial and anti-inflammatory agents.\u003c/p\u003e","manuscriptTitle":"Promising bioactivity of curcumin derivatives against malaria: in silico, in vitro and ITC studies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-08 13:17:58","doi":"10.21203/rs.3.rs-7148737/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-06T17:07:07+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-29T05:44:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-22T13:32:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"240929208526676587852565068425765512093","date":"2025-09-17T05:12:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3053269124650601272966479158007435599","date":"2025-09-16T05:28:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"144629003023481735450462118134118432095","date":"2025-09-15T12:37:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"97923457308356383701885388167356821625","date":"2025-08-20T07:44:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-16T10:34:51+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-13T08:46:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"142144686741191268090893445345291057602","date":"2025-08-05T14:46:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"66459940828977857770937771500524510772","date":"2025-08-05T10:35:57+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-05T04:22:20+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-07-22T18:55:06+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-21T05:58:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-18T13:42:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-07-17T11:37:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"79d463c4-ae25-49b7-9511-12985aaa38c0","owner":[],"postedDate":"August 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":52690340,"name":"Physical sciences/Chemistry"},{"id":52690341,"name":"Biological sciences/Computational biology and bioinformatics"},{"id":52690342,"name":"Biological sciences/Drug discovery"}],"tags":[],"updatedAt":"2025-12-22T16:04:27+00:00","versionOfRecord":{"articleIdentity":"rs-7148737","link":"https://doi.org/10.1038/s41598-025-32346-7","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-12-15 15:57:09","publishedOnDateReadable":"December 15th, 2025"},"versionCreatedAt":"2025-08-08 13:17:58","video":"","vorDoi":"10.1038/s41598-025-32346-7","vorDoiUrl":"https://doi.org/10.1038/s41598-025-32346-7","workflowStages":[]},"version":"v1","identity":"rs-7148737","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7148737","identity":"rs-7148737","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}