An ultrasound-assisted synthesis of novel Thiazole-pyrimidine hybrids: in-vitro PPA enzyme inhibition, DFT analysis, Molecular docking, MD simulation

An ultrasound-assisted synthesis of novel Thiazole-pyrimidine hybrids: in-vitro PPA enzyme inhibition, DFT analysis, Molecular docking, MD simulation | 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 Research Article An ultrasound-assisted synthesis of novel Thiazole-pyrimidine hybrids: in-vitro PPA enzyme inhibition, DFT analysis, Molecular docking, MD simulation Dilip C. Kanjariya, Hem N. Naik, Meet J. Sherashiya, Yogesh T. Naliapara, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5994323/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 4 You are reading this latest preprint version Abstract This study gives structural information about the novel thiazole-pyrimidine hybrids ( P1 to P15 ). The compounds were synthesized and yield optimized by sonochemistry, characterized using various spectroscopic techniques, including mass, 1 H-NMR, 13 C-NMR, and IR spectroscopy. The compounds were theoretically explored using the DFT approach with a B3LYP/6-311G (d, p) basis set, and their in vitro porcine pancreatic α-amylase (PPA) enzyme screening was done. Compared to the standard acarbose (IC 50 = 0.34 mM), novel thiazole-pyrimidine hybrids ( P1 to P15 ) demonstrated porcine pancreatic α-amylase inhibition ranging from IC 50 (0.33 to 0.73 mM). Molecular docking, MD simulation investigations, and ADMET were carried out to identify the active sites and explain the actions of the active substances by in silico molecular docking. The three active compounds P3 (IC 50 0.33 mM, -10.6 kcal/mol ), P2 (IC 50 0.37 mM, -10.5 kcal/mol), and P6 (IC 50 0.39 mM, -10.5 kcal/mol) were redocked at the active site of pig pancreatic alpha-amylase isoenzyme II (PDB ID: 1OSE ) to study the binding conformation and dynamics relevant to their activity. The binding interactions between P2, P3, and P6 with porcine pancreatic α-amylase showed porcine pancreatic α-amylase's inhibitory potential. thiazole-pyrimidine hybrids ultra-sound in-vitro PPA inhibition Density functional theory PPA isoenzyme II MD simulation Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Heterocyclic compounds are important in the domain of naturally occurring and physiologically active chemicals. Heterocyclic units are found in many natural products and bioactive chemicals, such as vitamins, antibiotics, and alkaloids. [1] Heterocycles are thought to be present in more than 85% of compounds with biological activity. These substances are used in agriculture, medicine, and even the synthesis of polymers. For example, nitrogen-containing heterocycles such as piperazines are found in medicinal compounds used to treat malaria, ulcers, and cancer. The basic parent backbone of many biologically active pharmaceutical and naturally occurring substances is a nitrogen heterocyclic structure. [1–4] The unique function, low toxicity, and quick intracellular absorption of nitrogen-containing heterocycles make them common in medications, pesticides, dyes, and other products. They are also commonly present in living organisms' metabolites. Additionally, aminopyrimidines are helpful heterocyclic nuclei for creating physiologically important chemicals and pharmacological medications (some noteworthy examples include vitamin B-1, thiamine, and cytosine). The skeleton of some well-known synthetic medicinal products, such as the pyrimidine, thiazole, piperidine, and piperazine nuclei, is one example of the structural framework of these materials, which can be readily modified to create biologically active substances or organic functional materials. (Figure 1). [3, 5, 6] New, strong, broad-spectrum medications are still required because glycaemic control pharmacotherapy is now insufficient. To improve efficacy while reducing side effects, multi-target therapies for type 2 diabetes are being developed more frequently as a result of developments in pathophysiology, pharmacology, and molecular biology. Type 2 diabetes mellitus (T2DM) is characterised by either insufficient insulin production by the pancreas or insulin resistance, which is the inactivation of certain proteins involved in the insulin signalling cascade. Blood glucose levels are lowered by this chronic metabolic disorder, which also has a detrimental effect on people's quality of life everywhere.[7, 8] Porcine and human pancreatic α-amylase enzymes were 87.1% similar in sequence alignment, score similarity, matching residues, and conserved regions studies, according to bioinformatics homology. The amino acid sequences of both α-amylase enzymes are often retained in humans and pigs because they carry out the same biological activity during digestion, namely, breaking down complex carbohydrates (starches) into simpler sugars like glucose and maltose. Because of their conservation of function, the amino acid sequences of these enzymes often share similarities. The general structure of α-amylase is maintained in all animals, including pigs and humans.[9] The active site for the hydrolysis of carbohydrates is located within its catalytic domain. In certain aspects, the α-amylase enzyme types seen in pigs and humans are very similar. These regions determine the enzyme's catalytic activity and substrate binding. Although the amino acid sequences of pig and human α-amylases differ greatly due to their evolutionary histories, they share the same structure and function. Because of the preservation of crucial functional domains, they can perform the same enzymatic role in the digestion of carbohydrates.[10] We continued our effort towards developing novel PPA inhibitors interested in creating thiazole-pyrimidine hybrids using inexpensive, readily accessible 4,6-dichloro-2-methylpyrimidine. High regioselectivity, high yields, and experimental simplicity are the desired qualities of this synthesis, and its effectiveness as an in vitro and in silico inhibition of porcine pancreatic α-amylase (PPA) is being studied. it is easily accessible as a meat industry byproduct. Assays are straightforward and reasonably priced. Using porcine enzymes avoids ethical concerns associated with sourcing human enzymes and simplifies regulatory compliance. About 80–85% of the amino acid sequences of PPA and human pancreatic alpha-amylase are identical. It is a dependable model for research about human digestion because of the highly conserved catalytic residues and active site shape. PPA's application in computational modeling and structure-function studies is supported by its well-characterized crystal structure, which is available in the Protein Data Bank (PDB ID: 1OSE). Results and Discussion Chemistry Synthesis of the novel thiazole-pyrimidine hybrids steps listed in Scheme 1 were utilized. Using the method previously described, the first step involves cyclizing 4-hydroxythiobenzamide (1) with 2-chloroacetoacetic acid ethyl ester (2) in refluxing ethanol to produce 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (3) . After that 4,6-dihydroxy-2-methyl pyrimidine (6) was synthesized from the starting compound acetimidamide (4) and diethyl malonate (5) in the presence of sodium ethoxide [20]. Phosphoryl chloride replaced hydroxyl groups in hydroxyl groups in 4,6-dihydroxy-2-methyl pyrimidine (6) with chlorine to form a compound 4,6-dichloro-2-methylpyrimidine (7) . 4,6-dichloro-2-methylpyrimidine (7) and compound 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (3) dissolved in DMF; the presence of potassium carbonate then reacted to form a compound ethyl 2- (4-( (6-chloro-2-methylpyrimidin-4-yl) oxy) phenyl) -4-methylthiazole-5-carboxylate (8) . The last step entailed replacing with 2°-amine derivatives (piperazine/piperidine/morpholine) for the residual chlorine in compound ethyl 2-(4-((6-chloro-2-methylpyrimidin-4-yl) oxy) phenyl)-4-methylthiazole-5-carboxylate (8) to obtain the final compounds ( P1 to P15 ). yields utilizing the conventional method to the Ultra-sound approach specified in Table 1 and characterized by ATR-FTIR, 1 H-NMR, 13 C-NMR, and mass spectrometry, as detailed in the supplemental section. Biology Furthermore, it is noteworthy that porcine and human pancreatic α-amylase share similar biological functions and feature active site amino acids. Porcine pancreatic α-amylase is a widely used target to investigate the antidiabetic potential of compounds. Additionally, we looked at the potential in vitro antidiabetic properties against porcine pancreatic α-amylase enzyme inhibition for the novel thiazole-pyrimidine hybrids ( P1 to P15 ). Hence, for our in vitro and in silico investigations, we employed the porcine pancreatic α-amylase protein denoted as PDB ID:1OSE. [11–16]According to Table 1 , The range of IC 50 values for the novel thiazole-pyrimidine hybrids ( P1 to P15 ) is 0.33 mM to 0.73 mM observed compared to acarbose obtaining antagonistic efficiency at IC 50 value of 0.34 mM. Among all compounds, good inhibition was shown by P3, P2, and P6 against porcine pancreatic α-amylase with IC 50 values of 0.33 mM, 0.37 mM, and 0.39 mM respectively. Figure 2 indicates results imply that it has been good to moderate inhibitory effect against porcine pancreatic α-amylase enzymes involved in the digestion of carbohydrates. DFT study Frontier Molecular Orbitals play a major role in the electrical configuration and are frequently used to assess the chemical reactivity of novel thiazole-pyrimidine hybrids. The ΔE gap (eV), chemical hardness, chemical potential, electronegativity, and electrophilicity shown in Table 2 may be calculated using the HOMO-LUMO orbital energies. To be more precise, a molecule that has a greater E HOMO tends to be closer to electrophiles and is an improved electron donor. The opposite is also true; a molecule with a lower E LUMO is more of an electron acceptor and attracts nucleophiles more strongly.[14]. Particularly annoyed to compare with molecules P4, P7, P10, and P9 having small energy gaps that are more leading and polarizable and have strong chemical reactivity and low kinetic stability, larger HOMO-LUMO energy gaps ( P2, P5, P11, and P12 ) molecules are typically stable with low chemical reactivity. Thus, it is clear from Table 2 that compounds P7 and P4 are hard and more stable (less reactive), while compounds P12, P11, and P5 are soft and the least stable (more reactive). Compounds P1¸ P3, P6, P8, P13, P14, and P15 are the medium compared to others. Compounds with greater chemical potential values (μ) are more reactive than those with small electronic chemical potentials. According to chemical potential (μ) the compounds also P4 and P7 promise greater chemical potential for the reactivity than the others. The surfaces and the variations between the energies of the orbital of the FMO (HOMO, LUMO) were obtained from the Density Functional Theory. Figures 3 show the HOMO-LUMO energy gap graphs and optimized geometry respectively. Table 2. Calculated quantum chemical parameters for the novel thiazole-pyrimidine hybrids ( P1 to P15 ) under investigation. Hybrids (a.u.) E HOMO (eV) (eV) (eV) [μ=(E HOMO +E LUMO )/2] Chemical hardness [η=(E LUMO -E HOMO )/2] [ω = μ2/(2η)] Dipole moment (Debye) P1 -2901.76 -0.2197 -0.0783 0.141 -0.149 0.070 0.157 3.5557 P2 -2712.55 -0.2212 -0.0744 0.147 -0.147 0.073 0.148 2.8889 P3 -2649.02 -0.2212 -0.0822 0.139 -0.151 0.069 0.165 3.2609 P4 -2097.06 -0.1955 -0.0736 0.121 -0.134 0.060 0.148 3.4561 P5 -2005.79 -0.2221 -0.0752 0.147 -0.148 0.073 0.150 7.6452 P6 -2252.93 -0.2142 -0.0737 0.141 -0.143 0.070 0.147 3.0578 P7 -2097.04 -0.1914 -0.0767 0.115 -0.134 0.057 0.156 6.2300 P8 -1814.03 -0.2189 -0.0731 0.145 -0.146 0.072 0.146 3.6343 P9 -2442.11 -0.2117 -0.0784 0.133 -0.145 0.066 0.157 5.4741 P10 -2021.80 -0.2052 -0.0762 0.129 -0.140 0.064 0.153 6.9569 P11 -2097.35 -0.2230 -0.0751 0.147 -0.149 0.073 0.150 2.0406 P12 -1771.26 -0.2259 -0.0772 0.148 -0.151 0.074 0.154 5.7591 P13 -1982.49 -0.2139 -0.0769 0.137 -0.145 0.068 0.154 6.2126 P14 -1830.03 -0.2131 -0.0761 0.137 -0.144 0.068 0.152 6.9178 P15 -1790.71 -0.2121 -0.0761 0.136 -0.144 0.068 0.152 7.4950 Molecular Docking To determine the mechanisms of interaction, the strongest molecules found in the active sites of the enzymes according to the study were molecular docked using Auto Dock Tools (1.5.7). The method used to evaluate the binding affinities of ligands and receptors was molecular docking. Acarbose was redocked with its binding energies (PDB ID:1OSE, resolution: 2.30 Å) to ensure uniformity in the molecular docking process. The novel thiazole-pyrimidine hybrids ( P1 to P15 ) ranged from -8.7 to -10.6 kcal/mol against the porcine pancreatic α-amylase protein. The docking scores of ligands P2, P3, and P6 were -10.5, -10.6, and -10.5 kcal/mol, respectively. Ligand P1 shown binding affinity -10.2 kcal/mol and hydrophobic interaction with Ile49, Val51, Trp59, Tyr62, Gln63, Ala107, Leu162, Val163, Ala198, while Van der Waals Interaction shown by these residue Val50, Thr52, Asn53, Trp58, His101, Gly104, Ala108, Gly112, Leu165, Asp197, His299, Asp300, His305. Ligand P2 shown binding affinity -10.5 kcal/mol, residue from the 1OSE interacted through hydrogen bonding shown by Gly106 (2.10), Ala107 (3.01), while hydrophobic interaction with hyTrp58, Trp59, Tyr62, Val163, Lys200, His201, Ile235, His299, Ala307, Gln63, and Van der Waals interactions observed with Gly104, Ser105, Tyr151, Leu162, Gly164, Leu165, Ala198, Ser199, Asp300, Gly306. Ligand P3 shown binding affinity -10.6 kcal/mol and hydrophobic interaction with Trp58, Trp59, Tyr62, Gly104, Leu162, Val163, Lys200, His201, Ile235, His299, Asp300, Val51, while Van der Waals Interaction shown by these residue Gln63, Ala107, Gly106, Tyr151, Leu165, Ala198, Glu233, Val234, His305, Gly306. Ligand P4 shown binding affinity -9.7 kcal/mol when formed complex with 1OSE residue His299 (2.02), hydrophobic interaction with Ile49, Val51, Trp59, Tyr62, Gln63, Ala108, Glu233, while Van der Waals Interaction shown by these residues Val50, Trp58, His101, Gly106, Leu162, Leu165, Gly164, Asp300, His305 with 1OSE. Ligand P5 shown binding affinity -9.9 kcal/mol and when formed complex with 1OSE residue His299 (2.12) interacted through hydrogen bonding, while hydrophobic interaction shown by Ile49, Val51, Trp59, Tyr62, Ala107, Ala108, Val163, residue from 1OSE shown Van der Waals Interaction Val50, Thr52, Trp58, His101, Gly104, Leu162, GLy164, Leu165, Arg195, Asp197, Ala198, Glu233, Asp300. Ligand P6 shown binding affinity -10.6 kcal/mol residue from the 1OSE interacted through hydrogen bonding shown through Gly106 (2.14), and Ala107 (2.99), while hydrophobic interaction shown by Trp58, Trp59, Tyr62, Ala107, Val163, Ala198, Lys200, His201, Glu233, Ile235, His299, His305, Ala307, while Van der Waals Interaction shown by these residue Gln63, Gly104, Ser105, Tyr151, Leu162, GLy164, Leu165, Asp300. Ligand P7 shown binding affinity -9.9 kcal/mol and His299 (2.33) of 1OSE shown hydrogen bonding, hydrophobic interaction with Ile49, Val51, Tyr62, Ala107, Val163, while Van der Waals Interaction shown by these residue Val50, Thr52, Asn53, Gln63, Trp58 Leu165, His101, Gly104, Ala108, Gly112, Leu162, Gly164, Leu165, Asp197, Ala198, Glu233, Asp300. Ligand P8 shown binding affinity -9.3 kcal/mol and His299 (2.10) of 1OSE shown hydrogen bonding, hydrophobic interaction with Ile49, Val51, Trp59, Tyr62, Ala107, Val163, while Van der Waals Interaction shown by these residue Asn53, Trp58, Gln63, Gly104, Gly164, Leu165, Asp197, His101, Leu162, Ala198, Arg195, Glu233, Asp300, His305. Ligand P9 shown binding affinity -10.2 kcal/mol and hydrophobic interaction with Ile49, Val51, Ala107, Ala108, while Van der Waals Interaction shown by these residue Thr52, Asn53, Val50, Leu165, Gly104, His101, Arg195, Asp197, Ala198, Glu233. Ligand P10 shown binding affinity -8.7 kcal/mol and hydrophobic interaction with Glu233, His305, while Van der Waals Interaction shown by these residue Leu165, ala198, Glu233, Lys200, Gly306, Arg195, Asp197, Trp357. Ligand P11 shown binding affinity -9.2 kcal/mol formation of hydrogen bonding with PPAII Hia201 (1.89), and His305 (2.49) while other residue interacted through hydrophobic interaction with which are Trp59, Tyr62, Tyr151, Leu162, Val163, His299, Asp300, while Van der Waals Interaction shown by these residue Trp58, Asn53, Val51, Gly104, Leu165, Gln63, Ile235, Gly306, Lys200, Ala307. Ligand P12 shown binding affinity -8.8 kcal/mol and formation of hydrogen bonding with PPAII residue with His299 (2.12), no hydrophobic interacted any residues from PPAII while Van der Waals Interaction shown by these residue Trp58, Gly164, Gly104, Gly106, Leu165, His101, Leu162, Asp197, Ala198, Glu233, Arg195, Asp300. Ligands P13, P14 and P15 obtained binding affinity -10.0, -8.9, -8.9 kcal/mol respectively, among all these three ligands not interacted through hydrogen bonding as well as hydrophobic interaction with PPAII. only interactions happened between Van der Waals Interaction shown by these residues Val50, Thr52, Asn53, Gly104, Gly106, Gly164, Leu165, Arg195, Asp197, Glu233, Asp300 respectively. By binding the enzyme's active site and mimicking natural substrates, hybrids such as P2, P3 , and P6 potentially inhibit PPA by interacting with the hydrolysis of starch. Critical residues possess strong hydrogen-bonding and hydrophobic interactions that increase their inhibitory capability and affinity. These residues interacted similarly through H-bonds with His201, Gly306, and His305 as well as other interactions of residues are Leu162, Val163, Asp197, Ala198, Lys 200, Glu233, and Ile235 highlighted in Table 3 . In the active site, the conformations of P2, P3, P6 , and acarbose nearly overlapped, as Figure 4 (A-C) illustrates respectively others are shown in the supplementary section (Figure S1-S12). A study on anti-diabetic compounds ( P1 to P15 ) found that compound DV-P3 had a greater inhibitory effect against the porcine pancreatic α-amylase protein than the rest of the synthesized compounds. The 2D and 3D interaction between the ligands P2, P3, P6 , and acarbose is shown in Figure 4, other ligand interactions are incorporated in the supplementary file.[14, 17–19] Table 3. The relevant interaction residues of the PPAII (PDB ID: 1OSE) and the novel thiazole-pyrimidine hybrids ( P1 to P15 )’s binding affinity (kcal/mol). Hybrid Binding energy kcal/mol [PDB ID: 1OSE] Conventional H-bonding interaction (Å) Hydrophobic interaction Van der Waals Interaction P1 -10.2 - Ile49, Val51, Trp59, Tyr62, Gln63, Ala107, Leu162, Val163, Ala198 Val50, Thr52, Asn53, Trp58, His101, Gly104, Ala108, Gly112, Leu165, Asp197, His299, Asp300, His305 P2 -10.5 Gly106 (2.10), Ala107 (3.01) Trp58, Trp59, Tyr62, Val163, Lys200, His201, Ile235, His299, Ala307 Gln63, Gly104, Ser105, Tyr151, Leu162, Gly164, Leu165, Ala198, Ser199, Asp300, Gly306 P3 -10.6 - Trp58, Trp59, Tyr62, Gly104, Leu162, Val163, Lys200, His201, Ile235, His299, Asp300 Val51, Gln63, Ala107, Gly106, Tyr151, Leu165, Ala198, Glu233, Val234, His305, Gly306 P4 -9.7 His299 (2.02) Ile49, Val51, Trp59, Tyr62, Gln63, Ala108, Glu233 Val50, Trp58, His101, Gly106, Leu162, Leu165, Gly164, Asp300, His305 P5 -9.9 His299 (2.12) Ile49, Val51, Trp59, Tyr62, Ala107, Ala108, Val163 Val50, Thr52, Trp58, His101, Gly104, Leu162, GLy164, Leu165, Arg195, Asp197, Ala198, Glu233, Asp300 P6 -10.5 Gly106 (2.14), Ala107 (2.99) Trp58, Trp59, Tyr62, Ala107, Val163, Ala198, Lys200, His201, Glu233, Ile235, His299, His305, Ala307 Gln63, Gly104, Ser105, Tyr151, Leu162, GLy164, Leu165, Asp300 P7 -9.9 His299 (2.33) Ile49, Val51, Tyr62, Ala107, Val163 Val50, Thr52, Asn53, Gln63, Trp58 Leu165, His101, Gly104, Ala108, Gly112, Leu162, Gly164, Leu165, Asp197, Ala198, Glu233, Asp300 P8 -9.3 His299 (2.10) Ile49, Val51, Trp59, Tyr62, Ala107, Val163 Asn53, Trp58, Gln63, Gly104, Gly164, Leu165, Asp197, His101, Leu162, Ala198, Arg195, Glu233, Asp300, His305 P9 -10.2 - Ile49, Val51, Ala107, Ala108 Thr52, Asn53, Val50, Leu165, Gly104, His101, Arg195, Asp197, Ala198, Glu233 P10 -8.7 - Glu233, His305 Leu165, ala198, Glu233, Lys200, Gly306, Arg195, Asp197, Trp357 P11 -9.2 Hia201 (1.89), His305 (2.49) Trp59, Tyr62, Tyr151, Leu162, Val163, His299, Asp300 Trp58, Asn53, Val51, Gly104, Leu165, Gln63, Ile235, Gly306, Lys200, Ala307 P12 -8.8 His299 (2.12) - Trp58, Gly164, Gly104, Gly106, Leu165, His101, Leu162, Asp197, Ala198, Glu233, Arg195, Asp300 P13 -10.0 - - Gly164, Gly104, Val50, Thr52, Leu165, Asn53, Asp197, Arg195, Glu233, ASP300 P14 -8.9 - - Gly164, Gly104, Gly106, Val50, Leu165, Thr52, Asp197, Arg195, Glu233, Asp300 P15 -8.9 - - Gly164, Gly104, Gly106, Leu165, Asp197, Arg195, Asp300 Acarbose -7.3 Tyr62 (2.84), Gln63(2.51, 2.57, 2.92), Asp197(1.89), Ala198(2.92) Glu233(2.10), Asp300(2.99), His305(1.74) Asp300 Ile49, Val51, Trp59, His101, Gly104, Ala107, Ala108, Leu162, Val163, Leu165, Arg195, Ile235, Gly306 MD Simulation For the three top compounds found in the study, a 100 nanosecond molecular dynamics simulation was run on the ligand-protein complex. Acquiring an improved comprehension of the ligand's binding to the enzyme's active site was the aim of this simulation. A molecular dynamics simulation investigation was necessary to examine the stability and dynamic changes in the ligand-protein complex under a physiological condition simulation. Radius of Gyration, Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and hydrogen bond analysis are crucial parameters used in MD simulations to assess the structural and dynamic characteristics of proteins. Together, these parameters offer the foundation for evaluating the stability of protein-ligand complexes in the dynamically transforming environment. Root-mean-square deviation (RMSD) The structural stability and conformational changes of a system over time can be evaluated with the use of RMSD. Significant conformational changes in the system during the simulation are indicated by high RMSD values. A low RMSD indicates that a system is stable and maintains its original conformation throughout time.[14, 20, 21] The P2_1OSE Complex and P3_1OSE Complex RMSD values were almost constant (≈ 2.5 Å) between 0 and 40 ns. Following that, these two systems' RMSD values progressively rose until 60 ns, at which point they converged to a steady value (Figure 4A). As opposed to this, the RMSD for the P6_1OSE Complex steadily rose until 30 ns and then held steady till the very end. The P2_1OSE Complex has moderate structural variations, as indicated by the mean RMSD value of 3.19 Å. With an RMSD of 3.23 Å, the P3_1OSE Complex similarly behaves to the P2_1OSE Complex. In comparison with the other two complexes, the P6_1OSE Complex has a little larger RMSD value of 3.55 Å (Figure 5A). Following an initial period of volatility, the three complexes' consistent RMSD values indicate that these systems eventually achieve equilibrium and retain a comparatively stable shape. Variations in the ligand conformations, binding affinities, or the intrinsic structural flexibility of the protein may be the cause of the disparities in RMSD values between the complexes. Root mean square fluctuation (RMSF) In molecular dynamics (MD) simulations and structural biology, RMSF is a frequently used metric to evaluate the flexibility and fluctuations of individual atoms or groups of atoms inside a molecule or molecular complex while a simulation. RMSF sheds light on a system's dynamic behaviour and is especially helpful in identifying the hard or highly flexible components of a biomolecule.[22–25] A graph with the x-axis is commonly used to display RMSF values. Significant swings are suggested by high RMSF values, whereas stability or rigidity is indicated by low values. Throughout the simulation, it became clear that some protein areas—especially the loop sections—showed larger amounts of variation than other protein regions. The P2_1OSE Complex, P3_1OSE Complex, and P6_1OSE Complex were found to have a number of interacting residues. The stability and behaviour of the corresponding complexes are greatly influenced by these interactions. In the P2 _1OSE Complex, residues Ile49, Val50, Val51, Thr52, Asn53, Pro54, Trp58, Trp59, Tyr62, Gln63, His101, Cys103, Gly104, Ser105, Gly106, Ala107, Ala108, Ile148, Tyr151, Val157, Leu162, Val163, Gly164, Leu165, Asp197, Ala198, Lys200, His201, Glu233, Ile235, Leu237, Ile242, Asn298, His299, Asp300, His305, Gly306, Ala307, Glu352, Val354, Asp356, and Trp357 involved in complex interactions, suggesting a network of stabilizing contacts. In the P3 _1OSE Complex, Glu29, Ile49, Val50, Val51, Thr52, Asn53, Pro54, Ser55, Trp58, Trp59, Tyr62, Gln63, Asn88, His101, Met102, Cys103, Gly104, Ser105, Gly106, Ala107, Ala108, Ala109, Tyr151, Asn152, Val157, Leu162, Val163, Gly164, Leu165, Asp197, Ala198, Lys200, His201, Glu233, Ile235, Leu237, Glu240, Gln243, Ser245, Glu246, Phe248, Trp284, Gly285, Phe286, Met287, Pro288, Arg291, His299, Asp300, Arg303, His305, Gly306, Ala307, Asn347, Val349, Asn350, Val354, Asn355, Asp356, and Trp357 residues contribute to the interaction network, indicating the importance of these contacts for complex stability. Meanwhile, the P6 _1OSE Complex exhibits interactions involving Val51, Asn53, Pro54, Trp58, Trp59, Tyr62, Gln63, His101, Gly104, Ser105, Gly106, Ala107, Leu162, Val163, Gly164, Leu165, Arg195, Asp197, Ala198, Lys200, His201, Glu233, Val234, Ile235, Leu237, Phe256, Ala260, Asn298, His299, Asp300, His305, Gly306, Ala307, Gly308, Gly309, Ala310, Ser311, and Asp356 emphasizing their role in maintaining complex integrity. These interactions provide insight into the major contributors in these molecular connections and underline the complex and dynamic character of protein-ligand binding. The stability of P2, P3, and P6 in the 1OSE protein is demonstrated by the low RMSF values displayed by these interacting residues. The P2_1OSE Complex, P3_1OSE Complex, and P6_1OSE Complex have, on average, RMSF values of 1.18 Å, 1.30 Å, and 1.06 Å, respectively ( Figure 5B ). A complex with a lower average RMSF is believed to be more structurally stable and exhibits less overall variance in atomic conditions. Radius of Gyration (RGyr) Utilise the Radius of Gyration (RGyr) to determine the overall size and compactness of a molecule or chemical complex. It provides information about the three-dimensional distribution of atoms inside the system and is a useful tool for understanding biomolecular shape and structural changes. The RGyr value indicates the average distance between the atoms and the nucleus of mass. While a lower Rg denotes a more compact and securely folded structure, a higher RGyr denotes a more stretched or less compact structure.[26] The RGyr findings highlight the structural characteristics of the P2_1OSE Complex, _1OSE Complex, and P6_1OSE Complex. The lowest minimum RGyr value, 20.140 Å, is found in the P2_1OSE Complex. This implies that during the simulation, these complexes may adopt highly compact conformations, which could demonstrate structural stability in particular states. Likewise, the near-range maximum RGyr values indicate that the complexes investigate more extended or open conformations at certain points during the simulation; the P6_1OSE Complex has the highest maximum RGyr at 21.693 Å ( Figure 5C ). The usual compactness of the P2_1OSE Complex, P3_1OSE Complex, and P6_1OSE Complex is indicated by their respective average RGyr values of 20.97 Å, 21.16 Å, and 21.08 Å. All three complexes have similar structural characteristics. It is important to note that Figure 5C shows no frames with larger or more a typical change, suggesting that all three compounds are stable. These results show the molecule's inherent flexibility, plasticity, and ability to maintain structural changes while returning to a more compact, desired form. Hydrogen bond analysis A hydrogen bond is a type of non-covalent contact that happens when two electronegative atoms—typically oxygen, nitrogen, or fluorine—share a hydrogen atom. The structural integrity of proteins during a variety of physiological processes depends on these connections. The P2_1OSE Complex, P3_1OSE Complex, and P6_1OSE Complex hydrogen bond investigations reveal differences in hydrogen bond interactions. The binding affinity has a close relationship with these interactions. Interestingly, all three complexes exhibit at least one stabilising hydrogen bond at the very least (Table 4). However, a higher binding affinity may be indicated by the P3_1OSE Complex's stronger and more frequent hydrogen bond interactions. .[26, 27] It has a maximum of three hydrogen bonds and an average of 0.63. Conversely, the P6_1OSE Complex's lower average of 0.23 hydrogen bonds (Figure 5D) suggests a moderate interaction profile. In conclusion, the ligands P2, P3, and P6 show exceptional stability and strong affinity for the binding cavity of the 1OSE protein. These ligands and the protein create stable complexes, according to the combined results of the RMSD, RMSF, and hydrogen bond formation investigations; P3 exhibits a somewhat more dynamic interaction pattern. Table 4. The investigated complexes' minimum, maximum, and average values for several parameters, as well as their RMSD, RMSF, RGyr, and hydrogen bonding. P2_1OSE Complex P3_1OSE Complex P6_1OSE Complex Root-mean-square deviation Å (RMSD) Minimum 3.19 3.23 3.55 Maximum 4.00 3.85 4.21 Average 3.19 3.23 3.55 Root-mean-square fluctuation Å (RMSF) Minimum 0.45 0.52 0.50 Maximum 6.20 6.19 4.04 Average 1.18 1.30 1.06 The radius of gyration Å (RGyr) Minimum 20.140 20.300 20.156 Maximum 21.647 21.568 21.693 Average 20.97 21.16 21.08 Hydrogen bonding Minimum 1.00 1.00 1.00 Maximum 2.00 3.00 2.00 Average 0.52 0.63 0.23 In silico ADMET The results of the novel thiazole-pyrimidine hybrids ( P1 to P15 )'s in-silico ADMET profiling are displayed in Table 5. According to the Lipinski rule of five, an oral medication must have a molecular weight of less than 500 g/mol, a topological polar surface area of less than 140 Å2, several rotatable bonds of 0 < 9, -6 < Log S < 0, donor atoms of hydrogen bonds of ≤ 5, acceptors of hydrogen bonds of ≤ 10, and log P of ≤ 5. [28, 29] Among the new thiazole-pyrimidine hybrids ( P1–P15 ), P8, P12, P14 , and P15 had molecular weights below 500 g/mol, whereas the others had molecular weights above that. The sites at positions 6 to 8 of the new thiazole-pyrimidine hybrids ( P1 to P15 ) can accept hydrogen bonds. The proposed moiety' total polar surface area falls within an acceptable range of 140 Å2, and the unique thiazole-pyrimidine hybrids ( P1 to P15 ) sequences have a log P partition coefficient value of 5. All synthetic substances have limited gastrointestinal (GI) absorption, whereas P8, P10, P12, P13, P14, and P15 have high GI absorption. The protein permeability glycoprotein (P-gp) is essential for evaluating active efflux through biological membranes. The possibility that each of the newly synthesised thiazole-pyrimidine hybrids ( P1 to P15 ) could function as a P-gp substrate or inhibitor was thus ascertained. The egg-shaped model ( Figure S13 ) displays the white portion signifying HIA (Human Intestinal Absorption) and the yellow yolk area signifying BBB penetration. Compounds with low absorption and little brain penetration are included in the grey zone. It is expected that the molecule will have the same active efflux capacity across biological membranes as P-glycoprotein (PGP). When compounds P1, P4, P5, P9, P10, and P13 display blue, it means that they are substrates (PGP+). Simultaneously, P2, P3, P6, P8, P11, P12, P14, and P15 display red for non-substrate (PGP−). It is found to be important, especially when studying the outflow of xenobiotics in the central nervous system. Based on the results shown in Table 5 , ADMET shows that the novel thiazole-pyrimidine hybrids ( P1 to P15 ) follow the maximum Lipinski rule, indicating that the compound has physicochemical characteristics like those of a drug.[30–33] Table 5. in-silico physicochemical and pharmacokinetic descriptors for the novel thiazole-pyrimidine hybrids ( P1 to P15 ) and acarbose under investigation. Entry I II III IV V VI VII VIII IX X XI XII P1 C 28 H 27 Cl 2 N 5 O 3 S 584.52 0 6 8 5.84 -8.05 108.92 Low Yes No 2 P2 C 35 H 34 ClN 5 O 3 S 640.19 0 7 10 6.68 -8.79 108.92 Low No No 2 P3 C 30 H 29 ClN 6 O 4 S 605.11 1 7 8 5.54 -7.47 143.47 Low No No 1 P4 C 29 H 31 N 5 O 4 S 545.65 0 7 9 4.95 -6.93 118.15 Low Yes No 1 P5 C 30 H 32 N 4 O 3 S 528.67 0 6 9 6.06 -7.55 105.68 Low Yes No 2 P6 C 35 H 35 N 5 O 3 S 605.75 0 7 10 6.15 -8.19 108.92 Low No No 2 P7 C 29 H 31 N 5 O 4 S 545.65 0 7 9 4.92 -6.93 118.15 Low Yes No 1 P8 C 25 H 30 N 4 O 3 S 466.6 0 6 7 5.12 -6.61 105.68 High No No 0 P9 C 28 H 28 ClN 5 O 3 S 550.07 0 6 8 5.52 -7.45 108.92 Low Yes No 1 P10 C 29 H 31 N 5 O 3 S 529.65 0 7 8 4.92 -6.77 108.92 High Yes No 1 P11 C 27 H 33 N 5 O 5 S 539.65 0 8 10 4.54 -6.15 135.22 Low No No 1 P12 C 22 H 24 N 4 O 4 S 440.52 0 7 7 3.8 -5.15 114.91 High No No 0 P13 C 28 H 29 N 5 O 3 S 515.63 0 6 8 4.81 -6.85 108.92 High Yes No 1 P14 C 24 H 29 N 5 O 3 S 467.58 0 7 8 4.1 -5.58 108.92 High No No 0 P15 C 23 H 27 N 5 O 3 S 453.56 0 7 7 3.8 -5.34 108.92 High No No 0 Acarbose C 25 H 43 NO 18 645.6 14 19 9 -6.41 2.13 321.17 Low Yes No 3 I) Molecular Formula, II) Molecular Weight, III) H-bond donors, IV) H-bond acceptors, V) Rotatable bonds, VI) Log P o/w , VII) Log S, VIII) TPSA (Ų), IX) GI absorption, X) Pgp substrate, XI) BBB permeant, XII) Lipinski Rule of Five violations Conclusion In conclusion, the novel thiazole-pyrimidine hybrids ( P1 to P15 ) were synthesized using the ultrasound-assisted method and optimized with 61-82 % yields. along with their in vitro inhibition efficacy against the porcine pancreatic α-amylase enzyme. They were further confirmed by 1 H-NMR, 13 C-NMR, Mass, and IR- spectroscopy. Acarbose (IC 50 0.34 mM), was employed as the standard to compare these molecular hybrids in vitro porcine pancreatic α-amylase inhibitory efficiency. Maximum porcine pancreatic α-amylase inhibition was observed for compounds P3 (IC 50 0.33 mM), P2 (IC 50 0.37 mM, and P6 (IC 50 0.39 mM), from Table 1. This is also supported by molecular docking and molecular dynamic simulation from the active site of 1OSE residue His201, Gly306, His305 as hydrogen bonding interaction, for the hydrophobic interaction Leu162, Val163, Asp197, Ala198, Lys200, Glu233, Ile235 are played a major role to the inhibition for the porcine pancreatic α-amylase enzyme. Experimental Materials and Methods Materials 4,6-dichloro-2-methylpyrimidine was purchased from BLD Pharma (India), and Acetamidine hydrochloride, diethyl malonate, 4-hydroxythiobenzamide, ethyl 2-chloro-3-oxo butanoate from Sigma-Aldrich (India), and the solvents from Merck were used without further purification. TLC monitored the completion and purity of the reactions, performed on silica gel aluminium 60 F -254 thin layer plates procured from Merck, and visualization on TLC was achieved by UV chamber and iodine indicator. The synthesized compounds underwent an in vitro antidiabetic screening, employing pure α-amylase sourced from porcine pancreas acquired from supplier Sigma-Aldrich, India (Catalogue No. A6255). Synthesis Scheme 1 shows the synthesis of the proposed conjunction component. In contrast to traditional approaches, we report a relatively short timeframe for achieving a considerable improvement in compound yield by an efficient and straightforward synthesis of thiazole-pyrimidine-2°-amine appended ( P1 to P15 ) under sonochemistry. This study endures our continuous attempts to develop novel synthetic hybrids using sonochemistry techniques. Synthesis of 2-(4-hydroxyphenyl)-4-methyl thiazole-5-carboxylic acid ethyl ester (3) From the previously reported procedure initially, 4-hydroxythiobenzamide (1eq.) (1) , ethyl 2-chloro-3-oxo butanoate (1.2 eq.) ( 2 ), and 20 ml of ethanol were taken in a round-bottomed flask and the reaction mixture was refluxed for 3 h to get 2-(4-hydroxyphenyl)-4-methyl thiazole-5-carboxylic acid ethyl ester ( 3 ), the reaction was monitored by TLC (3:7; EtOAc/n-Hexane) at a time interval of 15 min. After completion of the reaction, the mixture was quenched into the crushed ice. The solid obtained was washed with cold water, air-dried, and recrystallized from ethanol to get the pure compounds (yield:83%).[34–37] Synthesis of 4,6-dihydroxy-2-methyl pyrimidine (6) Acetamidine hydrochloride (0.50 mmol) ( 4 ), diethyl malonate (0.52 mmol) ( 5 ), and methanol were mixed at room temperature. As well as that, a 30% sodium methoxide. Gently introduce a methanol (1.53 mmol) solution to the mixture. For three hours, the mixture was mixed. Once chilled to room temperature, the mixes were combined. solid mass was obtained which was washed by washing with methanol, filtered, collected, and then 350 ml of water, after being dissolved. The watery mixture was acidic by freezing and using a lot of powerful hydrochloric acid with ice, to adjust 2 pH and obtaining and weighing a 4,6-dihydroxy-2-methyl pyrimidine ( 6 ), a white crystalline solid after sedimentation and washing in methanol and water. [38] Synthesis of 4,6 dichloro-2-methyl pyrimidine (7) Triethylamine (0.12 mol) was gradually added to a mixture of 4,6-dihydroxy-2-methylpyrimidine ( 6 ) (0.10 mol) and phosphoryl chloride (0.50 mol) below 75 °C. After about four hours, the mixture was refluxed while being stirred. The excess phosphorus oxychloride was removed by vacuum distillation. The residue was then mixed with 150 ml of cold water, extracted with ethyl acetate, and the organic layer was dried on magnesium sulphate. After the solvent was removed under vacuum, the crude product was recrystallized using petroleum ether to produce 4,6-dichloro-2-methyl pyrimidine ( 7 ).[38] Synthesis of ethyl 2-(4-((6-chloro-2-methylpyrimidin-4-yl) oxy) phenyl)-4-methylthiazole-5-carboxylate (8) 4,6-dichloro-2-methyl pyrimidine ( 7 ) (0.5g, 0.00286 mol) and 2-(4-hydroxyphenyl)-4-methyl thiazole-5-carboxylic acid ethyl ester ( 3 ) (0.67g, 0.00257 mol was dissolved in dimethylformamide (30 mL) and K 2 CO 3 (1.17 g, 0.00859 mol), was added to it and allowed to stir at room temperature for 8 h to get compound ethyl 2-(4-((6-chloro-2-methylpyrimidin-4-yl)oxy)phenyl)-4-methylthiazole-5-carboxylate ( 8 ) with 87% yield. The reaction was monitored using thin-layer chromatography (3:7; EtOAc/n-Hexane). then, the mixture was poured into crushed ice water to obtain the solid crude product filtered, and recrystallized by ethanol: DMF (1:1) to get a white crystal of the compound ( 8 ).[14] Synthesis of novel thiazole-pyrimidine hybrids (P1 to P15) Ethyl 2-(4-((6-chloro-2-methylpyrimidin-4-yl) oxy)phenyl) -4-methylthiazole-5-carboxylate ( 8 ) (0.00077 mol) was dissolved in dimethylformamide (30 mL) and K 2 CO 3 (0.0023 mol), 2°-amines (0.00077 mol) was added to it and allowed to stir at reflux temperature for 6-8 h with 45 to 74 % yield or same mole ratio of the reactants was treated by ultrasound irradiation for about 60 °C put 170 to 195 min at 40 kHz power to get optimized yield 61 to 82 % ( P1 to P15 ), which is listed in Table 1 . The reaction was monitored using thin-layer chromatography (3:7; EtOAc/n-Hexane). After the completion of the reaction, the mixture was poured into crushed ice water to obtain the solid crude product filtered and concentrated under reduced pressure, and recrystallized by ethanol.[14] Spectroscopic data of synthesized novel thiazole-pyrimidine hybrids (P1 to P15). Ethyl 2-( 4-( (6-(4-( 2, 3-dichlorophenyl) piperazin-1-yl) -2-methylpyrimidin-4-yl) oxy) phenyl) -4-methylthiazole-5-carboxylate (P1, C 28 H 27 Cl 2 N 5 O 3 S) White solid, mp: 178–179 °C: FT-IR (υ max cm -1 ): 2972 str.(–C–H), 1701 str. (ester -C=O), 1100 bend.(ether -C-O-C); 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm); 8.03 – 7.98 (m, 2H, H-Ar), 7.25 – 7.17 (m, 4H, Ar), 6.95 – 6.93 (m, 2H, H-Ar), 5.77 (s, 1H, pyrimidine H-C), 4.38 – 4.34 (m, 2H,-CH 2 ), 3.78 – 3.77 (m, 4H,-CH 2 ), 3.09 (m, 4H,-CH 2 ), 2.96 (s, 3H,-CH 3 ), 2.89 (s, 3H,-CH 3 ), 1.39 (t, J = 6.3 Hz, 3H,-CH 3 ): 13 C-NMR (125 MHz, CDCl 3 ) δ(ppm); 170.13, 169.04, 167.86, 164.70, 162.25, 161.02, 155.67, 154.79, 150.73, 134.72, 129.72, 128.36, 125.21, 121.86, 121.72, 121.56, 118.77, 118.57, 83.78, 61.29, 51.04, 44.40, 26.07, 17.54, 14.71: ESI-MS: m/z 585.15 [ M +H]: Calculated %: C 28 H 27 Cl 2 N 5 O 3 S: C, 57.54; H, 4.66; Cl, 12.13; N, 11.98; S, 5.48; found: C, 57.74; H, 4.70; Cl, 12.18; N, 11.89; S, 5.50. Ethyl 2-(4-((6-(4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -2- methyl pyrimidin-4-yl) oxy) phenyl) -4-methylthiazole-5-carboxylate (P2, C 35 H 34 ClN 5 O 3 S) White solid, mp: 205–207 °C: FT-IR (υ max cm -1 ): 2990 str.(–C–H), 1717 str. (ester -C=O), 1106 bend.(ether -C-O-C); 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm); 7.97 – 7.95 (m, 2H, H-Ar), 7.37– 7.36 (m, 5H, H-Ar), 7.26-7.24 (m, 4H, H-Ar), 7.19 (t,2H, J=5.2 Hz, H-Ar), 5.89 (s, 1H, benzhydryl, -C-H), 5.67 (s, 1H, pyrimidine H-C), 4.39 – 4.34 (m, 4H,-CH 2 ), 4.24-4.23 (q, J=6.2 Hz, 2H, -CH 2 ), 3.60 – 3.57 (m, 4H,-CH 2 ), 2.77 (s, 3H,-CH 3 ), 2.43 (s, 3H,-CH 3 ), 1.39 (t, J = 6.3 Hz, 3H,-CH 3 ): 13 C-NMR (125 MHz, CDCl 3 ) δ(ppm); 170.04, 169.05, 167.83, 164.55, 162.27, 161.03, 155.74, 141.58, 140.80 132.82, 129.62, 129.22, 129.06, 128.72, 128.71, 128.35, 127.90, 127.34, 121.64, 121.49, 83.83, 75.43, 61.26, 51.38, 44.27, 25.81, 17.55, 14.90: ESI-MS: m/z 640.10 [ M + H] : Calculated %: C 35 H 34 ClN 5 O 3 S: C, 65.66; H, 5.35; Cl, 5.54; N, 10.94; S, 5.01; Found %: C, 65.70; H, 5.31; Cl, 5.55; N, 11.01; S, 5.03. Ethyl 2-(4-((6-(4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) piperidin-1-yl)-2-methylpyrimidin-4-yl) oxy) phenyl) -4-methylthiazole-5-carboxylate (P3, C 30 H 29 ClN 6 O 4 S) White solid, mp: 185–187 °C: FT-IR (υ max cm -1 ): 2999 str. (–C–H), 1720 str. (ester -C=O), 1680 str. (amide -C=O), 1026 bend. (ether -C-O-C); 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm); 8.55 (s,1H, H-N), 8.02 – 7.95 (m, 2H, H-Ar), 7.90– 7.80 (dd, J= 8.1,2.1 Hz, 1H, benzimidazole, H-Ar), 7.24-7.21 (m, 1H, H-Ar), 7.19-7.17 (d, J=2.2 Hz, 1H, H-Ar), 7.12-7.10 (d, J=2.1 Hz,1H, H-Ar), 7.05-6.96 (m,1H, H-Ar), 5.82 (s, 1H,pyrimidine H-C), 4.61 – 4.60 (q, J=6.1 Hz, 2H, -CH 2 ), 4.38-4.32 (m, 1H, piperidine H-C) 2.99- 2.96 (m, 1H, H-C), 2.77 (s, 3H,-CH 3 ), 2.46 (s, 3H,-CH 3 ), 2.38– 2.27 (m, 4H,-CH 2 ), 1.39 (t, J = 6.1 Hz, 3H,-CH 3 ): 13 C-NMR (125 MHz, CDCl 3 ) δ(ppm); 169.05, 168.05, 167.53, 162.34, 156.79, 145.84, 144.32, 129.73, 129.05, 128.65, 128.59, 128.37, 127.58, 121.64, 116.04, 110.20, 109.86, 83.77, 61.28, 51.95, 43.92, 28.87, 25.96, 17.50, 14.33: ESI-MS: m/z 606.10 [ M + H]: Calculated %: C 30 H 29 ClN 6 O 4 S: C, 59.55; H, 4.83; Cl, 5.86; N, 13.89; S, 5.30; Found %: C, 59.59; H, 4.90; Cl, 5.81; N, 13.82; S, 5.34. Ethyl 2-(4-((6-(4-(2-methoxyphenyl) piperazin-1-yl) -2-methylpyrimidin-4-yl) oxy) phenyl)-4-methylthiazole-5-carboxylate (P4, C 29 H 31 N 5 O 4 S) White solid, mp: 171–173 °C: FT-IR (υ max cm -1 ): 3002 str.(–C–H), 1714 str. (ester -C=O), 1009 bend. (ether -C-O-C); 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm); 8.02–7.97 (m, 3H, H-Ar), 7.28 – 7.21 (m, 2H, H-Ar), 7.04-7.03 (d, J=8.4 Hz, 1H, H-Ar), 6.93-6.88 (m, 2H, H-Ar ), 5.76 (s, 1H,pyrimidine H-C), 4.38 – 4.35 (m, 2H,-CH 2 ), 3.88 (m, 4H,-CH 2 ), 3.78 (m, 4H,-CH 2 ), 3.11 (s, 3H, -O-CH 3 ), 2.77 (s, 3H,-CH 3 ), 2.44 (s, 3H,-CH 3 ), 1.40 (t, J = 6.3 Hz, 3H,-CH 3 ): 13 C-NMR (125 MHz, CDCl 3 ) δ(ppm); 170.12, 169.04, 167.87, 164.70, 162.23, 155.82, 152.34, 140.88, 129.62, 128.33, 121.62, 121.11, 118.37, 111.45, 83.73, 61.24, 55.44, 50.42, 44.41, 26.01, 17.52, 14.33: ESI-MS: m/z: 546.20 [ M +H]: Calculated %: C 29 H 31 N 5 O 4 S: C, 63.83; H, 5.73; N, 12.83; S, 5.88; Found %: C, 69.59; H, 5.02; N, 12.82; S, 5.34. Ethyl 2-(4-((6-(4-benzylpiperidin-1-yl)-2-methylpyrimidin-4-yl) oxy) phenyl)-4-methylthiazole-5-carboxylate (P5, C 30 H 32 N 4 O 3 S) White solid, mp: 155–158 °C: FT-IR (υ max cm -1 ): 3012 str. (–C–H), 1721 str. (ester -C=O), 1012 bend. (ether -C-O-C); 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm); 7.99-7.96 (m, 2H, H-Ar), 7.30 – 7.26 (m, 3H, H-Ar), 7.20-7.18 (dd, J= 5.4, 3.6 Hz, 2H, H-Ar), 7.15-7.13 (dd, J= 5.3, 3.2 Hz, 2H, H-Ar ), 5.71 (s, 1H, pyrimidine H-C), 4.36 – 4.35 (q, J= 5.1 Hz, 2H,-CH 2 ), 3.84-3.79 (m, 4H, -CH 2 ), 3.55-3.43 (m, 4H,-CH 2 ), 2.77 (s, 3H,-CH 3 ), 2.56-2.55 (d, J= 6.9 Hz, 2H, -CH 2 ), 2.41 (s, 3H, -CH 3 ), 1.38 (t, J = 6.1 Hz, 3H, -CH 3 ), 1.25-1.20 (m, 1H, piperidine, -H-C): 13 C-NMR (125 MHz, CDCl 3 ) δ (ppm); 170.02, 169.16, 164.30, 161.04, 155.93, 151.91, 150.32, 140.02, 129.20, 128.38, 128.36, 128.23, 127.86, 125.92, 121.52, 84.20, 62.56, 47.60, 43.05, 39.67, 32.03, 26.41, 19.10, 13.80: ESI-MS: m/z: 529.10 [ M + H]: Calculated %: C 30 H 32 N 4 O 3 S: C, 68.16; H, 6.10; N, 10.60; S, 6.06; Found %: C, 68.10; H, 6.18; N, 10.64; S, 6.16 Ethyl 2-(4-( (6-( 4-benzhydrylpiperazin-1-yl) -2-methyl pyrimidin-4-yl) oxy) phenyl) -4-methylthiazole-5-carboxylate (P6, C 35 H 35 N 5 O 3 S) White solid, mp: 201–203°C: FT-IR (υ max cm -1 ) : 3003 str. (–C–H), 1723 str. (ester -C=O), 1012 bend. (ether -C-O-C); 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm); 8.01 – 7.92 (m, 2H, H-Ar), 7.44 – 7.37 (m, 4H, H-Ar), 7.30 -7.26 (m, 4H, H-Ar), 7.19 (d, J=5.2, Hz, 4H, H-Ar), 5.86 (s, 1H, benzhydryl, -C-H), 5.67 (s, 1H, pyrimidine, H-C), 4.37 – 4.33 (q, J=6.2 Hz, 2H, -CH 2 ), 3.65 – 3.61 (m, 4H,-CH 2 ), 2.76 (s, 3H,-CH 3 ), 2.46-2.44 (m, 4H, -CH 2 ), 2.40 (s, 3H,-CH 3 ), 1.38(t, J = 6.3 Hz, 3H,-CH 3 ): 13 C-NMR (125 MHz, CDCl 3 ) δ(ppm); 170.05, 167.82, 164.56 162.27, 161.02, 155.78, 141.92, 129.63, 128.66, 128.29, 127.95, 121.56, 83.72, 70.81, 61.23, 51.49, 44.27, 25.95, 17.51, 14.33: ESI-MS: m/z: 606.15 [ M +H] : Calculated %: C 35 H 35 N 5 O 3 S: C, 69.40; H, 5.82; N, 11.56; S, 5.29; Found %: C, 69.43; H, 5.85; N, 11.52; S, 5.23. Ethyl 2-(4-((6-(4-(4-methoxyphenyl) piperazin-1-yl)-2-methyl pyrimidin-4-yl) oxy) phenyl)-4-methylthiazole-5-carboxylate (P7, C 29 H 31 N 5 O 4 S) White solid, mp: 172–174 °C: FT-IR (υ max cm -1 ): 2989 str. (–C–H), 1718 str. (ester -C=O), 1005 bend. (ether -C-O-C); 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm); 7.99–7.98 (m, 2H, H-Ar), 7.22 – 7.20 (m, 2H, H-Ar), 6.99-6.85 (dd, J = 5.1, 3.5 Hz, 4H, H-Ar), 5.77 (s, 1H,pyrimidine, H-C), 4.37 – 4.34 (q, J=6.4 Hz, 2H, -CH 2 ), 3.87-3.72 (m, 4H,-CH 2 ), 3.13 (m, 4H,-CH 2 ), 2.78 (s, 3H,-CH 3 ), 2.65 (s, 3H, -O-CH 3 ), 2.45 (s, 3H,-CH 3 ), 1.39 (t, J = 6.3 Hz, 3H,-CH 3 ): 13 C-NMR (125 MHz, CDCl 3 ) δ(ppm); 170.12, 169.07, 167.93, 164.53, 162.28, 161.05, 155.70, 154.70, 144.82, 129.71, 128.36, 121.73, 121.57, 119.12, 114.75, 83.85, 61.29, 55.36, 50.90, 44.12, 25.81, 17.56, 14.48: ESI-MS: m/z 546.10 [ M + H]: Calculated % : C 29 H 31 N 5 O 4 S: C, 63.83; H, 5.73; N, 12.83; S, 5.88; Found %: C, 63.81; H, 5.70; N, 12.80; S, 5.81. Ethyl 2- (4- ((6- (3,5-dimethylpiperidin-1-yl) -2-methylpyrimidin-4-yl) oxy) phenyl) -4-methylthiazole-5-carboxylate (P8, C 25 H 30 N 4 O 3 S) White solid, mp: 150–152 °C: FT-IR (υ max cm -1 ): 3009 str. (–C–H), 1711 str. (ester -C=O), 1013 bend. (ether -C-O-C); 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm); 8.03–7.96 (dd, J= 5.1, 3.6 Hz, 2H, H-Ar), 7.20 – 7.19 (q, J = 5.0, 1.8, 2H, H-Ar), 5.76 (s, 1H, pyrimidine H-C), 4.38 – 4.34 (q, J = 6.4 Hz, 2H, -CH 2 ), 3.69-3.66 (m, 4H,-CH 2 ), 3.18-3.16 (m, 4H,-CH 2 ), 2.78 (s, 3H,-CH 3 ), 2.42 (s, 3H,-CH 3 ), 2.32-2.27 (t, J = 13.8 Hz, 2H, piperidine-CH 2 ), 1.63 (m, 2H, piperidine, -H-C), 1.39 (t, J= 6.1 Hz, 3H, -CH 3 ), 0.94-0.92 (d, J=6.6 Hz, 6H, -CH 3 ): 13 C-NMR (125 MHz, CDCl 3 ) δ(ppm); 169.89, 167.80, 164.18, 162.30, 161.04, 158.42, 156.07, 129.35, 128.26, 124.16, 121.31, 83.79, 61.22, 51.44, 42.53, 30.87, 26.05, 19.14, 17.52, 14.33: ESI-MS: m/z: 467.20 [ M +H]: Elemental Analysis calculated for: C 25 H 30 N 4 O 3 S: C, 64.35; H, 6.48; N, 12.01; S, 6.87; found: C, 64.31; H, 6.49; N, 12.21; S, 6.33. Ethyl 2-(4-((6-(4-(3-chlorophenyl) piperazin-1-yl)-2-methylpyrimidin-4-yl) oxy) phenyl)-4-methylthiazole-5-carboxylate (P9, C 28 H 28 ClN 5 O 3 S) White solid, mp: 189–191°C: FT-IR (υ max cm -1 ): 2915 str. (–C–H), 1708 str. (ester -C=O), 1006 bend. (ether -C-O-C); 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm); 8.00-7.98 (d, J = 8.3 Hz, 2H, H-Ar), 7.22 – 7.20 (t, J = 8.4, 2.5 Hz, 1H, H-Ar), 7.18-7.17 (d, J=8.4 Hz, 2H, H-Ar), 6.89-6.84(m, 2H, H-Ar), 6.80-6.78 (m, 1H, H-Ar ), 5.77 (s, 1H,pyrimidine H-C), 4.38 – 4.34 (q, J = 7.1 Hz, 2H,-CH 2 ), 3.76-3.74 (q, J = 5.2 Hz, 4H,-CH 2 ), 3.28-3.25 (q, J = 5.2 Hz, 4H, -CH 2 ), 2.78 (s, 3H,-CH 3 ), 2.44 (s, 3H,-CH 3 ), 1.39 (t, J = 6.2 Hz, 3H,-CH 3 ): 13 C-NMR (125 MHz, CDCl 3 ) δ(ppm); 170.16, 169.04, 167.96, 164.51, 162.26, 161.04, 155.69, 151.96, 135.10, 130.172, 129.72, 128.33, 121.86, 121.64, 119.90, 116.07, 114.15, 83.87, 61.26, 48.44, 43.84, 26.00, 17.53, 14.34: ESI-MS: m/z: 550.25 [ M +H]: Calculated %: C 28 H 28 ClN 5 O 3 S: C, 61.14; H, 5.13; Cl, 6.44; N, 12.73; S, 5.83; Found %: C, 61.11; H, 5.18; Cl, 6.40; N, 12.77; S, 5.89 Ethyl 4-methyl-2-(4-((2-methyl-6-(4-methyl-2-phenylpiperazin-1-yl) pyrimidin-4-yl) oxy) phenyl) thiazole-5-carboxylate (P10, C 29 H 31 N 5 O 3 S) White solid, mp: 178–180 °C: FT-IR (υ max cm -1 ): 2996 str. (–C–H), 1712 str. (ester -C=O), 1014 bend. (ether -C-O-C); 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm); 8.00 - 7.98 (d, J= 7.9, 2H, H-Ar), 7.52 – 7.49 (m, 2H, H-Ar), 7.27 – 7.16 (m, 5H, H-Ar), 5.75 (s, 1H, pyrimidine, H-C), 4.51-49 (dd, J = 5.4, 4.6 Hz, 1H), 4.38-4.34 (q, J = 6.3 Hz, 2H, -CH 2 ), 3.97 - 3.94 (dd, J = 6.0, 4.3 Hz, 2H, -CH 2 ), 3.31-3.24 (m, 2H, -CH 2 ), 3.23-3.19 (m, 2H, -CH 2 ) 2.78 (s, 3H), 2.47 (s, 3H), 2.35 (s, 3H), 1.38 (t, J = 6.4 Hz, 3H): 13 C-NMR (125 MHz, CDCl 3 ) δ(ppm); 169.11, 168.11, 167.62, 166.34, 163.65, 155.99, 155.07, 142.66, 130.11, 129.40, 128.76, 128.28, 127.83, 126.56, 126.43, 125.99, 125.77, 122.73, 121.24, 83.02, 61.18, 61.04, 55.23, 53.10, 44.52, 43.60, 25.52, 17.65, 14.32: ESI-MS: m/z: 530.20 [ M +H]: Calculated % : C 29 H 31 N 5 O 3 S: C, 65.76; H, 5.90; N, 13.22; S, 6.05; Found %: C, 65.78; H, 5.95; N, 13.20; S, 6.01. Ethyl 2-(4-((6-(4-(tert-butoxy carbonyl) piperazin-1-yl)-2-methylpyrimidin-4-yl) oxy) phenyl)-4-methylthiazole-5-carboxylate (P11, C 27 H 33 N 5 O 5 S) White solid, mp: 168–169 °C: FT-IR (υ max cm -1 ): 3012 str. (–C–H), 1723 str. (ester -C=O), 1714 str. (ester -C=O) 1010 bend. (ether -C-O-C); 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm); 8.02–7.97 (m, 2H, H-Ar), 7.25 – 7.22 (m, 2H, H-Ar), 5.78 (s, 1H,pyrimidine H-C), 4.37 – 4.33 (q, J=6.4 Hz, 2H,-CH 2 ), 3.67-3.61 (m, 4H,-CH 2 ), 3.55-3.50 (m, 4H,-CH 2 ), 2.75 (s, 3H,-CH 3 ), 2.44 (s, 3H,-CH 3 ), 1.46 (s, 9H, -CH 3 ), 1.38 (t, J = 6.3 Hz, 3H,-CH 3 ): 13 C-NMR (125 MHz, CDCl 3 ) δ(ppm); 169.11, 168.26, 167.02, 165.42, 164.21, 158.05, 155.49, 154.07, 129.26, 128.48, 126.56, 125.07, 121.67, 84.44, 82.81, 61.54, 47.57, 43.10, 30.27, 25.94, 17.72, 14.31: ESI-MS: m/z: 540.15 [ M + H]: Calculated % : C 27 H 33 N 5 O 5 S: C, 60.09; H, 6.16; N, 12.98; S, 5.94; found: C, 60.02; H, 6.18; N, 12.92; S, 5.99 Ethyl 4-methyl-2-(4-((2-methyl-6-morpholinopyrimidin-4-yl) oxy) phenyl) thiazole-5-carboxylate (P12, C 22 H 24 N 4 O 4 S) White solid, mp: 157–159 °C: FT-IR (υ max cm -1 ): 2995 str. (–C–H), 1710 str. (ester -C=O), 1010 bend. (ether -C-O-C); 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm); 8.00–7.95 (m, 2H, H-Ar), 7.27 – 7.24 (m, 2H, H-Ar), 5.89 (s, 1H,pyrimidine H-C), 4.38 – 4.34 (q, J = 6.4 Hz, 2H,-CH 2 ), 3.93-3.86 (m, 4H,-CH 2 ), 3.60- 3.58 (m, 4H,-CH 2 ), 2.76 (s, 3H,-CH 3 ), 2.45 (s, 3H,-CH 3 ), 1.39 (t, J = 6.3 Hz, 3H,-CH 3 ): 13 C-NMR (125 MHz, CDCl 3 ) δ(ppm); 169.53, 167.76, 165.14, 164.36, 162.58, 156.13, 155.49, 129.26, 128.62, 127.77, 125.57, 121.10, 83.45, 64.94, 64.80, 61.75, 47.57, 47.36, 25.66, 17.43, 14.17: ESI-MS: m/z 441.10 [ M +H] : Calculated %: C 22 H 24 N 4 O 4 S: C, 59.98; H, 5.49; N, 12.72; S, 7.28; Found %: C, 59.93; H, 5.59; N, 12.77; S, 7.38 Ethyl 4-methyl-2-(4-((2-methyl-6-(4-phenylpiperazin-1-yl) pyrimidin-4-yl) oxy) phenyl) thiazole-5-carboxylate (P13, C 28 H 29 N 5 O 3 S) White solid, mp: 177–179 °C: FT-IR (υ max cm -1 ): 3090 str. (–C–H), 1720 str. (ester -C=O), 1020 bend. (ether -C-O-C); 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm); 8.02 – 7.98 (dd, J= 8.0, 1.3, 2H, H-Ar), 7.36- 7.34 (tt, J = 8.6, 1.3 Hz, 2H), 7.27 – 7.23 (m, 2H, H-Ar), 7.14 – 7.10 (m, 3H, H-Ar), 5.72 (s, 1H,pyrimidine H-C), 4.41-4.37 (q, J = 6.4 Hz, 2H, -CH 2 ), 4.26 – 4.17 (m, 4H, -CH 2 ), 3.90 – 3.82 (m, 4H, -CH 2 ), 2.74 (s, 3H, -CH 3 ), 2.38 (s,3H, -CH 3 ), 1.40 (t, J = 6.4 Hz, 3H, -CH 3 ): 13 C-NMR (125 MHz, CDCl 3 ) δ(ppm); 169.67, 168.68, 165.56, 163.79, 162.80, 156.41, 155.35, 149.32, 129.68, 129.11, 128.33, 126.99, 126.42, 125.22, 121.53, 121.24, 118.48, 118.27, 83.17, 61.75, 46.37, 46.08, 44.45, 25.66, 16.23, 14.31: ESI-MS: m/z: 516.15 [ M + H] ;Calculated %: C 28 H 29 N 5 O 3 S: C, 65.22; H, 5.67; N, 13.58; S, 6.22; Found % : C, 65.21; H, 5.64; N, 13.59; S, 6.21 Ethyl 2-(4-((6-(4-ethylpiperazin-1-yl)-2-methylpyrimidin-4-yl) oxy) phenyl)-4-methylthiazole-5-carboxylate (P14, C 24 H 29 N 5 O 3 S) White solid, mp: 161–163 °C: FT-IR (υ max cm -1 ): 3030 str. (–C–H), 1720 str. (ester -C=O), 1020 bend. (ether -C-O-C); 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm); 7.97-7.93 (ddd, J = 9.1, 8.2, 1.6 Hz, 2H, H-Ar), 7.26 – 7.24 (m, 2H, H-Ar), 5.70 (s, 1H,pyrimidine H-C), 4.38-4.34 (q, J = 6.4 Hz, 2H, -CH 2 ), 3.73 – 3.63 (m, 4H, -CH 2 ), 2.96 – 2.88 (m, 4H, -CH 2 ), 2.73 (s, 3H, -CH 3 ), 2.51-2.47 (q, J = 7.0 Hz, 2H, -CH 3 ), 2.40 (s, 3H, -CH 3 ), 1.39-1.37 (t, J = 6.3 Hz, 3H, -CH 3 ), 1.16- 1.13 (t, J = 7.0 Hz, 3H, -CH 3 ) : 13 C-NMR (125 MHz, CDCl 3 ) δ(ppm); 169.46, 168.11, 164.41, 164.00, 163.39, 156.20, 155.35, 128.90, 128.28, 128.27, 125.14, 121.60, 83.80, 61.68, 52.60, 51.97, 44.10, 25.73, 16.02, 14.38, 12.19: ESI-MS: m/z 468.25 [ M + H] : Calculate %: C 24 H 29 N 5 O 3 S: C, 1.65; H, 6.25; N, 14.98; S, 6.86; Found %: C, 61.63; H, 6.28; N, 14.92; S, 6.89 Ethyl 4-methyl-2-(4-((2-methyl-6-(4-methylpiperazin-1-yl) pyrimidin-4-yl) oxy) phenyl) thiazole-5-carboxylate (P15, C 23 H 27 N 5 O 3 S) White solid, mp: 158–160 °C: FT-IR (υ max cm -1 ): 3010 str. (–C–H), 1713 str. (ester -C=O), 1010 bend. (ether -C-O-C); 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm); 7.95–7.93 (m, 3H, H-Ar), 7.26 – 7.22 (m, 2H, H-Ar), 5.76 (s, 1H,pyrimidine H-C), 4.36 – 4.32 (q, J=6.4 Hz, 2H,-CH 2 ), 3.79- 3.70 (m, 4H,-CH 2 ), 3.01 (s, 3H, -CH 3 ), 2.72 (s, 3H,-CH 3 ), 2.52-2.44 (m, 4H,-CH 2 ), 2.36 (s, 3H,-CH 3 ), 1.40 (t, J = 6.3 Hz, 3H,-CH 3 ): 13 C-NMR (125 MHz, CDCl 3 ) δ(ppm); 166.93, 166.71, 164.41, 163.40, 161.85, 157.68, 156.90, 128.28, 127.69, 125.77, 120.52, 83.59, 61.14, 54.44, 46.16, 45.04, 25.04, 16.85, 14.29: ESI-MS: m/z 454.21 [ M + H]; Calculated %: C 23 H 27 N 5 O 3 S: C, 60.91; H, 6.00; N, 15.44; S, 7.07; Found %: C, 60.93; H, 6.04; N, 15.47; S, 7.10. In vitro α-amylase inhibitory screening The in vitro porcine pancreatic α-amylase inhibitory test was carried out using our previously reported investigation. To prepare samples with 50, 100, 150, and 200 μg/mL concentrations, the synthesized thiazole-pyrimidine hybrids ( P1 to P15 ) were dissolved in DMSO. Ten minutes were spent at 25°C incubating 200 μL of the sample with 200 μL of the α-amylase solution (100 mg in 100 mL of sodium phosphate buffer pH 7). The mixture was then incubated at 25 °C for 10 minutes with 200 μL of starch solution (1 g of starch in 100 mL of deionized water), 200 μg/mL of 5-dinitro salicylic acid (DNSA), a colouring agent, was added, to halt the reaction. The vials were heated in a water bath for 10 minutes, allowed to cool to room temperature, and then diluted with 10 mL of distilled water before the absorbance was measured in a UV-visible spectrometer. Using formula 1 and IC 50 values obtained by the standard curve approach, the percentage of inhibition utilized to quantify the α-amylase inhibitory activity was calculated and expressed in μg/ml in Table 1 and Figure 3 . [13, 14, 39] Where B sample is the absorbance of the sample at different concentrations and A blank is the control absorbance. In silico studies Quantum chemical parameters calculation The density functional theory (DFT) approach was used for thiazole-pyrimidine hybrids ( P1 to P15 ).[40, 41] DFT was used to solve the Schrödinger equation for the N-electron system. Density functional theory (DFT) can be used to understand the thermodynamic parameters, the energy of the highest occupied molecular orbital (HOMO), and the energy of the lowest unoccupied molecular orbital (LUMO).[42] Additionally, several physiochemical descriptors were computed using the HOMO and LUMO energies. These explanations aid in our comprehension of the molecule's electron distribution and acceptance patterns. The following method was used for B3LYP/6-311 G (d, p) used the basis set to compute the optimization. The GAUSSIAN 09 W program was utilized to do the computations. Table 2 shows all the quantum chemical parameters for FMOs.[14] Ligand preparation To minimize energy, this work used Gaussian 09 to sketch 3D structures for the novel thiazole-pyrimidine hybrids ( P1 to P15 ). The PDB file format was utilized to convert all minimized structures before doing molecular docking research.[43] Receptor preparation The protein with the X-ray crystal structure, procaine pancreatic α-amylase isoenzyme II (PPAII) complexed with nitrite and acarbose (PDB ID:1OSE), was obtained at a resolution of 2.30 Å from the RCSB protein data bank PDB (http://www.rcsb.org/pdb). With Discovery Studio Visualizer 2021, the protein target's water molecules, ions, heteroatoms, and other ligands were eliminated. The protein target's downloaded structure was transformed into PDB format to facilitate molecular docking studies.[14, 17–19] Molecular Docking Compounds were docked against PPAII (PDB ID: 1OSE) in silico molecular docking studies. The docking scoring function was carried out using Auto Dock 1.5.7 docking software, flexible-ligand rigid-receptor docking was carried out, and precise docking conditions were chosen by using the redocking protocol. To dock ligands into active protein sites and determine the binding affinities of the docked molecules, the interactions were examined. Auto Dock 1.5.7 was used to create the grid for the studies. The grid on the protein 1OSE's ligand-binding site was centred at X:32.480, Y:42.610, and Z: -2.309, with three dimensions of 0.375 Å and a size of 40 x 40 x 40 Å each. The protein's exhaustiveness value was established at 24. [14, 44] Molecular Dynamics (MD) Simulation PDB ID: 1OSE shows the optimal docking position of the interesting chemicals P2, P3 , and P6 associated with the porcine pancreatic α-amylase isoenzyme II (PPAII). MC Schrödinger Desmond MD simulation software was used to evaluate the simulation. It was set up on a Z4 HP workstation running Ubuntu 22.04.2 LTS 64-bit, equipped with an Intel Xeon W-2245 @ 3.90 GHz processor, 8 cores, CUDA 12, and an NVIDIA RTX A4000 graphics processing unit. The OPLS3e force field and the SPC solvation model were used in the MD simulations, and the previously published protocols were adhered to during the simulation and other experimental stages. The simulation lasted 100 nanoseconds, during which time the trajectory was captured once per 100 picoseconds. Desmond's Simulation Interaction Diagram was used to evaluate the stability and binding orientation of the ligand using MD trajectory data.[14, 45–47] ADMET studies Lipinski's rule of five was used in the proposed novel thiazole-pyrimidine hybrids ( P1 to P15 ) to decide which ones need more study before the proposal. 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Appl Biochem Biotechnol. https://doi.org/10.1007/s12010-023-04731-3 Channabasappa V, Kumara K, Kariyappa Ak (2021) Design, synthesis of coumarin tethered 1,2,3-triazoles analogues, evaluation of their antimicrobial and α-amylase inhibition activities. Journal of Chemical Sciences 133:130. https://doi.org/10.1007/s12039-021-01997-0 Şahin İ, Çeşme M, Yüce N, Tümer F (2023) Discovery of new 1,4-disubstituted 1,2,3-triazoles: in silico ADME profiling, molecular docking and biological evaluation studies. J Biomol Struct Dyn 41:1988–2001. https://doi.org/10.1080/07391102.2022.2025905 Sicak Y (2021) Design and antiproliferative and antioxidant activities of furan-based thiosemicarbazides and 1,2,4-triazoles: their structure-activity relationship and SwissADME predictions. 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Research on Chemical Intermediates 47:1139–1160. https://doi.org/10.1007/s11164-020-04321-6 Naik CG, Malik GM, Parekh HM (2019) Novel coumarin derivatives: Synthesis, characterization and antimicrobial activity. South African Journal of Chemistry 72:248–252. https://doi.org/10.17159/0379-4350/2019/V72A32 Kilaru RB, Valasani KR, Yellapu NK, et al (2014) Design, synthesis, in silico and in vitro studies of novel 4-methylthiazole-5-carboxylic acid derivatives as potent anti-cancer agents. Bioorg Med Chem Lett 24:4580–4585. https://doi.org/10.1016/j.bmcl.2014.07.058 Badvel S, Tummaluru VR, Katta VR, et al (2015) Synthesis, characterization and antimicrobial activities of amide derivatives of febuxostat intermediate. Organic Communications 8:43–51 Zhou S, Xu D, Wang Z, et al (2014) An Efficient and Convenient Synthesis of 4,6-Dichloro-2-methyl-5-nitropy. 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J Biomol Struct Dyn 40:6308–6329. https://doi.org/10.1080/07391102.2021.1882340 Kamble AA, Kamble RR, Chougala LS, et al (2017) Photophysical, Electrochemical Studies of Novel Pyrazol‐4‐yl‐2,3‐dihydroquinazolin‐4(1 H )‐ones and Their Anticancer Activity. ChemistrySelect 2:6882–6890. https://doi.org/10.1002/slct.201700498 Sherashiya MJ, Kanjariya DC, Naliapara YT, Jauhari S (2024) Greener and Highly Efficient Synthesis, In Silico ADMET and Molecular Docking Studies of Potent Antimicrobial Thiophene Clubbed Pyrazole‐1,2,3‐Triazole Hybrids. ChemistrySelect 9:. https://doi.org/10.1002/slct.202304017 Jadhav NC, Pahelkar AR, Desai N V., Telvekar VN (2017) Design, synthesis and molecular docking study of novel pyrrole-based α-amylase and α-glucosidase inhibitors. Medicinal Chemistry Research 26:2675–2691. https://doi.org/10.1007/s00044-017-1965-z El Bakri Y, Karthikeyan S, Lai C-H, et al (2024) New tetrahydroisoquinoline-4-carbonitrile derivatives as potent agents against cyclin-dependent kinases, crystal structures, and computational studies. J Biomol Struct Dyn 42:5053–5071. https://doi.org/10.1080/07391102.2023.2224899 Maliyakkal N, Ahmad I, Kumar S, et al (2023) A structural approach to investigate halogen substituted MAO-B inhibitors using QSAR modeling, molecular dynamics, and conceptual DFT analysis. Journal of Saudi Chemical Society 27:101675. https://doi.org/10.1016/j.jscs.2023.101675 Naik HN, Kanjariya D, Parveen S, et al (2024) Dalbergia sissoo phytochemicals as EGFR inhibitors: an in vitro and in silico approach. J Biomol Struct Dyn 42:5415–5427. https://doi.org/10.1080/07391102.2023.2229437 Bhujbal SP, Keretsu S, Cho SJ (2021) Molecular Modelling Studies on Pyrazole Derivatives for the Design of Potent Rearranged during Transfection Kinase Inhibitors. Molecules 26:691. https://doi.org/10.3390/molecules26030691. Channa Basappa V, Hamse Kameshwar V, Kumara K, et al (2020) Design and synthesis of coumarin-triazole hybrids: biocompatible anti-diabetic agents, in silico molecular docking and ADME screening. Heliyon 6:e05290. https://doi.org/10.1016/j.heliyon.2020.e05290 Vawhal PK, Jadhav SB (2022) Design, synthesis, and biological evaluation of 3-chloro-2-oxo-N-(arylcarbamoyl)-2H-1-benzopyran-6-sulfonamide derivatives as potential DPP-IV inhibitors. Int J Health Sci (Qassim) 373–392. https://doi.org/10.53730/ijhs.v6nS3.5190. Table Table 1 is available in the Supplementary Files section. Scheme Scheme 1 is available in the Supplementary Files section. Supplementary Files Table1.docx ELECTRONICSI.docx Scheme1.docx Cite Share Download PDF Status: Under Revision Version 1 posted Reviewers agreed at journal 24 Jun, 2025 Reviewers invited by journal 30 Mar, 2025 Editor assigned by journal 10 Feb, 2025 First submitted to journal 10 Feb, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5994323","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":435901875,"identity":"36371f77-283f-413f-9655-bc013826c073","order_by":0,"name":"Dilip C. Kanjariya","email":"","orcid":"","institution":"Sardar Vallabhbhai National Institute of Technology","correspondingAuthor":false,"prefix":"","firstName":"Dilip","middleName":"C.","lastName":"Kanjariya","suffix":""},{"id":435901876,"identity":"aa5f8979-a6cf-4e25-8526-099d2f5476c3","order_by":1,"name":"Hem N. 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Jauhari","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYFCCAwzMQJKHjb2x8QGIwUe0Fj6ew4cNwHqJsQekhUFOIi1NAsQgqEW+8fAz6YKaezJsEjlmlV9z7GTYGJgfPrqBR4vBgWNm0jOOFfOw8bwxuy27LRnoMDZj4xx8WhgOmEnzsCUAvZ9jdltyGzNQCw+bND4t8g3Hv0nz/ANqYcgxK5bcVk9YC8OBM2bSvG1ALRxpaYwftx0mrMXgwJlia94+oBZgIEszbjvOw8ZMwC/yM45vvM3zLcFevr2x8ePPbdX2/OzNDx/jdZjEAQSbmQdM4lMOAvwNCDbjD0KqR8EoGAWjYEQCAIWoQaxGuUnyAAAAAElFTkSuQmCC","orcid":"","institution":"Sardar Vallabhbhai National Institute of Technology","correspondingAuthor":true,"prefix":"","firstName":"Smita","middleName":"","lastName":"Jauhari","suffix":""}],"badges":[],"createdAt":"2025-02-09 20:39:43","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5994323/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5994323/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":80897041,"identity":"6ff01c07-213c-4f61-8a5a-2b3591b86090","added_by":"auto","created_at":"2025-04-18 12:21:21","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":246103,"visible":true,"origin":"","legend":"\u003cp\u003eThe concept for the design of novel thiazole-pyrimidine hybrids from well-known FDA-approved drugs bearing pyrimidine, thiazole, and 2°-amine nuclei.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5994323/v1/1db453ee25def45f4362ed41.png"},{"id":80896863,"identity":"8d22d3a6-1f0a-4388-97b8-5bf83c1f46c5","added_by":"auto","created_at":"2025-04-18 12:13:21","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":891393,"visible":true,"origin":"","legend":"\u003cp\u003eA graphical diagram of porcine pancreatic α-amylase enzyme inhibition screening of the novel thiazole-pyrimidine hybrids (\u003cstrong\u003eP1\u003c/strong\u003e to \u003cstrong\u003eP15\u003c/strong\u003e).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5994323/v1/59d586ceed0cc3754e820af8.png"},{"id":80897042,"identity":"d54271e9-8750-4d4b-ba56-44ff7c38f2d3","added_by":"auto","created_at":"2025-04-18 12:21:22","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":300912,"visible":true,"origin":"","legend":"\u003cp\u003eThe energies found in \u003cstrong\u003eA)\u003c/strong\u003e \u003cstrong\u003eP2\u003c/strong\u003e, \u003cstrong\u003eB)\u003c/strong\u003e \u003cstrong\u003eP3\u003c/strong\u003e, and \u003cstrong\u003eC)\u003c/strong\u003e \u003cstrong\u003eP6’\u003c/strong\u003es HOMO and LUMO orbits and optimized geometry.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5994323/v1/5336219b446b6432d1386a6a.png"},{"id":80896864,"identity":"9a55f621-6069-4680-b861-9c52c169e26f","added_by":"auto","created_at":"2025-04-18 12:13:22","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":599366,"visible":true,"origin":"","legend":"\u003cp\u003eResidual interaction at the active site of the porcine pancreatic α-amylase enzyme (PDB ID: 1OSE) complex with ligands \u003cstrong\u003eA)\u003c/strong\u003e \u003cstrong\u003eP2\u003c/strong\u003e, \u003cstrong\u003eB) P3\u003c/strong\u003e, and \u003cstrong\u003eC) P6 \u003c/strong\u003ein 2D and 3D.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5994323/v1/da7c7ddd6a2c2a894748e7d4.png"},{"id":80897043,"identity":"e82e32b5-4d1f-4a9f-9715-2d391fd2444b","added_by":"auto","created_at":"2025-04-18 12:21:22","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":407773,"visible":true,"origin":"","legend":"\u003cp\u003eMD simulation analysis \u003cstrong\u003eP2_\u003c/strong\u003e1OSE Complex (blue), \u003cstrong\u003eP3\u003c/strong\u003e_1OSE Complex(red), and \u003cstrong\u003eP6\u003c/strong\u003e_1OSE Complex(green); \u003cstrong\u003eA)\u003c/strong\u003e Time-dependent protein Cα atoms RMSD; \u003cstrong\u003eB)\u003c/strong\u003eProtein individual amino acid RMSF; \u003cstrong\u003eC)\u003c/strong\u003e Radius of gyration analysis data obtained from MD trajectory; \u003cstrong\u003eD)\u003c/strong\u003e Time-dependent Hydrogen bond analysis showing the atom or residue number, and the y-axis indicating the RMSF value in angstroms (Å).\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-5994323/v1/ee75a24e70932641fc2ae95b.png"},{"id":80897672,"identity":"041198c9-29b5-4557-9a3c-f83f5b543208","added_by":"auto","created_at":"2025-04-18 12:29:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4870128,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5994323/v1/05518835-8a8a-4c6d-8ec4-88a003211040.pdf"},{"id":80896858,"identity":"b4a1c640-885e-4585-ae24-8218db38db5e","added_by":"auto","created_at":"2025-04-18 12:13:21","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":65743,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5994323/v1/913185ff5c3e57b35715f65e.docx"},{"id":80896868,"identity":"a075a3c5-5a74-474b-861c-2112c7161bbf","added_by":"auto","created_at":"2025-04-18 12:13:23","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":69543264,"visible":true,"origin":"","legend":"","description":"","filename":"ELECTRONICSI.docx","url":"https://assets-eu.researchsquare.com/files/rs-5994323/v1/bc9e534d560d77ead65baa2c.docx"},{"id":80896862,"identity":"b4c1fe56-84ee-4ad5-9beb-4ae5618190ec","added_by":"auto","created_at":"2025-04-18 12:13:21","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":28880,"visible":true,"origin":"","legend":"","description":"","filename":"Scheme1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5994323/v1/e2238f509da9a892c37ffe46.docx"}],"financialInterests":"","formattedTitle":"An ultrasound-assisted synthesis of novel Thiazole-pyrimidine hybrids: in-vitro PPA enzyme inhibition, DFT analysis, Molecular docking, MD simulation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHeterocyclic compounds are important in the domain of naturally occurring and physiologically active chemicals. Heterocyclic units are found in many natural products and bioactive chemicals, such as vitamins, antibiotics, and alkaloids. [1] Heterocycles are thought to be present in more than 85% of compounds with biological activity. These substances are used in agriculture, medicine, and even the synthesis of polymers. For example, nitrogen-containing heterocycles such as piperazines are found in medicinal compounds used to treat malaria, ulcers, and cancer. The basic parent backbone of many biologically active pharmaceutical and naturally occurring substances is a nitrogen heterocyclic structure. [1\u0026ndash;4]\u003csup\u003e\u0026nbsp;\u003c/sup\u003eThe unique function, low toxicity, and quick intracellular absorption of nitrogen-containing heterocycles make them common in medications, pesticides, dyes, and other products. They are also commonly present in living organisms\u0026apos; metabolites. Additionally, aminopyrimidines are helpful heterocyclic nuclei for creating physiologically important chemicals and pharmacological medications (some noteworthy examples include vitamin B-1, thiamine, and cytosine).\u0026nbsp;The skeleton of some well-known synthetic medicinal products, such as the pyrimidine, thiazole, piperidine, and piperazine nuclei, is one example of the structural framework of these materials, which can be readily modified to create biologically active substances or organic functional materials. \u003cstrong\u003e(Figure 1).\u003c/strong\u003e [3, 5, 6]\u003c/p\u003e\n\u003cp\u003eNew, strong, broad-spectrum medications are still required because glycaemic control pharmacotherapy is now insufficient. To improve efficacy while reducing side effects, multi-target therapies for type 2 diabetes are being developed more frequently as a result of developments in pathophysiology, pharmacology, and molecular biology. Type 2 diabetes mellitus (T2DM) is characterised by either insufficient insulin production by the pancreas or insulin resistance, which is the inactivation of certain proteins involved in the insulin signalling cascade. Blood glucose levels are lowered by this chronic metabolic disorder, which also has a detrimental effect on people\u0026apos;s quality of life everywhere.[7, 8] Porcine and human pancreatic \u0026alpha;-amylase enzymes were 87.1% similar in sequence alignment, score similarity, matching residues, and conserved regions studies, according to bioinformatics homology. The amino acid sequences of both \u0026alpha;-amylase enzymes are often retained in humans and pigs because they carry out the same biological activity during digestion, namely, breaking down complex carbohydrates (starches) into simpler sugars like glucose and maltose. Because of their conservation of function, the amino acid sequences of these enzymes often share similarities. The general structure of \u0026alpha;-amylase is maintained in all animals, including pigs and humans.[9] The active site for the hydrolysis of carbohydrates is located within its catalytic domain. In certain aspects, the \u0026alpha;-amylase enzyme types seen in pigs and humans are very similar. These regions determine the enzyme\u0026apos;s catalytic activity and substrate binding. Although the amino acid sequences of pig and human \u0026alpha;-amylases differ greatly due to their evolutionary histories, they share the same structure and function. Because of the preservation of crucial functional domains, they can perform the same enzymatic role in the digestion of carbohydrates.[10] \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe continued our effort towards developing novel PPA inhibitors interested in creating thiazole-pyrimidine hybrids using inexpensive, readily accessible 4,6-dichloro-2-methylpyrimidine. High regioselectivity, high yields, and experimental simplicity are the desired qualities of this synthesis, and its effectiveness as an \u003cem\u003ein vitro\u0026nbsp;\u003c/em\u003eand \u003cem\u003ein silico\u003c/em\u003e inhibition of porcine pancreatic \u0026alpha;-amylase (PPA) is being studied. \u0026nbsp;it is easily accessible as a meat industry byproduct. Assays are straightforward and reasonably priced. Using porcine enzymes avoids ethical concerns associated with sourcing human enzymes and simplifies regulatory compliance. About 80\u0026ndash;85% of the amino acid sequences of PPA and human pancreatic alpha-amylase are identical. It is a dependable model for research about human digestion because of the highly conserved catalytic residues and active site shape. PPA\u0026apos;s application in computational modeling and structure-function studies is supported by its well-characterized crystal structure, which is available in the Protein Data Bank (PDB ID: 1OSE).\u003c/p\u003e"},{"header":"Results and Discussion","content":"\u003cp\u003e\u003cstrong\u003eChemistry\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSynthesis of the novel thiazole-pyrimidine hybrids steps listed in \u003cstrong\u003eScheme 1\u003c/strong\u003e were utilized. Using the method previously described, the first step involves cyclizing 4-hydroxythiobenzamide \u003cstrong\u003e(1)\u003c/strong\u003e with 2-chloroacetoacetic acid ethyl ester \u003cstrong\u003e(2)\u003c/strong\u003e in refluxing ethanol to produce 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester \u003cstrong\u003e(3)\u003c/strong\u003e. After that 4,6-dihydroxy-2-methyl pyrimidine \u003cstrong\u003e(6)\u003c/strong\u003e was synthesized from the starting compound acetimidamide \u003cstrong\u003e(4)\u003c/strong\u003e and diethyl malonate \u003cstrong\u003e(5)\u003c/strong\u003e in the presence of sodium ethoxide [20]. Phosphoryl chloride replaced hydroxyl groups in hydroxyl groups in 4,6-dihydroxy-2-methyl pyrimidine \u003cstrong\u003e(6)\u003c/strong\u003e with chlorine to form a compound 4,6-dichloro-2-methylpyrimidine \u003cstrong\u003e(7)\u003c/strong\u003e. 4,6-dichloro-2-methylpyrimidine \u003cstrong\u003e(7)\u003c/strong\u003e and compound 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester \u003cstrong\u003e(3)\u003c/strong\u003e dissolved in DMF; the presence of potassium carbonate then reacted to form a compound ethyl 2- (4-( (6-chloro-2-methylpyrimidin-4-yl) oxy) phenyl) -4-methylthiazole-5-carboxylate \u003cstrong\u003e(8)\u003c/strong\u003e. The last step entailed replacing with 2\u0026deg;-amine derivatives (piperazine/piperidine/morpholine) for the residual chlorine in compound ethyl 2-(4-((6-chloro-2-methylpyrimidin-4-yl) oxy) phenyl)-4-methylthiazole-5-carboxylate \u003cstrong\u003e(8)\u003c/strong\u003e to obtain the final compounds (\u003cstrong\u003eP1\u0026nbsp;\u003c/strong\u003eto\u003cstrong\u003e\u0026nbsp;P15\u003c/strong\u003e). yields utilizing the conventional method to the Ultra-sound approach specified in \u003cstrong\u003eTable 1\u003c/strong\u003e and characterized by ATR-FTIR, \u003csup\u003e1\u003c/sup\u003eH-NMR, \u003csup\u003e13\u003c/sup\u003eC-NMR, and mass spectrometry, as detailed in the supplemental section.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBiology\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFurthermore, it is noteworthy that porcine and human pancreatic \u0026alpha;-amylase share similar biological functions and feature active site amino acids. Porcine pancreatic \u0026alpha;-amylase is a widely used target to investigate the antidiabetic potential of compounds. Additionally, we looked at the potential \u003cem\u003ein vitro\u003c/em\u003e antidiabetic properties against porcine pancreatic \u0026alpha;-amylase enzyme inhibition for the novel thiazole-pyrimidine hybrids (\u003cstrong\u003eP1\u0026nbsp;\u003c/strong\u003eto\u003cstrong\u003e\u0026nbsp;P15\u003c/strong\u003e). Hence, for our \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein silico\u003c/em\u003e investigations, we employed the porcine pancreatic \u0026alpha;-amylase protein denoted as PDB ID:1OSE. [11\u0026ndash;16]According to \u003cstrong\u003eTable 1\u003c/strong\u003e, The range of IC\u003csub\u003e50\u003c/sub\u003e values for the novel thiazole-pyrimidine hybrids (\u003cstrong\u003eP1\u0026nbsp;\u003c/strong\u003eto\u003cstrong\u003e\u0026nbsp;P15\u003c/strong\u003e) is 0.33\u0026nbsp;mM\u0026nbsp;to 0.73 mM\u0026nbsp;observed compared to acarbose obtaining antagonistic efficiency at IC\u003csub\u003e50\u0026nbsp;\u003c/sub\u003evalue\u003csub\u003e\u0026nbsp;\u003c/sub\u003eof\u003csub\u003e\u0026nbsp;\u003c/sub\u003e0.34 mM. Among all compounds, good inhibition was shown by \u003cstrong\u003eP3, P2,\u003c/strong\u003e and \u003cstrong\u003eP6\u003c/strong\u003e against porcine pancreatic \u0026alpha;-amylase with IC\u003csub\u003e50\u0026nbsp;\u003c/sub\u003evalues of 0.33 mM, 0.37 mM, and 0.39 mM respectively. \u003cstrong\u003eFigure 2\u0026nbsp;\u003c/strong\u003eindicates results imply that it has been good to moderate inhibitory effect against porcine pancreatic \u0026alpha;-amylase\u0026nbsp;enzymes involved in the digestion of carbohydrates.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDFT study\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFrontier Molecular Orbitals play a major role in the electrical configuration and are frequently used to assess the chemical reactivity of novel thiazole-pyrimidine hybrids. The \u0026Delta;E gap (eV), chemical hardness, chemical potential, electronegativity, and electrophilicity shown in \u003cstrong\u003eTable 2\u003c/strong\u003e may be calculated using the HOMO-LUMO orbital energies. \u0026nbsp;To be more precise, a molecule that has a greater E\u003csub\u003eHOMO\u003c/sub\u003e tends to be closer to electrophiles and is an improved electron donor. The opposite is also true; a molecule with a lower E\u003csub\u003eLUMO\u003c/sub\u003e is more of an electron acceptor and attracts nucleophiles more strongly.[14]. Particularly annoyed to compare with molecules \u003cstrong\u003eP4, P7, P10,\u0026nbsp;\u003c/strong\u003eand\u003cstrong\u003e\u0026nbsp;P9\u003c/strong\u003e having small energy gaps that are more leading and polarizable and have strong chemical reactivity and low kinetic stability, larger HOMO-LUMO energy gaps (\u003cstrong\u003eP2, P5, P11,\u0026nbsp;\u003c/strong\u003eand\u003cstrong\u003e\u0026nbsp;P12\u003c/strong\u003e) molecules are typically stable with low chemical reactivity. Thus, it is clear from \u003cstrong\u003eTable 2\u003c/strong\u003e that compounds \u003cstrong\u003eP7\u003c/strong\u003e and \u003cstrong\u003eP4\u003c/strong\u003e are hard and more stable (less reactive), while compounds \u003cstrong\u003eP12, P11,\u0026nbsp;\u003c/strong\u003eand\u003cstrong\u003e\u0026nbsp;P5\u003c/strong\u003e are soft and the least stable (more reactive). Compounds \u003cstrong\u003eP1\u0026cedil; P3, P6, P8, P13, P14,\u0026nbsp;\u003c/strong\u003eand \u003cstrong\u003eP15\u003c/strong\u003e are the medium compared to others. Compounds with greater chemical potential values (\u0026mu;) are more reactive than those with small electronic chemical potentials. According to chemical potential (\u0026mu;) the compounds also \u003cstrong\u003eP4\u0026nbsp;\u003c/strong\u003eand\u003cstrong\u003e\u0026nbsp;P7\u003c/strong\u003e promise greater chemical potential for the reactivity than the others. The surfaces and the variations between the energies of the orbital of the FMO (HOMO, LUMO) were obtained from the Density Functional Theory. \u003cstrong\u003eFigures 3\u0026nbsp;\u003c/strong\u003eshow the HOMO-LUMO energy gap graphs and optimized geometry respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Calculated quantum chemical parameters for the novel thiazole-pyrimidine hybrids (\u003cstrong\u003eP1\u0026nbsp;\u003c/strong\u003eto\u003cstrong\u003e\u0026nbsp;P15\u003c/strong\u003e) under investigation.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHybrids\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e(a.u.)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eE\u003csub\u003eHOMO\u0026nbsp;\u003c/sub\u003e(eV)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e(eV)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e(eV)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e[\u0026mu;=(E\u003csub\u003eHOMO\u003c/sub\u003e+E\u003csub\u003eLUMO\u003c/sub\u003e)/2]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChemical\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ehardness\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[\u0026eta;=(E\u003csub\u003eLUMO\u003c/sub\u003e-E\u003csub\u003eHOMO\u003c/sub\u003e)/2]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e[\u0026omega; = \u0026mu;2/(2\u0026eta;)]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDipole moment (Debye)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-2901.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.2197\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.0783\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.141\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e-0.149\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.070\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.157\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e3.5557\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-2712.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.2212\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.0744\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.147\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e-0.147\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.073\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.148\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e2.8889\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-2649.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.2212\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.0822\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.139\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e-0.151\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.069\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.165\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e3.2609\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-2097.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.1955\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.0736\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.121\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e-0.134\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.060\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.148\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e3.4561\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-2005.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.2221\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.0752\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.147\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e-0.148\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.073\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e7.6452\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-2252.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.2142\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.0737\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.141\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e-0.143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.070\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.147\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e3.0578\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-2097.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.1914\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.0767\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e-0.134\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.057\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.156\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e6.2300\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-1814.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.2189\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.0731\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e-0.146\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.072\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.146\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e3.6343\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-2442.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.2117\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.0784\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.133\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e-0.145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.066\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.157\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e5.4741\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-2021.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.2052\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.0762\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.129\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e-0.140\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.064\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.153\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e6.9569\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-2097.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.2230\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.0751\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.147\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e-0.149\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.073\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e2.0406\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-1771.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.2259\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.0772\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.148\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e-0.151\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.074\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.154\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e5.7591\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP13\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-1982.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.2139\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.0769\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.137\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e-0.145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.068\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.154\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e6.2126\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP14\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-1830.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.2131\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.0761\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.137\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e-0.144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.068\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.152\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e6.9178\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-1790.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.2121\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e-0.0761\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.136\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e-0.144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.068\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.152\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e7.4950\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eMolecular Docking\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo determine the mechanisms of interaction, the strongest molecules found in the active sites of the enzymes according to the study were molecular docked using Auto Dock Tools (1.5.7). The method used to evaluate the binding affinities of ligands and receptors was molecular docking. Acarbose was redocked with its binding energies (PDB ID:1OSE, resolution: 2.30 \u0026Aring;) to ensure uniformity in the molecular docking process. The novel thiazole-pyrimidine hybrids (\u003cstrong\u003eP1\u003c/strong\u003e to \u003cstrong\u003eP15\u003c/strong\u003e) ranged from -8.7 to -10.6 kcal/mol against the porcine pancreatic \u0026alpha;-amylase protein. The docking scores of ligands \u003cstrong\u003eP2, P3,\u0026nbsp;\u003c/strong\u003eand\u003cstrong\u003e\u0026nbsp;P6\u003c/strong\u003e were -10.5, -10.6, and -10.5 kcal/mol, respectively. Ligand \u003cstrong\u003eP1\u003c/strong\u003e shown binding affinity -10.2 kcal/mol and hydrophobic interaction with Ile49, Val51, Trp59, Tyr62, Gln63, Ala107, Leu162, Val163, Ala198, while Van der Waals Interaction shown by these residue Val50, Thr52, Asn53, Trp58, His101, Gly104, Ala108, Gly112, Leu165, Asp197, His299, Asp300, His305. Ligand \u003cstrong\u003eP2\u003c/strong\u003e shown binding affinity -10.5 kcal/mol, residue from the 1OSE interacted through hydrogen bonding shown by Gly106 (2.10), Ala107 (3.01), while hydrophobic interaction with hyTrp58, Trp59, Tyr62, Val163, Lys200, His201, Ile235, His299, Ala307, Gln63, and Van der Waals interactions observed with Gly104, Ser105, Tyr151, Leu162, Gly164, Leu165, Ala198, Ser199, Asp300, Gly306. Ligand \u003cstrong\u003eP3\u003c/strong\u003e shown binding affinity -10.6 kcal/mol and hydrophobic interaction with Trp58, Trp59, Tyr62, Gly104, Leu162, Val163, Lys200, His201, Ile235, His299, Asp300, Val51, while Van der Waals Interaction shown by these residue Gln63, Ala107, Gly106, Tyr151, Leu165, Ala198, Glu233, Val234, His305, Gly306. Ligand \u003cstrong\u003eP4\u003c/strong\u003e shown binding affinity -9.7 kcal/mol when formed complex with 1OSE residue His299 (2.02), hydrophobic interaction with Ile49, Val51, Trp59, Tyr62, Gln63, Ala108, Glu233, while Van der Waals Interaction shown by these residues Val50, Trp58, His101, Gly106, Leu162, Leu165, Gly164, Asp300, His305 with 1OSE. \u0026nbsp;Ligand \u003cstrong\u003eP5\u003c/strong\u003e shown binding affinity -9.9 kcal/mol and when formed complex with 1OSE residue His299 (2.12) interacted through hydrogen bonding, while hydrophobic interaction shown by Ile49, Val51, Trp59, Tyr62, Ala107, Ala108, Val163, residue from 1OSE shown Van der Waals Interaction Val50, Thr52, Trp58, His101, Gly104, Leu162, GLy164, Leu165, Arg195, Asp197, Ala198, Glu233, Asp300. Ligand \u003cstrong\u003eP6\u003c/strong\u003e shown binding affinity -10.6 kcal/mol residue from the 1OSE interacted through hydrogen bonding shown through Gly106 (2.14), and Ala107 (2.99), while hydrophobic interaction shown by Trp58, Trp59, Tyr62, Ala107, Val163, Ala198, Lys200, His201, Glu233, Ile235, His299, His305, Ala307, while Van der Waals Interaction shown by these residue Gln63, Gly104, Ser105, Tyr151, Leu162, GLy164, Leu165, Asp300. Ligand \u003cstrong\u003eP7\u003c/strong\u003e shown binding affinity -9.9 kcal/mol and His299 (2.33) of 1OSE shown hydrogen bonding, hydrophobic interaction with Ile49, Val51, Tyr62, Ala107, Val163, while Van der Waals Interaction shown by these residue Val50, Thr52, Asn53, Gln63, Trp58 Leu165, His101, Gly104, Ala108, Gly112, Leu162, Gly164, Leu165, Asp197, Ala198, Glu233, Asp300. Ligand \u003cstrong\u003eP8\u003c/strong\u003e shown binding affinity -9.3 kcal/mol and His299 (2.10) of 1OSE shown hydrogen bonding, hydrophobic interaction with Ile49, Val51, Trp59, Tyr62, Ala107, Val163, while Van der Waals Interaction shown by these residue Asn53, Trp58, Gln63, Gly104, Gly164, Leu165, Asp197, His101, Leu162, Ala198, Arg195, Glu233, Asp300, His305. Ligand \u003cstrong\u003eP9\u003c/strong\u003e shown binding affinity -10.2 kcal/mol and hydrophobic interaction with Ile49, Val51, Ala107, Ala108, while Van der Waals Interaction shown by these residue Thr52, Asn53, Val50, Leu165, Gly104, His101, Arg195, Asp197, Ala198, Glu233. Ligand \u003cstrong\u003eP10\u003c/strong\u003e shown binding affinity -8.7 kcal/mol and hydrophobic interaction with Glu233, His305, while Van der Waals Interaction shown by these residue Leu165, ala198, Glu233, Lys200, Gly306, Arg195, Asp197, Trp357. Ligand \u003cstrong\u003eP11\u003c/strong\u003e shown binding affinity -9.2 kcal/mol formation of hydrogen bonding with PPAII Hia201 (1.89), and His305 (2.49) while other residue interacted through hydrophobic interaction with which are Trp59, Tyr62, Tyr151, Leu162, Val163, His299, Asp300, while Van der Waals Interaction shown by these residue Trp58, Asn53, Val51, Gly104, Leu165, Gln63, Ile235, Gly306, Lys200, Ala307. Ligand \u003cstrong\u003eP12\u003c/strong\u003e shown binding affinity -8.8 kcal/mol and formation of hydrogen bonding with PPAII residue with His299 (2.12), no hydrophobic interacted any residues from PPAII while Van der Waals Interaction shown by these residue Trp58, Gly164, Gly104, Gly106, Leu165, His101, Leu162, Asp197, Ala198, Glu233, Arg195, Asp300. Ligands \u003cstrong\u003eP13, P14\u0026nbsp;\u003c/strong\u003eand\u003cstrong\u003e\u0026nbsp;P15\u0026nbsp;\u003c/strong\u003eobtained binding affinity -10.0, -8.9, -8.9 kcal/mol respectively, among all these three ligands not interacted through hydrogen bonding as well as hydrophobic interaction with PPAII. only interactions happened between Van der Waals Interaction shown by these residues Val50, Thr52, Asn53, Gly104, Gly106, Gly164, Leu165, Arg195, Asp197, Glu233, Asp300 respectively. By binding the enzyme\u0026apos;s active site and mimicking natural substrates, hybrids such as \u003cstrong\u003eP2, P3\u003c/strong\u003e, and\u0026nbsp;\u003cstrong\u003eP6\u003c/strong\u003e potentially inhibit PPA by interacting with the hydrolysis of starch.\u003cbr\u003eCritical residues possess strong hydrogen-bonding and hydrophobic interactions that increase their inhibitory capability and affinity. These residues interacted similarly through H-bonds with His201, Gly306, and His305 as well as other interactions of residues are Leu162, Val163, Asp197, Ala198, Lys 200, Glu233, and Ile235 highlighted in \u003cstrong\u003eTable 3\u003c/strong\u003e. In the active site, the conformations of \u003cstrong\u003eP2, P3, P6\u003c/strong\u003e, and acarbose nearly overlapped, as \u003cstrong\u003eFigure 4 (A-C)\u003c/strong\u003e illustrates respectively others are shown in the supplementary section \u003cstrong\u003e(Figure S1-S12).\u0026nbsp;\u003c/strong\u003eA study on anti-diabetic compounds (\u003cstrong\u003eP1\u0026nbsp;\u003c/strong\u003eto\u003cstrong\u003e\u0026nbsp;P15\u003c/strong\u003e) found that compound DV-P3 had a greater inhibitory effect against the porcine pancreatic \u0026alpha;-amylase protein than the rest of the synthesized compounds. The 2D and 3D interaction between the ligands \u003cstrong\u003eP2, P3, P6\u003c/strong\u003e, and acarbose is shown in \u003cstrong\u003eFigure 4,\u0026nbsp;\u003c/strong\u003eother ligand interactions are incorporated in the supplementary file.[14, 17\u0026ndash;19]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u0026nbsp;\u003c/strong\u003eThe relevant interaction residues of the PPAII (PDB ID: 1OSE) and the novel thiazole-pyrimidine hybrids (\u003cstrong\u003eP1\u003c/strong\u003e to \u003cstrong\u003eP15\u003c/strong\u003e)\u0026rsquo;s binding affinity (kcal/mol).\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"805\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHybrid\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBinding energy kcal/mol\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[PDB ID: 1OSE]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConventional \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;H-bonding interaction (\u0026Aring;)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHydrophobic interaction\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 251px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVan der Waals Interaction\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e-10.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eIle49, Val51, Trp59, Tyr62, Gln63, Ala107, Leu162, Val163, Ala198\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 251px;\"\u003e\n \u003cp\u003eVal50, Thr52, Asn53, Trp58, His101, Gly104, Ala108, Gly112, Leu165, Asp197, His299, Asp300, His305\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e-10.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003eGly106 (2.10), Ala107 (3.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eTrp58, Trp59, Tyr62, Val163, Lys200, His201, Ile235, His299, Ala307\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 251px;\"\u003e\n \u003cp\u003eGln63, Gly104, Ser105, Tyr151, Leu162, Gly164, Leu165, Ala198, Ser199, Asp300, Gly306\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e-10.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eTrp58, Trp59, Tyr62, Gly104, Leu162, Val163, Lys200, His201, Ile235, His299, Asp300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 251px;\"\u003e\n \u003cp\u003eVal51, Gln63, Ala107, Gly106, Tyr151, Leu165, Ala198, Glu233, Val234, His305, Gly306\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e-9.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003eHis299 (2.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eIle49, Val51, Trp59, Tyr62, Gln63, Ala108, Glu233\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 251px;\"\u003e\n \u003cp\u003eVal50, Trp58, His101, Gly106, Leu162, Leu165, Gly164, Asp300, His305\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e-9.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003eHis299 (2.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eIle49, Val51, Trp59, Tyr62, Ala107, Ala108, Val163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 251px;\"\u003e\n \u003cp\u003eVal50, Thr52, Trp58, His101, Gly104, Leu162, GLy164, Leu165, Arg195, Asp197, Ala198, Glu233, Asp300\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e-10.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003eGly106 (2.14), Ala107 (2.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eTrp58, Trp59, Tyr62, Ala107, Val163, Ala198, Lys200, His201, Glu233, Ile235, His299, His305, Ala307\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 251px;\"\u003e\n \u003cp\u003eGln63, Gly104, Ser105, Tyr151, Leu162, GLy164, Leu165, Asp300\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e-9.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003eHis299 (2.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eIle49, Val51, Tyr62, Ala107, Val163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 251px;\"\u003e\n \u003cp\u003eVal50, Thr52, Asn53, Gln63, Trp58 Leu165, His101, Gly104, Ala108, Gly112, Leu162, Gly164, Leu165, Asp197, Ala198, Glu233, Asp300\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e-9.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003eHis299 (2.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eIle49, Val51, Trp59, Tyr62, Ala107, Val163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 251px;\"\u003e\n \u003cp\u003eAsn53, Trp58, Gln63, Gly104, Gly164, Leu165, Asp197, His101, Leu162, Ala198, Arg195, Glu233, Asp300, His305\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e-10.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eIle49, Val51, Ala107, Ala108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 251px;\"\u003e\n \u003cp\u003eThr52, Asn53, Val50, Leu165, Gly104, His101, Arg195, Asp197, Ala198, Glu233\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e-8.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eGlu233, His305\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 251px;\"\u003e\n \u003cp\u003eLeu165, ala198, Glu233, Lys200, Gly306, Arg195, Asp197, Trp357\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e-9.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003eHia201 (1.89), His305 (2.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eTrp59, Tyr62, Tyr151, Leu162, Val163, His299, Asp300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 251px;\"\u003e\n \u003cp\u003eTrp58, Asn53, Val51, Gly104, Leu165, Gln63, Ile235, Gly306, Lys200, Ala307\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e-8.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003eHis299 (2.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 251px;\"\u003e\n \u003cp\u003eTrp58, Gly164, Gly104, Gly106, Leu165, His101, Leu162, Asp197, Ala198, Glu233, Arg195, Asp300\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP13\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e-10.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 251px;\"\u003e\n \u003cp\u003eGly164, Gly104, Val50, Thr52, Leu165, Asn53, Asp197, Arg195, Glu233, ASP300\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP14\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e-8.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 251px;\"\u003e\n \u003cp\u003eGly164, Gly104, Gly106, Val50, Leu165, Thr52, Asp197, Arg195, Glu233, Asp300\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e-8.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 251px;\"\u003e\n \u003cp\u003eGly164, Gly104, Gly106, Leu165, Asp197, Arg195, Asp300\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAcarbose\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e-7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003eTyr62 (2.84), Gln63(2.51, 2.57, 2.92), Asp197(1.89), Ala198(2.92) Glu233(2.10), Asp300(2.99), His305(1.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eAsp300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 251px;\"\u003e\n \u003cp\u003eIle49, Val51, Trp59, His101, Gly104, Ala107, Ala108, Leu162, Val163, Leu165, Arg195, Ile235, Gly306\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\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMD Simulation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor the three top compounds found in the study, a 100 nanosecond molecular dynamics simulation was run on the ligand-protein complex. Acquiring an improved comprehension of the ligand\u0026apos;s binding to the enzyme\u0026apos;s active site was the aim of this simulation. A molecular dynamics simulation investigation was necessary to examine the stability and dynamic changes in the ligand-protein complex under a physiological condition simulation. Radius of Gyration, Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and hydrogen bond analysis are crucial parameters used in MD simulations to assess the structural and dynamic characteristics of proteins. Together, these parameters offer the foundation for evaluating the stability of protein-ligand complexes in the dynamically transforming environment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eRoot-mean-square deviation (RMSD)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe structural stability and conformational changes of a system over time can be evaluated with the use of RMSD. Significant conformational changes in the system during the simulation are indicated by high RMSD values. A low RMSD indicates that a system is stable and maintains its original conformation throughout time.[14, 20, 21]\u0026nbsp;The P2_1OSE Complex and P3_1OSE Complex RMSD values were almost constant (\u0026asymp; 2.5 \u0026Aring;) between 0 and 40 ns. Following that, these two systems\u0026apos; RMSD values progressively rose until 60 ns, at which point they converged to a steady value (Figure 4A). As opposed to this, the RMSD for the P6_1OSE Complex steadily rose until 30 ns and then held steady till the very end. The P2_1OSE Complex has moderate structural variations, as indicated by the mean RMSD value of 3.19 \u0026Aring;. With an RMSD of 3.23 \u0026Aring;, the P3_1OSE Complex similarly behaves to the P2_1OSE Complex. In comparison with the other two complexes, the P6_1OSE Complex has a little larger RMSD value of 3.55 \u0026Aring; (Figure 5A). Following an initial period of volatility, the three complexes\u0026apos; consistent RMSD values indicate that these systems eventually achieve equilibrium and retain a comparatively stable shape. Variations in the ligand conformations, binding affinities, or the intrinsic structural flexibility of the protein may be the cause of the disparities in RMSD values between the complexes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eRoot mean square fluctuation (RMSF)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn molecular dynamics (MD) simulations and structural biology, RMSF is a frequently used metric to evaluate the flexibility and fluctuations of individual atoms or groups of atoms inside a molecule or molecular complex while a simulation. RMSF sheds light on a system\u0026apos;s dynamic behaviour and is especially helpful in identifying the hard or highly flexible components of a biomolecule.[22\u0026ndash;25]\u003csup\u003e\u0026nbsp;\u003c/sup\u003eA graph with the x-axis is commonly used to display RMSF values. Significant swings are suggested by high RMSF values, whereas stability or rigidity is indicated by low values. Throughout the simulation, it became clear that some protein areas\u0026mdash;especially the loop sections\u0026mdash;showed larger amounts of variation than other protein regions. The P2_1OSE Complex, P3_1OSE Complex, and P6_1OSE Complex were found to have a number of interacting residues. The stability and behaviour of the corresponding complexes are greatly influenced by these interactions. In the \u003cstrong\u003eP2\u003c/strong\u003e_1OSE Complex, residues Ile49, Val50, Val51, Thr52, Asn53, Pro54, Trp58, Trp59, Tyr62, Gln63, His101, Cys103, Gly104, Ser105, Gly106, Ala107, Ala108, Ile148, Tyr151, Val157, Leu162, Val163, Gly164, Leu165, Asp197, Ala198, Lys200, His201, Glu233, Ile235, Leu237, Ile242, Asn298, His299, Asp300, His305, Gly306, Ala307, Glu352, Val354, Asp356, and Trp357 involved in complex interactions, suggesting a network of stabilizing contacts. \u0026nbsp;In the \u003cstrong\u003eP3\u003c/strong\u003e_1OSE Complex, Glu29, Ile49, Val50, Val51, Thr52, Asn53, Pro54, Ser55, Trp58, Trp59, Tyr62, Gln63, Asn88, His101, Met102, Cys103, Gly104, Ser105, Gly106, Ala107, Ala108, Ala109, Tyr151, Asn152, Val157, Leu162, Val163, Gly164, Leu165, Asp197, Ala198, Lys200, His201, Glu233, Ile235, Leu237, Glu240, Gln243, Ser245, Glu246, Phe248, Trp284, Gly285, Phe286, Met287, Pro288, Arg291, His299, Asp300, Arg303, His305, Gly306, Ala307, Asn347, Val349, Asn350, Val354, Asn355, Asp356, and Trp357 residues contribute to the interaction network, indicating the importance of these contacts for complex stability. \u0026nbsp; Meanwhile, the \u003cstrong\u003eP6\u003c/strong\u003e_1OSE Complex exhibits interactions involving Val51, Asn53, Pro54, Trp58, Trp59, Tyr62, Gln63, His101, Gly104, Ser105, Gly106, Ala107, Leu162, Val163, Gly164, Leu165, Arg195, Asp197, Ala198, Lys200, His201, Glu233, Val234, Ile235, Leu237, Phe256, Ala260, Asn298, His299, Asp300, His305, Gly306, Ala307, Gly308, Gly309, Ala310, Ser311, and Asp356 emphasizing their role in maintaining complex integrity. These interactions provide insight into the major contributors in these molecular connections and underline the complex and dynamic character of protein-ligand binding. The stability of P2, P3, and P6 in the 1OSE protein is demonstrated by the low RMSF values displayed by these interacting residues. The P2_1OSE Complex, P3_1OSE Complex, and P6_1OSE Complex have, on average, RMSF values of 1.18 \u0026Aring;, 1.30 \u0026Aring;, and 1.06 \u0026Aring;, respectively (\u003cstrong\u003eFigure 5B\u003c/strong\u003e). A complex with a lower average RMSF is believed to be more structurally stable and exhibits less overall variance in atomic conditions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eRadius of Gyration (RGyr)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUtilise the Radius of Gyration (RGyr) to determine the overall size and compactness of a molecule or chemical complex. It provides information about the three-dimensional distribution of atoms inside the system and is a useful tool for understanding biomolecular shape and structural changes. The RGyr value indicates the average distance between the atoms and the nucleus of mass. While a lower Rg denotes a more compact and securely folded structure, a higher RGyr denotes a more stretched or less compact structure.[26] The RGyr findings highlight the structural characteristics of the P2_1OSE Complex, _1OSE Complex, and P6_1OSE Complex. The lowest minimum RGyr value, 20.140 \u0026Aring;, is found in the P2_1OSE Complex. This implies that during the simulation, these complexes may adopt highly compact conformations, which could demonstrate structural stability in particular states. Likewise, the near-range maximum RGyr values indicate that the complexes investigate more extended or open conformations at certain points during the simulation; the P6_1OSE Complex has the highest maximum RGyr at 21.693 \u0026Aring; (\u003cstrong\u003eFigure 5C\u003c/strong\u003e). The usual compactness of the P2_1OSE Complex, P3_1OSE Complex, and P6_1OSE Complex is indicated by their respective average RGyr values of 20.97 \u0026Aring;, 21.16 \u0026Aring;, and 21.08 \u0026Aring;. All three complexes have similar structural characteristics. It is important to note that \u003cstrong\u003eFigure 5C\u003c/strong\u003e shows no frames with larger or more a typical change, suggesting that all three compounds are stable. These results show the molecule\u0026apos;s inherent flexibility, plasticity, and ability to maintain structural changes while returning to a more compact, desired form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHydrogen bond analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA hydrogen bond is a type of non-covalent contact that happens when two electronegative atoms\u0026mdash;typically oxygen, nitrogen, or fluorine\u0026mdash;share a hydrogen atom. The structural integrity of proteins during a variety of physiological processes depends on these connections. The P2_1OSE Complex, P3_1OSE Complex, and P6_1OSE Complex hydrogen bond investigations reveal differences in hydrogen bond interactions. The binding affinity has a close relationship with these interactions. Interestingly, all three complexes exhibit at least one stabilising hydrogen bond at the very least (Table 4). However, a higher binding affinity may be indicated by the P3_1OSE Complex\u0026apos;s stronger and more frequent hydrogen bond interactions. .[26, 27] \u0026nbsp;It has a maximum of three hydrogen bonds and an average of 0.63. Conversely, the P6_1OSE Complex\u0026apos;s lower average of 0.23 hydrogen bonds (Figure 5D) suggests a moderate interaction profile. In conclusion, the ligands P2, P3, and P6 show exceptional stability and strong affinity for the binding cavity of the 1OSE protein. These ligands and the protein create stable complexes, according to the combined results of the RMSD, RMSF, and hydrogen bond formation investigations; P3 exhibits a somewhat more dynamic interaction pattern.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u003c/strong\u003e The investigated complexes\u0026apos; minimum, maximum, and average values for several parameters, as well as their RMSD, RMSF, RGyr, and hydrogen bonding.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"567\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP2_1OSE Complex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP3_1OSE Complex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP6_1OSE Complex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 567px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRoot-mean-square deviation \u0026Aring; (RMSD)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eMinimum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e3.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e3.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e3.55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eMaximum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e3.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e4.21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eAverage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e3.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e3.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e3.55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 567px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRoot-mean-square fluctuation \u0026Aring; (RMSF)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eMinimum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eMaximum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e6.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e6.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e4.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eAverage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e1.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e1.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 567px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eThe radius of gyration \u0026Aring; (RGyr)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eMinimum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e20.140\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e20.300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e20.156\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eMaximum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e21.647\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e21.568\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e21.693\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eAverage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e20.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e21.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e21.08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 567px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHydrogen bonding\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eMinimum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eMaximum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e2.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e3.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e2.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eAverage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eIn silico\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;ADMET\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of the novel thiazole-pyrimidine hybrids (\u003cstrong\u003eP1 to P15\u003c/strong\u003e)\u0026apos;s in-silico ADMET profiling are displayed in Table 5. According to the Lipinski rule of five, an oral medication must have a molecular weight of less than 500 g/mol, a topological polar surface area of less than 140 \u0026Aring;2, several rotatable bonds of 0 \u0026lt; 9, -6 \u0026lt; Log S \u0026lt; 0, donor atoms of hydrogen bonds of \u0026le; 5, acceptors of hydrogen bonds of \u0026le; 10, and log P of \u0026le; 5. [28, 29] Among the new thiazole-pyrimidine hybrids (\u003cstrong\u003eP1\u0026ndash;P15\u003c/strong\u003e), \u003cstrong\u003eP8, P12, P14\u003c/strong\u003e, and \u003cstrong\u003eP15\u003c/strong\u003e had molecular weights below 500 g/mol, whereas the others had molecular weights above that. The sites at positions 6 to 8 of the new thiazole-pyrimidine hybrids (\u003cstrong\u003eP1 to P15\u003c/strong\u003e) can accept hydrogen bonds. The proposed moiety\u0026apos; total polar surface area falls within an acceptable range of 140 \u0026Aring;2, and the unique thiazole-pyrimidine hybrids (\u003cstrong\u003eP1\u003c/strong\u003e to \u003cstrong\u003eP15\u003c/strong\u003e) sequences have a log P partition coefficient value of 5. All synthetic substances have limited gastrointestinal (GI) absorption, whereas \u003cstrong\u003eP8, P10, P12, P13, P14, and P15\u003c/strong\u003e have high GI absorption. The protein permeability glycoprotein (P-gp) is essential for evaluating active efflux through biological membranes. The possibility that each of the newly synthesised thiazole-pyrimidine hybrids (\u003cstrong\u003eP1\u003c/strong\u003e to \u003cstrong\u003eP15\u003c/strong\u003e) could function as a P-gp substrate or inhibitor was thus ascertained. The egg-shaped model (\u003cstrong\u003eFigure S13\u003c/strong\u003e) displays the white portion signifying HIA (Human Intestinal Absorption) and the yellow yolk area signifying BBB penetration. Compounds with low absorption and little brain penetration are included in the grey zone. It is expected that the molecule will have the same active efflux capacity across biological membranes as P-glycoprotein (PGP). When compounds \u003cstrong\u003eP1, P4, P5, P9, P10, and P13\u003c/strong\u003e display blue, it means that they are substrates (PGP+). Simultaneously, \u003cstrong\u003eP2, P3, P6, P8, P11, P12, P14, and P15\u003c/strong\u003e display red for non-substrate (PGP\u0026minus;). It is found to be important, especially when studying the outflow of xenobiotics in the central nervous system. Based on the results shown in \u003cstrong\u003eTable 5\u003c/strong\u003e, ADMET shows that the novel thiazole-pyrimidine hybrids (\u003cstrong\u003eP1 to P15\u003c/strong\u003e) follow the maximum Lipinski rule, indicating that the compound has physicochemical characteristics like those of a drug.[30\u0026ndash;33]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5.\u003c/strong\u003e in-silico physicochemical and pharmacokinetic descriptors for the novel thiazole-pyrimidine hybrids (\u003cstrong\u003eP1\u0026nbsp;\u003c/strong\u003eto\u003cstrong\u003e\u0026nbsp;P15\u003c/strong\u003e) and acarbose under investigation.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"642\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEntry\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003eVI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003eVII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003eVIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003eIX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eXI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003eXII\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eC\u003csub\u003e28\u003c/sub\u003eH\u003csub\u003e27\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e584.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e5.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e-8.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e108.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eC\u003csub\u003e35\u003c/sub\u003eH\u003csub\u003e34\u003c/sub\u003eClN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e640.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e6.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e-8.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e108.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eC\u003csub\u003e30\u003c/sub\u003eH\u003csub\u003e29\u003c/sub\u003eClN\u003csub\u003e6\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e605.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e5.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e-7.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e143.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eC\u003csub\u003e29\u003c/sub\u003eH\u003csub\u003e31\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e545.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e4.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e-6.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e118.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eC\u003csub\u003e30\u003c/sub\u003eH\u003csub\u003e32\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e528.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e6.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e-7.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e105.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eC\u003csub\u003e35\u003c/sub\u003eH\u003csub\u003e35\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e605.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e6.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e-8.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e108.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eC\u003csub\u003e29\u003c/sub\u003eH\u003csub\u003e31\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e545.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e4.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e-6.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e118.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eC\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e30\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e466.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e5.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e-6.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e105.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eC\u003csub\u003e28\u003c/sub\u003eH\u003csub\u003e28\u003c/sub\u003eClN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e550.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e5.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e-7.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e108.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eC\u003csub\u003e29\u003c/sub\u003eH\u003csub\u003e31\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e529.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e4.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e-6.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e108.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eC\u003csub\u003e27\u003c/sub\u003eH\u003csub\u003e33\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e5\u003c/sub\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e539.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e4.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e-6.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e135.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eC\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e440.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e-5.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e114.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP13\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eC\u003csub\u003e28\u003c/sub\u003eH\u003csub\u003e29\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e515.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e4.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e-6.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e108.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP14\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eC\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e29\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e467.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e4.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e-5.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e108.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eC\u003csub\u003e23\u003c/sub\u003eH\u003csub\u003e27\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e453.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e-5.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e108.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAcarbose\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eC\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e43\u003c/sub\u003eNO\u003csub\u003e18\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e645.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e-6.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42px;\"\u003e\n \u003cp\u003e2.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e321.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"13\" style=\"width: 642px;\"\u003e\n \u003cp\u003eI) Molecular Formula, II) Molecular Weight, III) H-bond donors, IV) H-bond acceptors, V) Rotatable bonds, VI) Log P\u003csub\u003eo/w\u003c/sub\u003e, VII) Log S, VIII) TPSA (\u0026Aring;\u0026sup2;), IX) GI absorption, X) Pgp substrate, XI) BBB permeant, XII) Lipinski Rule of Five violations\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, the novel thiazole-pyrimidine hybrids (\u003cstrong\u003eP1\u003c/strong\u003e to \u003cstrong\u003eP15\u003c/strong\u003e) were synthesized using the ultrasound-assisted method and optimized with 61-82 % yields. along with their \u003cem\u003ein vitro\u003c/em\u003e inhibition efficacy against\u0026nbsp;the porcine pancreatic \u0026alpha;-amylase enzyme. They were further confirmed by \u003csup\u003e1\u003c/sup\u003eH-NMR, \u003csup\u003e13\u003c/sup\u003eC-NMR, Mass, and IR- spectroscopy. Acarbose (IC\u003csub\u003e50\u003c/sub\u003e 0.34\u0026nbsp;mM), was employed as the standard to compare these molecular hybrids \u003cem\u003ein vitro\u003c/em\u003e porcine pancreatic \u0026alpha;-amylase\u0026nbsp;inhibitory efficiency. Maximum\u0026nbsp;porcine pancreatic \u0026alpha;-amylase\u0026nbsp;inhibition was observed for compounds \u003cstrong\u003eP3\u003c/strong\u003e (IC\u003csub\u003e50\u003c/sub\u003e 0.33\u0026nbsp;mM), \u003cstrong\u003eP2\u003c/strong\u003e (IC\u003csub\u003e50\u003c/sub\u003e 0.37\u0026nbsp;mM,\u0026nbsp;and \u003cstrong\u003eP6\u003c/strong\u003e (IC\u003csub\u003e50\u003c/sub\u003e 0.39 mM), from \u003cstrong\u003eTable 1.\u003c/strong\u003e This is also supported by molecular docking and molecular dynamic simulation from the active site of 1OSE residue His201, Gly306, His305 as hydrogen bonding interaction, for the hydrophobic interaction Leu162, Val163, Asp197, Ala198, Lys200, Glu233, Ile235 are played a major role to the inhibition for the porcine pancreatic \u0026alpha;-amylase enzyme.\u003c/p\u003e"},{"header":"Experimental ","content":"\u003cp\u003e\u003cstrong\u003eMaterials and Methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e4,6-dichloro-2-methylpyrimidine was purchased from BLD Pharma (India), and Acetamidine hydrochloride, diethyl malonate, 4-hydroxythiobenzamide, ethyl 2-chloro-3-oxo butanoate from Sigma-Aldrich (India), and the solvents from Merck were used without further purification. TLC monitored the completion and purity of the reactions, performed on silica gel aluminium 60 F\u003csub\u003e-254\u003c/sub\u003e thin layer plates procured from Merck, and visualization on TLC was achieved by UV chamber and iodine indicator. The synthesized compounds underwent an in vitro antidiabetic screening, employing pure \u0026alpha;-amylase sourced from porcine pancreas acquired from supplier Sigma-Aldrich, India (Catalogue No. A6255).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSynthesis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eScheme 1\u003c/strong\u003e shows the synthesis of the proposed conjunction component. In contrast to traditional approaches, we report a relatively short timeframe for achieving a considerable improvement in compound yield by an efficient and straightforward synthesis of thiazole-pyrimidine-2\u0026deg;-amine appended (\u003cstrong\u003eP1\u003c/strong\u003e to \u003cstrong\u003eP15\u003c/strong\u003e) under sonochemistry. This study endures our continuous attempts to develop novel synthetic hybrids using sonochemistry techniques.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSynthesis of \u003cem\u003e2-(4-hydroxyphenyl)-4-methyl thiazole-5-carboxylic acid ethyl ester\u003c/em\u003e (3)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFrom the previously reported procedure initially, 4-hydroxythiobenzamide (1eq.) \u003cstrong\u003e(1)\u003c/strong\u003e, ethyl 2-chloro-3-oxo butanoate (1.2 eq.) (\u003cstrong\u003e2\u003c/strong\u003e), and 20 ml of ethanol were taken in a round-bottomed flask and the reaction mixture was refluxed for 3 h to get 2-(4-hydroxyphenyl)-4-methyl thiazole-5-carboxylic acid ethyl ester (\u003cstrong\u003e3\u003c/strong\u003e), the reaction was monitored by TLC (3:7; EtOAc/n-Hexane) at a time interval of 15 min. After completion of the reaction, the mixture was quenched into the crushed ice. The solid obtained was washed with cold water, air-dried, and recrystallized from ethanol to get the pure compounds (yield:83%).[34\u0026ndash;37]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSynthesis of \u003cem\u003e4,6-dihydroxy-2-methyl pyrimidine\u003c/em\u003e (6)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAcetamidine hydrochloride (0.50 mmol) (\u003cstrong\u003e4\u003c/strong\u003e), diethyl malonate (0.52 mmol) (\u003cstrong\u003e5\u003c/strong\u003e), and methanol were mixed at room temperature. As well as that, a 30% sodium methoxide. Gently introduce a methanol (1.53 mmol) solution to the mixture. For three hours, the mixture was mixed. Once chilled to room temperature, the mixes were combined. solid mass was obtained which was washed by washing with methanol, filtered, collected, and then 350 ml of water, after being dissolved. The watery mixture was acidic by freezing and using a lot of powerful hydrochloric acid with ice, to adjust 2 pH and obtaining and weighing a 4,6-dihydroxy-2-methyl pyrimidine (\u003cstrong\u003e6\u003c/strong\u003e), a white crystalline solid after sedimentation and washing in methanol and water. [38]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSynthesis of \u003cem\u003e4,6 dichloro-2-methyl pyrimidine\u0026nbsp;\u003c/em\u003e(7)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTriethylamine (0.12 mol) was gradually added to a mixture of 4,6-dihydroxy-2-methylpyrimidine (\u003cstrong\u003e6\u003c/strong\u003e) (0.10 mol) and phosphoryl chloride (0.50 mol) below 75 \u0026deg;C. After about four hours, the mixture was refluxed while being stirred. The excess phosphorus oxychloride was removed by vacuum distillation. The residue was then mixed with 150 ml of cold water, extracted with ethyl acetate, and the organic layer was dried on magnesium sulphate. After the solvent was removed under vacuum, the crude product was recrystallized using petroleum ether to produce 4,6-dichloro-2-methyl pyrimidine (\u003cstrong\u003e7\u003c/strong\u003e).[38]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSynthesis of \u003cem\u003eethyl 2-(4-((6-chloro-2-methylpyrimidin-4-yl) oxy) phenyl)-4-methylthiazole-5-carboxylate\u0026nbsp;\u003c/em\u003e(8)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e4,6-dichloro-2-methyl pyrimidine (\u003cstrong\u003e7\u003c/strong\u003e) (0.5g, 0.00286 mol) and 2-(4-hydroxyphenyl)-4-methyl thiazole-5-carboxylic acid ethyl ester (\u003cstrong\u003e3\u003c/strong\u003e) (0.67g, 0.00257 mol was dissolved in dimethylformamide (30 mL) and K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e (1.17 g, 0.00859 mol), was added to it and allowed to stir at room temperature for 8 h to get compound ethyl 2-(4-((6-chloro-2-methylpyrimidin-4-yl)oxy)phenyl)-4-methylthiazole-5-carboxylate (\u003cstrong\u003e8\u003c/strong\u003e) with 87% yield. The reaction was monitored using thin-layer chromatography (3:7; EtOAc/n-Hexane). then, the mixture was poured into crushed ice water to obtain the solid crude product filtered, and recrystallized by ethanol: DMF (1:1) to get a white crystal of the compound (\u003cstrong\u003e8\u003c/strong\u003e).[14]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSynthesis of novel thiazole-pyrimidine hybrids (P1 to P15)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthyl 2-(4-((6-chloro-2-methylpyrimidin-4-yl) oxy)phenyl) -4-methylthiazole-5-carboxylate (\u003cstrong\u003e8\u003c/strong\u003e) (0.00077 mol) was dissolved in dimethylformamide (30 mL) and K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e (0.0023 mol), 2\u0026deg;-amines (0.00077 mol) was added to it and allowed to stir at reflux temperature for 6-8 h with 45 to 74 % yield or same mole ratio of the reactants was treated by ultrasound irradiation for about 60 \u0026deg;C put 170 to 195 min at 40 kHz power to get optimized yield 61 to 82 % (\u003cstrong\u003eP1\u0026nbsp;\u003c/strong\u003eto\u003cstrong\u003e\u0026nbsp;P15\u003c/strong\u003e), which is listed in \u003cstrong\u003eTable 1\u003c/strong\u003e. The reaction was monitored using thin-layer chromatography (3:7; EtOAc/n-Hexane). After the completion of the reaction, the mixture was poured into crushed ice water to obtain the solid crude product filtered and concentrated under reduced pressure, and recrystallized by ethanol.[14]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSpectroscopic data of synthesized novel thiazole-pyrimidine hybrids\u003cem\u003e\u0026nbsp;\u003c/em\u003e(P1 to P15).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthyl 2-( 4-( (6-(4-( 2, 3-dichlorophenyl) piperazin-1-yl) -2-methylpyrimidin-4-yl) oxy) phenyl) -4-methylthiazole-5-carboxylate (P1, C\u003csub\u003e28\u003c/sub\u003eH\u003csub\u003e27\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS)\u0026nbsp;\u003c/strong\u003eWhite solid, mp: 178\u0026ndash;179 \u0026deg;C: FT-IR (\u0026upsilon;\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ecm\u003csup\u003e-1\u003c/sup\u003e): 2972 str.(\u0026ndash;C\u0026ndash;H), 1701 str. (ester -C=O), 1100 bend.(ether -C-O-C); \u003csup\u003e1\u003c/sup\u003eH-NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; (ppm); 8.03 \u0026ndash; 7.98 (m, 2H, H-Ar), 7.25 \u0026ndash; 7.17 (m, 4H, Ar), 6.95 \u0026ndash; 6.93 (m, 2H, H-Ar), 5.77 (s, 1H, pyrimidine H-C), 4.38 \u0026ndash; 4.34 (m, 2H,-CH\u003csub\u003e2\u003c/sub\u003e), 3.78 \u0026ndash; 3.77 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 3.09 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 2.96 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 2.89 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 1.39 (t, J = 6.3 Hz, 3H,-CH\u003csub\u003e3\u003c/sub\u003e): \u003csup\u003e13\u003c/sup\u003eC-NMR (125 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta;(ppm); 170.13, 169.04, 167.86, 164.70, 162.25, 161.02, 155.67, 154.79, 150.73, 134.72, 129.72, 128.36, 125.21, 121.86, 121.72, 121.56, 118.77, 118.57, 83.78, 61.29, 51.04, 44.40, 26.07, 17.54, 14.71: ESI-MS: m/z 585.15 [\u003cem\u003eM\u003c/em\u003e+H]: Calculated %: C\u003csub\u003e28\u003c/sub\u003eH\u003csub\u003e27\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS: C, 57.54; H, 4.66; Cl, 12.13; N, 11.98; S, 5.48; found: C, 57.74; H, 4.70; Cl, 12.18; N, 11.89; S, 5.50.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthyl 2-(4-((6-(4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -2- methyl pyrimidin-4-yl) oxy) phenyl) -4-methylthiazole-5-carboxylate (P2, C\u003csub\u003e35\u003c/sub\u003eH\u003csub\u003e34\u003c/sub\u003eClN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS)\u0026nbsp;\u003c/strong\u003eWhite solid, mp: 205\u0026ndash;207 \u0026deg;C: FT-IR (\u0026upsilon;\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ecm\u003csup\u003e-1\u003c/sup\u003e): 2990 str.(\u0026ndash;C\u0026ndash;H), 1717 str. (ester -C=O), 1106 bend.(ether -C-O-C); \u003csup\u003e1\u003c/sup\u003eH-NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;\u0026nbsp;(ppm); 7.97 \u0026ndash; 7.95 (m, 2H, H-Ar), 7.37\u0026ndash; 7.36 (m, 5H, H-Ar), 7.26-7.24 (m, 4H, H-Ar), 7.19 (t,2H, J=5.2 Hz, H-Ar), 5.89 (s, 1H, benzhydryl, -C-H), 5.67 (s, 1H, pyrimidine H-C), 4.39 \u0026ndash; 4.34 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 4.24-4.23 (q, J=6.2 Hz, 2H, -CH\u003csub\u003e2\u003c/sub\u003e), 3.60 \u0026ndash; 3.57 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 2.77 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 2.43 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 1.39 (t, J = 6.3 Hz, 3H,-CH\u003csub\u003e3\u003c/sub\u003e): \u003csup\u003e13\u003c/sup\u003eC-NMR (125 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;(ppm); 170.04, 169.05, 167.83, 164.55, 162.27, 161.03, 155.74, 141.58, 140.80 132.82, 129.62, 129.22, 129.06, 128.72, 128.71, 128.35, 127.90, 127.34, 121.64, 121.49, \u0026nbsp;83.83, 75.43, 61.26, 51.38, 44.27, 25.81, 17.55, 14.90: \u0026nbsp;ESI-MS: m/z 640.10 [\u003cem\u003eM\u0026nbsp;\u003c/em\u003e+ H] : Calculated %: C\u003csub\u003e35\u003c/sub\u003eH\u003csub\u003e34\u003c/sub\u003eClN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS: C, 65.66; H, 5.35; Cl, 5.54; N, 10.94; S, 5.01; Found %: C, 65.70; H, 5.31; Cl, 5.55; N, 11.01; S, 5.03.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthyl 2-(4-((6-(4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) piperidin-1-yl)-2-methylpyrimidin-4-yl) oxy) phenyl) -4-methylthiazole-5-carboxylate (P3, C\u003csub\u003e30\u003c/sub\u003eH\u003csub\u003e29\u003c/sub\u003eClN\u003csub\u003e6\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS)\u0026nbsp;\u003c/strong\u003eWhite solid, mp: 185\u0026ndash;187 \u0026deg;C: FT-IR (\u0026upsilon;\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ecm\u003csup\u003e-1\u003c/sup\u003e): 2999 str. (\u0026ndash;C\u0026ndash;H), 1720 str. (ester -C=O), 1680 str. (amide -C=O), 1026 bend. (ether -C-O-C); \u003csup\u003e1\u003c/sup\u003eH-NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;\u0026nbsp;(ppm); 8.55 (s,1H, H-N), 8.02 \u0026ndash; 7.95 (m, 2H, H-Ar), 7.90\u0026ndash; 7.80 (dd, J= 8.1,2.1 Hz, 1H, benzimidazole, H-Ar), 7.24-7.21 (m, 1H, H-Ar), 7.19-7.17 (d, J=2.2 Hz, 1H, H-Ar), 7.12-7.10 (d, J=2.1 Hz,1H, H-Ar), \u0026nbsp; 7.05-6.96 (m,1H, H-Ar), 5.82 (s, 1H,pyrimidine H-C), 4.61 \u0026ndash; 4.60 (q, J=6.1 Hz, 2H, -CH\u003csub\u003e2\u003c/sub\u003e), 4.38-4.32 (m, 1H, piperidine H-C) 2.99- 2.96 (m, 1H, H-C), 2.77 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 2.46 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 2.38\u0026ndash; 2.27 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 1.39 (t, J = 6.1 Hz, 3H,-CH\u003csub\u003e3\u003c/sub\u003e): \u003csup\u003e13\u003c/sup\u003eC-NMR (125 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;(ppm); 169.05, 168.05, 167.53, 162.34, 156.79, 145.84, 144.32, 129.73, 129.05, 128.65, 128.59, 128.37, 127.58, 121.64, 116.04, 110.20, 109.86, 83.77, 61.28, 51.95, 43.92, 28.87, 25.96, 17.50, 14.33: ESI-MS: m/z 606.10 [\u003cem\u003eM\u0026nbsp;\u003c/em\u003e+ H]: Calculated %: C\u003csub\u003e30\u003c/sub\u003eH\u003csub\u003e29\u003c/sub\u003eClN\u003csub\u003e6\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS: C, 59.55; H, 4.83; Cl, 5.86; N, 13.89; S, 5.30; Found %: C, 59.59; H, 4.90; Cl, 5.81; N, 13.82; S, 5.34.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthyl 2-(4-((6-(4-(2-methoxyphenyl) piperazin-1-yl) -2-methylpyrimidin-4-yl) oxy) phenyl)-4-methylthiazole-5-carboxylate (P4, C\u003csub\u003e29\u003c/sub\u003eH\u003csub\u003e31\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS)\u0026nbsp;\u003c/strong\u003eWhite solid, mp: 171\u0026ndash;173 \u0026deg;C: FT-IR (\u0026upsilon;\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ecm\u003csup\u003e-1\u003c/sup\u003e): 3002 str.(\u0026ndash;C\u0026ndash;H), 1714 str. (ester -C=O), 1009 bend. (ether -C-O-C);\u003csup\u003e1\u003c/sup\u003eH-NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;\u0026nbsp;(ppm); 8.02\u0026ndash;7.97 (m, 3H, H-Ar), 7.28 \u0026ndash; 7.21 (m, 2H, H-Ar), 7.04-7.03 (d, J=8.4 Hz, 1H, H-Ar), 6.93-6.88 (m, 2H, H-Ar ), 5.76 (s, 1H,pyrimidine H-C), 4.38 \u0026ndash; 4.35 (m, 2H,-CH\u003csub\u003e2\u003c/sub\u003e), 3.88 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 3.78 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 3.11 (s, 3H, -O-CH\u003csub\u003e3\u003c/sub\u003e), 2.77 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 2.44 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 1.40 (t, J = 6.3 Hz, 3H,-CH\u003csub\u003e3\u003c/sub\u003e): \u003csup\u003e13\u003c/sup\u003eC-NMR (125 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;(ppm); 170.12, 169.04, 167.87, 164.70, 162.23, 155.82, 152.34, 140.88, 129.62, 128.33, 121.62, 121.11, 118.37, 111.45, 83.73, 61.24, 55.44, 50.42, 44.41, 26.01, 17.52, 14.33: \u0026nbsp; ESI-MS: m/z: 546.20 [\u003cem\u003eM\u003c/em\u003e+H]: Calculated %: C\u003csub\u003e29\u003c/sub\u003eH\u003csub\u003e31\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS: C, 63.83; H, 5.73; N, 12.83; S, 5.88; Found %: C, 69.59; H, 5.02; N, 12.82; S, 5.34.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthyl 2-(4-((6-(4-benzylpiperidin-1-yl)-2-methylpyrimidin-4-yl) oxy) phenyl)-4-methylthiazole-5-carboxylate (P5, C\u003csub\u003e30\u003c/sub\u003eH\u003csub\u003e32\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS)\u0026nbsp;\u003c/strong\u003eWhite solid, mp: 155\u0026ndash;158 \u0026deg;C: FT-IR (\u0026upsilon;\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ecm\u003csup\u003e-1\u003c/sup\u003e): 3012 str. (\u0026ndash;C\u0026ndash;H), 1721 str. (ester -C=O), 1012 bend. (ether -C-O-C); \u003csup\u003e1\u003c/sup\u003eH-NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta;\u0026nbsp;(ppm); 7.99-7.96 (m, 2H, H-Ar), 7.30 \u0026ndash; 7.26 (m, 3H, H-Ar), 7.20-7.18 (dd, J= 5.4, 3.6 Hz, 2H, H-Ar), 7.15-7.13 (dd, J= 5.3, 3.2 Hz, 2H, H-Ar ), 5.71 (s, 1H, pyrimidine H-C), 4.36 \u0026ndash; 4.35 (q, J= 5.1 Hz, 2H,-CH\u003csub\u003e2\u003c/sub\u003e), 3.84-3.79 (m, 4H, -CH\u003csub\u003e2\u003c/sub\u003e), 3.55-3.43 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 2.77 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 2.56-2.55 (d, J= 6.9 Hz, 2H, -CH\u003csub\u003e2\u003c/sub\u003e), 2.41 (s, 3H, -CH\u003csub\u003e3\u003c/sub\u003e), 1.38 (t, J = 6.1 Hz, 3H, -CH\u003csub\u003e3\u003c/sub\u003e), 1.25-1.20 (m, 1H, piperidine, -H-C):\u0026nbsp;\u003csup\u003e13\u003c/sup\u003eC-NMR (125 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;\u0026nbsp;(ppm); 170.02, 169.16, 164.30, 161.04, 155.93, 151.91, 150.32, 140.02, 129.20, 128.38, 128.36, 128.23, 127.86, 125.92, 121.52, 84.20, 62.56, 47.60, 43.05, 39.67, 32.03, 26.41, 19.10, 13.80: ESI-MS: m/z: 529.10 [\u003cem\u003eM\u0026nbsp;\u003c/em\u003e+ H]: Calculated %: C\u003csub\u003e30\u003c/sub\u003eH\u003csub\u003e32\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS: C, 68.16; H, 6.10; N, 10.60; \u0026nbsp;S, 6.06; Found %: C, 68.10; H, 6.18; N, 10.64; S, 6.16\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthyl 2-(4-( (6-( 4-benzhydrylpiperazin-1-yl) -2-methyl pyrimidin-4-yl) oxy) phenyl) -4-methylthiazole-5-carboxylate (P6, C\u003csub\u003e35\u003c/sub\u003eH\u003csub\u003e35\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS)\u003c/strong\u003e White solid, mp: 201\u0026ndash;203\u0026deg;C: FT-IR (\u0026upsilon;\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ecm\u003csup\u003e-1\u003c/sup\u003e) : 3003 str. (\u0026ndash;C\u0026ndash;H), 1723 str. (ester -C=O), 1012 bend. (ether -C-O-C); \u003csup\u003e1\u003c/sup\u003eH-NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;\u0026nbsp;(ppm); 8.01 \u0026ndash; 7.92 (m, 2H, H-Ar), 7.44 \u0026ndash; 7.37 (m, 4H, H-Ar), 7.30 -7.26 (m, 4H, H-Ar), 7.19 (d, J=5.2, Hz, 4H, H-Ar), 5.86 (s, 1H, benzhydryl, -C-H), 5.67 (s, 1H, pyrimidine, H-C), 4.37 \u0026ndash; 4.33 (q, J=6.2 Hz, 2H, -CH\u003csub\u003e2\u003c/sub\u003e), 3.65 \u0026ndash; 3.61 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 2.76 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 2.46-2.44 (m, 4H, -CH\u003csub\u003e2\u003c/sub\u003e), 2.40 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 1.38(t, J = 6.3 Hz, 3H,-CH\u003csub\u003e3\u003c/sub\u003e): \u003csup\u003e13\u003c/sup\u003eC-NMR (125 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;(ppm); 170.05, 167.82, 164.56 162.27, 161.02, 155.78, 141.92, 129.63, 128.66, 128.29, 127.95, 121.56, 83.72, 70.81, 61.23, 51.49, 44.27, 25.95, 17.51, 14.33: \u0026nbsp;ESI-MS: m/z: 606.15 [\u003cem\u003eM\u003c/em\u003e+H] : Calculated %: C\u003csub\u003e35\u003c/sub\u003eH\u003csub\u003e35\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS: C, 69.40; H, 5.82; N, 11.56; S, 5.29; Found %: C, 69.43; H, 5.85; N, 11.52; S, 5.23.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthyl 2-(4-((6-(4-(4-methoxyphenyl) piperazin-1-yl)-2-methyl pyrimidin-4-yl) oxy) phenyl)-4-methylthiazole-5-carboxylate (P7, C\u003csub\u003e29\u003c/sub\u003eH\u003csub\u003e31\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS)\u0026nbsp;\u003c/strong\u003eWhite solid, mp: 172\u0026ndash;174 \u0026deg;C: FT-IR (\u0026upsilon;\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ecm\u003csup\u003e-1\u003c/sup\u003e): 2989 str. (\u0026ndash;C\u0026ndash;H), 1718 str. (ester -C=O), 1005 bend. (ether -C-O-C); \u003csup\u003e1\u003c/sup\u003eH-NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;\u0026nbsp;(ppm); 7.99\u0026ndash;7.98 (m, 2H, H-Ar), 7.22 \u0026ndash; 7.20 (m, 2H, H-Ar), 6.99-6.85 (dd, J = 5.1, 3.5 Hz, 4H, H-Ar), 5.77 (s, 1H,pyrimidine, H-C), 4.37 \u0026ndash; 4.34 (q, J=6.4 Hz, 2H, -CH\u003csub\u003e2\u003c/sub\u003e), 3.87-3.72 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 3.13 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 2.78 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 2.65 (s, 3H, -O-CH\u003csub\u003e3\u003c/sub\u003e), 2.45 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 1.39 (t, J = 6.3 Hz, 3H,-CH\u003csub\u003e3\u003c/sub\u003e): \u003csup\u003e13\u003c/sup\u003eC-NMR (125 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;(ppm); 170.12, 169.07, 167.93, 164.53, 162.28, 161.05, 155.70, 154.70, 144.82, 129.71, 128.36, 121.73, 121.57, 119.12, 114.75, 83.85, 61.29, 55.36, 50.90, 44.12, 25.81, 17.56, 14.48: ESI-MS: m/z 546.10 [\u003cem\u003eM\u0026nbsp;\u003c/em\u003e+ H]: Calculated % : C\u003csub\u003e29\u003c/sub\u003eH\u003csub\u003e31\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS: C, 63.83; H, 5.73; N, 12.83; S, 5.88; Found %: C, 63.81; H, 5.70; N, 12.80; S, 5.81.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthyl 2- (4- ((6- (3,5-dimethylpiperidin-1-yl) -2-methylpyrimidin-4-yl) oxy) phenyl) -4-methylthiazole-5-carboxylate (P8, C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e30\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS)\u0026nbsp;\u003c/strong\u003eWhite solid, mp: 150\u0026ndash;152 \u0026deg;C: FT-IR (\u0026upsilon;\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ecm\u003csup\u003e-1\u003c/sup\u003e): 3009 str. (\u0026ndash;C\u0026ndash;H), 1711 str. (ester -C=O), 1013 bend. (ether -C-O-C); \u003csup\u003e1\u003c/sup\u003eH-NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;\u0026nbsp;(ppm); 8.03\u0026ndash;7.96 (dd, J= 5.1, 3.6 Hz, \u0026nbsp;2H, H-Ar), 7.20 \u0026ndash; 7.19 (q, J = 5.0, 1.8, 2H, H-Ar), 5.76 (s, 1H, pyrimidine H-C), 4.38 \u0026ndash; 4.34 (q, J = 6.4 Hz, 2H, -CH\u003csub\u003e2\u003c/sub\u003e), 3.69-3.66 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 3.18-3.16 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 2.78 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 2.42 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 2.32-2.27 (t, J = 13.8 Hz, 2H, piperidine-CH\u003csub\u003e2\u003c/sub\u003e), 1.63 (m, 2H, piperidine, -H-C), 1.39 (t, J= 6.1 Hz, 3H, -CH\u003csub\u003e3\u003c/sub\u003e), 0.94-0.92 (d, J=6.6 Hz, 6H, -CH\u003csub\u003e3\u003c/sub\u003e): \u003csup\u003e13\u003c/sup\u003eC-NMR (125 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;(ppm); 169.89, 167.80, 164.18, 162.30, 161.04, 158.42, 156.07, 129.35, 128.26, 124.16, 121.31, 83.79, 61.22, 51.44, 42.53, 30.87, 26.05, 19.14, 17.52, 14.33: ESI-MS: m/z: 467.20 [\u003cem\u003eM\u003c/em\u003e+H]: Elemental Analysis calculated for: C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e30\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS: C, 64.35; H, 6.48; N, 12.01; S, 6.87; found: C, 64.31; H, 6.49; N, 12.21; S, 6.33.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthyl 2-(4-((6-(4-(3-chlorophenyl) piperazin-1-yl)-2-methylpyrimidin-4-yl) oxy) phenyl)-4-methylthiazole-5-carboxylate (P9, C\u003csub\u003e28\u003c/sub\u003eH\u003csub\u003e28\u003c/sub\u003eClN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS)\u0026nbsp;\u003c/strong\u003eWhite solid, mp: 189\u0026ndash;191\u0026deg;C: FT-IR (\u0026upsilon;\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ecm\u003csup\u003e-1\u003c/sup\u003e): 2915 str. (\u0026ndash;C\u0026ndash;H), 1708 str. (ester -C=O), 1006 bend. (ether -C-O-C);\u003csup\u003e1\u003c/sup\u003eH-NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;\u0026nbsp;(ppm); 8.00-7.98 (d, J = 8.3 Hz, 2H, H-Ar), 7.22 \u0026ndash; 7.20 (t,\u003cem\u003e\u0026nbsp;J\u003c/em\u003e = 8.4, 2.5 Hz, 1H, H-Ar), 7.18-7.17 (d, J=8.4 Hz, 2H, H-Ar), 6.89-6.84(m, 2H, H-Ar), 6.80-6.78 (m, 1H, H-Ar ), 5.77 (s, 1H,pyrimidine H-C), 4.38 \u0026ndash; 4.34 (q, \u003cem\u003eJ\u003c/em\u003e = 7.1 Hz, 2H,-CH\u003csub\u003e2\u003c/sub\u003e), 3.76-3.74 (q, \u003cem\u003eJ\u003c/em\u003e = 5.2 Hz, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 3.28-3.25 (q, J = 5.2 Hz, 4H, -CH\u003csub\u003e2\u003c/sub\u003e), 2.78 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 2.44 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 1.39 (t, \u003cem\u003eJ\u003c/em\u003e = 6.2 Hz, 3H,-CH\u003csub\u003e3\u003c/sub\u003e): \u003csup\u003e13\u003c/sup\u003eC-NMR (125 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;(ppm); 170.16, 169.04, 167.96, 164.51, 162.26, 161.04, 155.69, 151.96, 135.10, 130.172, 129.72, 128.33, 121.86, 121.64, 119.90, 116.07, 114.15, 83.87, 61.26, 48.44, 43.84, 26.00, 17.53, 14.34: \u0026nbsp;ESI-MS: m/z: 550.25 [\u003cem\u003eM\u003c/em\u003e+H]: Calculated %: C\u003csub\u003e28\u003c/sub\u003eH\u003csub\u003e28\u003c/sub\u003eClN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS: C, 61.14; H, 5.13; Cl, 6.44; N, 12.73; S, 5.83; Found %: C, 61.11; H, 5.18; Cl, 6.40; N, 12.77; S, 5.89\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthyl 4-methyl-2-(4-((2-methyl-6-(4-methyl-2-phenylpiperazin-1-yl) pyrimidin-4-yl) oxy) phenyl) thiazole-5-carboxylate (P10, C\u003csub\u003e29\u003c/sub\u003eH\u003csub\u003e31\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS)\u0026nbsp;\u003c/strong\u003eWhite solid, mp: 178\u0026ndash;180 \u0026deg;C: FT-IR (\u0026upsilon;\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ecm\u003csup\u003e-1\u003c/sup\u003e): 2996 str. (\u0026ndash;C\u0026ndash;H), 1712 str. (ester -C=O), 1014 bend. (ether -C-O-C);\u003csup\u003e1\u003c/sup\u003eH-NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;\u0026nbsp;(ppm); 8.00 - 7.98 (d, J= 7.9, 2H, H-Ar), 7.52 \u0026ndash; 7.49 (m, 2H, H-Ar), 7.27 \u0026ndash; 7.16 (m, 5H, H-Ar), 5.75 (s, 1H, pyrimidine, H-C), 4.51-49 (dd, \u003cem\u003eJ\u003c/em\u003e = 5.4, 4.6 Hz, 1H), 4.38-4.34 (q, \u003cem\u003eJ\u003c/em\u003e = 6.3 Hz, 2H, -CH\u003csub\u003e2\u003c/sub\u003e), 3.97 - 3.94 (dd, \u003cem\u003eJ\u003c/em\u003e = 6.0, 4.3 Hz, 2H, -CH\u003csub\u003e2\u003c/sub\u003e), 3.31-3.24 (m, 2H, -CH\u003csub\u003e2\u003c/sub\u003e), 3.23-3.19 (m, 2H, -CH\u003csub\u003e2\u003c/sub\u003e) 2.78 (s, 3H), 2.47 (s, 3H), 2.35 (s, 3H), 1.38 (t, \u003cem\u003eJ\u003c/em\u003e = 6.4 Hz, 3H): \u003csup\u003e13\u003c/sup\u003eC-NMR (125 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;(ppm); 169.11, 168.11, 167.62, 166.34, 163.65, 155.99, 155.07, 142.66, 130.11, 129.40, 128.76, 128.28, 127.83, 126.56, 126.43, 125.99, 125.77, 122.73, 121.24, 83.02, 61.18, 61.04, 55.23, 53.10, 44.52, 43.60, 25.52, 17.65, 14.32: \u0026nbsp;ESI-MS: m/z: 530.20 [\u003cem\u003eM\u003c/em\u003e+H]: Calculated % : C\u003csub\u003e29\u003c/sub\u003eH\u003csub\u003e31\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS: C, 65.76; H, 5.90; N, 13.22; S, 6.05; Found %: C, 65.78; H, 5.95; N, 13.20; S, 6.01.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthyl 2-(4-((6-(4-(tert-butoxy carbonyl) piperazin-1-yl)-2-methylpyrimidin-4-yl) oxy) phenyl)-4-methylthiazole-5-carboxylate (P11, C\u003csub\u003e27\u003c/sub\u003eH\u003csub\u003e33\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e5\u003c/sub\u003eS)\u0026nbsp;\u003c/strong\u003eWhite solid, mp: 168\u0026ndash;169 \u0026deg;C: FT-IR (\u0026upsilon;\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ecm\u003csup\u003e-1\u003c/sup\u003e): 3012 str. (\u0026ndash;C\u0026ndash;H), 1723 str. (ester -C=O), 1714 str. (ester -C=O) 1010 bend. (ether -C-O-C); \u003csup\u003e1\u003c/sup\u003eH-NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta;\u0026nbsp;(ppm); 8.02\u0026ndash;7.97 (m, 2H, H-Ar), 7.25 \u0026ndash; 7.22 (m, 2H, H-Ar), 5.78 (s, 1H,pyrimidine H-C), 4.37 \u0026ndash; 4.33 (q, J=6.4 Hz, 2H,-CH\u003csub\u003e2\u003c/sub\u003e), 3.67-3.61 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 3.55-3.50 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 2.75 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 2.44 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 1.46 (s, 9H, -CH\u003csub\u003e3\u003c/sub\u003e), 1.38 (t, J = 6.3 Hz, 3H,-CH\u003csub\u003e3\u003c/sub\u003e):\u0026nbsp;\u003csup\u003e13\u003c/sup\u003eC-NMR (125 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;(ppm); 169.11, 168.26, 167.02, 165.42, 164.21, 158.05, 155.49, 154.07, 129.26, 128.48, 126.56, 125.07, 121.67, 84.44, 82.81, 61.54, 47.57, 43.10, 30.27, 25.94, 17.72, 14.31: ESI-MS: m/z: 540.15 [\u003cem\u003eM\u0026nbsp;\u003c/em\u003e+ H]: Calculated % : C\u003csub\u003e27\u003c/sub\u003eH\u003csub\u003e33\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e5\u003c/sub\u003eS: C, 60.09; H, 6.16; N, 12.98; S, 5.94; found: C, 60.02; H, 6.18; N, 12.92; S, 5.99\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthyl 4-methyl-2-(4-((2-methyl-6-morpholinopyrimidin-4-yl) oxy) phenyl) thiazole-5-carboxylate (P12, C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS)\u0026nbsp;\u003c/strong\u003eWhite solid, mp: 157\u0026ndash;159 \u0026deg;C: FT-IR (\u0026upsilon;\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ecm\u003csup\u003e-1\u003c/sup\u003e): 2995 str. (\u0026ndash;C\u0026ndash;H), 1710 str. (ester -C=O), 1010 bend. (ether -C-O-C); \u003csup\u003e1\u003c/sup\u003eH-NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta;\u0026nbsp;(ppm); 8.00\u0026ndash;7.95 (m, 2H, H-Ar), 7.27 \u0026ndash; 7.24 (m, 2H, H-Ar), 5.89 (s, 1H,pyrimidine H-C), 4.38 \u0026ndash; 4.34 (q, \u0026nbsp;\u003cem\u003eJ\u003c/em\u003e = 6.4 Hz, 2H,-CH\u003csub\u003e2\u003c/sub\u003e), 3.93-3.86 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 3.60- 3.58 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 2.76 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 2.45 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 1.39 (t, J = 6.3 Hz, 3H,-CH\u003csub\u003e3\u003c/sub\u003e):\u0026nbsp;\u003csup\u003e13\u003c/sup\u003eC-NMR (125 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;(ppm); 169.53, 167.76, 165.14, 164.36, 162.58, 156.13, 155.49, 129.26, 128.62, 127.77, 125.57, 121.10, 83.45, 64.94, 64.80, 61.75, 47.57, 47.36, 25.66, 17.43, 14.17: ESI-MS: \u003cem\u003em/z\u0026nbsp;\u003c/em\u003e 441.10 [\u003cem\u003eM\u003c/em\u003e+H] : Calculated %: C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS: C, 59.98; H, 5.49; N, 12.72; S, 7.28; Found %: C, 59.93; H, 5.59; N, 12.77; S, 7.38\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthyl 4-methyl-2-(4-((2-methyl-6-(4-phenylpiperazin-1-yl) pyrimidin-4-yl) oxy) phenyl) thiazole-5-carboxylate (P13, C\u003csub\u003e28\u003c/sub\u003eH\u003csub\u003e29\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS)\u0026nbsp;\u003c/strong\u003eWhite solid, mp: 177\u0026ndash;179 \u0026deg;C: FT-IR (\u0026upsilon;\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ecm\u003csup\u003e-1\u003c/sup\u003e): 3090 str. (\u0026ndash;C\u0026ndash;H), 1720 str. (ester -C=O), 1020 bend. (ether -C-O-C); \u003csup\u003e1\u003c/sup\u003eH-NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;\u0026nbsp;(ppm); 8.02 \u0026ndash; 7.98 (dd, J= 8.0, 1.3, 2H, H-Ar), 7.36- 7.34 (tt, \u003cem\u003eJ\u003c/em\u003e = 8.6, 1.3 Hz, 2H), 7.27 \u0026ndash; 7.23 (m, 2H, H-Ar), 7.14 \u0026ndash; 7.10 (m, 3H, H-Ar), 5.72 (s, 1H,pyrimidine H-C), 4.41-4.37 (q, \u003cem\u003eJ\u003c/em\u003e = 6.4 Hz, 2H, -CH\u003csub\u003e2\u003c/sub\u003e), 4.26 \u0026ndash; 4.17 (m, 4H, -CH\u003csub\u003e2\u003c/sub\u003e), 3.90 \u0026ndash; 3.82 (m, 4H, -CH\u003csub\u003e2\u003c/sub\u003e), 2.74 (s, 3H, -CH\u003csub\u003e3\u003c/sub\u003e), 2.38 (s,3H, -CH\u003csub\u003e3\u003c/sub\u003e), 1.40 (t, J = 6.4 Hz, 3H, -CH\u003csub\u003e3\u003c/sub\u003e): \u003csup\u003e13\u003c/sup\u003eC-NMR (125 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;(ppm); 169.67, 168.68, 165.56, 163.79, 162.80, 156.41, 155.35, 149.32, 129.68, 129.11, 128.33, 126.99, 126.42, 125.22, 121.53, 121.24, 118.48, 118.27, 83.17, 61.75, 46.37, 46.08, 44.45, 25.66, 16.23, 14.31: ESI-MS: m/z: 516.15 [\u003cem\u003eM\u0026nbsp;\u003c/em\u003e+ H]\u003csup\u003e\u0026nbsp;\u003c/sup\u003e;Calculated %: C\u003csub\u003e28\u003c/sub\u003eH\u003csub\u003e29\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS: C, 65.22; H, 5.67; N, 13.58; \u0026nbsp;S, 6.22; Found % : C, 65.21; H, 5.64; N, 13.59; S, 6.21\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthyl 2-(4-((6-(4-ethylpiperazin-1-yl)-2-methylpyrimidin-4-yl) oxy) phenyl)-4-methylthiazole-5-carboxylate (P14, C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e29\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS)\u003c/strong\u003e White solid, mp: 161\u0026ndash;163 \u0026deg;C: FT-IR (\u0026upsilon;\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ecm\u003csup\u003e-1\u003c/sup\u003e): 3030 str. (\u0026ndash;C\u0026ndash;H), 1720 str. (ester -C=O), 1020 bend. (ether -C-O-C); \u003csup\u003e1\u003c/sup\u003eH-NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;\u0026nbsp;(ppm); 7.97-7.93 (ddd, \u003cem\u003eJ\u003c/em\u003e = 9.1, 8.2, 1.6 Hz, 2H, H-Ar), 7.26 \u0026ndash; 7.24 (m, 2H, H-Ar), 5.70 (s, 1H,pyrimidine H-C), 4.38-4.34 (q, \u003cem\u003eJ\u003c/em\u003e = 6.4 Hz, 2H, -CH\u003csub\u003e2\u003c/sub\u003e), 3.73 \u0026ndash; 3.63 (m, 4H, -CH\u003csub\u003e2\u003c/sub\u003e), 2.96 \u0026ndash; 2.88 (m, 4H, -CH\u003csub\u003e2\u003c/sub\u003e), 2.73 (s, 3H, -CH\u003csub\u003e3\u003c/sub\u003e), 2.51-2.47 (q, \u003cem\u003eJ\u003c/em\u003e = 7.0 Hz, 2H, -CH\u003csub\u003e3\u003c/sub\u003e), 2.40 (s, 3H, -CH\u003csub\u003e3\u003c/sub\u003e), 1.39-1.37 (t, \u003cem\u003eJ\u003c/em\u003e = 6.3 Hz, 3H, -CH\u003csub\u003e3\u003c/sub\u003e), 1.16- 1.13 (t, \u003cem\u003eJ\u003c/em\u003e = 7.0 Hz, 3H, -CH\u003csub\u003e3\u003c/sub\u003e) : \u003csup\u003e13\u003c/sup\u003eC-NMR (125 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;(ppm); 169.46, 168.11, 164.41, 164.00, 163.39, 156.20, 155.35, 128.90, 128.28, 128.27, 125.14, 121.60, 83.80, 61.68, 52.60, 51.97, 44.10, 25.73, 16.02, 14.38, 12.19: ESI-MS: m/z \u0026nbsp;468.25 [\u003cem\u003eM\u0026nbsp;\u003c/em\u003e+ H] : Calculate %: C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e29\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS: C, 1.65; H, 6.25; N, 14.98; S, 6.86; Found %: C, 61.63; H, 6.28; N, 14.92; S, 6.89\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthyl 4-methyl-2-(4-((2-methyl-6-(4-methylpiperazin-1-yl) pyrimidin-4-yl) oxy) phenyl) thiazole-5-carboxylate (P15, C\u003csub\u003e23\u003c/sub\u003eH\u003csub\u003e27\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS)\u003c/strong\u003e White solid, mp: 158\u0026ndash;160 \u0026deg;C: FT-IR (\u0026upsilon;\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ecm\u003csup\u003e-1\u003c/sup\u003e): 3010 str. (\u0026ndash;C\u0026ndash;H), 1713 str. (ester -C=O), 1010 bend. (ether -C-O-C); \u003csup\u003e1\u003c/sup\u003eH-NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;\u0026nbsp;(ppm); 7.95\u0026ndash;7.93 (m, 3H, H-Ar), 7.26 \u0026ndash; 7.22 (m, 2H, H-Ar), 5.76 (s, 1H,pyrimidine H-C), 4.36 \u0026ndash; 4.32 (q, J=6.4 Hz, 2H,-CH\u003csub\u003e2\u003c/sub\u003e), 3.79- 3.70 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 3.01 (s, 3H, -CH\u003csub\u003e3\u003c/sub\u003e), 2.72 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 2.52-2.44 (m, 4H,-CH\u003csub\u003e2\u003c/sub\u003e), 2.36 (s, 3H,-CH\u003csub\u003e3\u003c/sub\u003e), 1.40 (t, J = 6.3 Hz, 3H,-CH\u003csub\u003e3\u003c/sub\u003e): \u003csup\u003e13\u003c/sup\u003eC-NMR (125 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e)\u0026nbsp;\u0026delta;(ppm); 166.93, 166.71, 164.41, 163.40, 161.85, 157.68, 156.90, 128.28, 127.69, 125.77, 120.52, 83.59, 61.14, 54.44, 46.16, 45.04, 25.04, 16.85, 14.29: ESI-MS: m/z \u0026nbsp;454.21 [\u003cem\u003eM\u0026nbsp;\u003c/em\u003e+ H]; Calculated %: C\u003csub\u003e23\u003c/sub\u003eH\u003csub\u003e27\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS: C, 60.91; H, 6.00; N, 15.44; S, 7.07; Found %: C, 60.93; H, 6.04; N, 15.47; \u0026nbsp;S, 7.10.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eIn vitro\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u0026alpha;-amylase inhibitory screening\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe \u003cem\u003ein vitro\u003c/em\u003e porcine pancreatic \u0026alpha;-amylase inhibitory test was carried out using our previously reported investigation. To prepare samples with 50, 100, 150, and 200 \u0026mu;g/mL concentrations, the synthesized thiazole-pyrimidine hybrids (\u003cstrong\u003eP1\u003c/strong\u003e to \u003cstrong\u003eP15\u003c/strong\u003e) were dissolved in DMSO. Ten minutes were spent at 25\u0026deg;C incubating 200 \u0026mu;L of the sample with 200 \u0026mu;L of the \u0026alpha;-amylase solution (100 mg in 100 mL of sodium phosphate buffer pH 7). The mixture was then incubated at 25 \u0026deg;C for 10 minutes with 200 \u0026mu;L of starch solution (1 g of starch in 100 mL of deionized water), 200 \u0026mu;g/mL of 5-dinitro salicylic acid (DNSA), a colouring agent, was added, to halt the reaction. The vials were heated in a water bath for 10 minutes, allowed to cool to room temperature, and then diluted with 10 mL of distilled water before the absorbance was measured in a UV-visible spectrometer. Using formula 1 and IC\u003csub\u003e50\u003c/sub\u003e values obtained by the standard curve approach, the percentage of inhibition utilized to quantify the \u0026alpha;-amylase inhibitory activity was calculated and expressed in \u0026mu;g/ml in \u003cstrong\u003eTable 1\u003c/strong\u003e and \u003cstrong\u003eFigure 3\u003c/strong\u003e. [13, 14, 39]\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\" width=\"526\" height=\"73\"\u003e\u003c/p\u003e\n\u003cp\u003eWhere B sample is the absorbance of the sample at different concentrations and A blank is the control absorbance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eIn silico\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuantum chemical parameters calculation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe density functional theory (DFT) approach was used for thiazole-pyrimidine hybrids (\u003cstrong\u003eP1\u003c/strong\u003e to \u003cstrong\u003eP15\u003c/strong\u003e).[40, 41] DFT was used to solve the Schr\u0026ouml;dinger equation for the N-electron system. Density functional theory (DFT) can be used to understand the thermodynamic parameters, the energy of the highest occupied molecular orbital (HOMO), and the energy of the lowest unoccupied molecular orbital (LUMO).[42] Additionally, several physiochemical descriptors were computed using the HOMO and LUMO energies. These explanations aid in our comprehension of the molecule\u0026apos;s electron distribution and acceptance patterns. The following method was used for B3LYP/6-311 G (d, p) used the basis set to compute the optimization. The GAUSSIAN 09 W program was utilized to do the computations. \u003cstrong\u003eTable 2\u003c/strong\u003e shows all the quantum chemical parameters for FMOs.[14]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLigand preparation\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo minimize energy, this work used Gaussian 09 to sketch 3D structures for the novel thiazole-pyrimidine hybrids (\u003cstrong\u003eP1\u003c/strong\u003e to \u003cstrong\u003eP15\u003c/strong\u003e). The PDB file format was utilized to convert all minimized structures before doing molecular docking research.[43]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReceptor preparation\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe protein with the X-ray crystal structure, procaine pancreatic \u0026alpha;-amylase isoenzyme II (PPAII) complexed with nitrite and acarbose (PDB ID:1OSE), was obtained at a resolution of 2.30 \u0026Aring; from the RCSB protein data bank PDB (http://www.rcsb.org/pdb). With Discovery Studio Visualizer 2021, the protein target\u0026apos;s water molecules, ions, heteroatoms, and other ligands were eliminated. The protein target\u0026apos;s downloaded structure was transformed into PDB format to facilitate molecular docking studies.[14, 17\u0026ndash;19]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMolecular Docking\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCompounds were docked against PPAII (PDB ID: 1OSE) \u003cem\u003ein silico\u003c/em\u003e molecular docking studies. The docking scoring function was carried out using Auto Dock 1.5.7 docking software, flexible-ligand rigid-receptor docking was carried out, and precise docking conditions were chosen by using the redocking protocol. To dock ligands into active protein sites and determine the binding affinities of the docked molecules, the interactions were examined. Auto Dock 1.5.7 was used to create the grid for the studies. The grid on the protein 1OSE\u0026apos;s ligand-binding site was centred at X:32.480, Y:42.610, and Z: -2.309, with three dimensions of 0.375 \u0026Aring; and a size of 40 x 40 x 40 \u0026Aring; each. The protein\u0026apos;s exhaustiveness value was established at 24. [14, 44]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMolecular Dynamics (MD) Simulation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePDB ID: 1OSE shows the optimal docking position of the interesting chemicals \u003cstrong\u003eP2, P3\u003c/strong\u003e, and \u003cstrong\u003eP6\u003c/strong\u003e associated with the porcine pancreatic \u0026alpha;-amylase isoenzyme II (PPAII). MC Schr\u0026ouml;dinger Desmond MD simulation software was used to evaluate the simulation. It was set up on a Z4 HP workstation running Ubuntu 22.04.2 LTS 64-bit, equipped with an Intel Xeon W-2245 @ 3.90 GHz processor, 8 cores, CUDA 12, and an NVIDIA RTX A4000 graphics processing unit. The OPLS3e force field and the SPC solvation model were used in the MD simulations, and the previously published protocols were adhered to during the simulation and other experimental stages. The simulation lasted 100 nanoseconds, during which time the trajectory was captured once per 100 picoseconds. Desmond\u0026apos;s Simulation Interaction Diagram was used to evaluate the stability and binding orientation of the ligand using MD trajectory data.[14, 45\u0026ndash;47]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eADMET studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLipinski\u0026apos;s rule of five was used in the proposed novel thiazole-pyrimidine hybrids (\u003cstrong\u003eP1\u003c/strong\u003e to \u003cstrong\u003eP15\u003c/strong\u003e) to decide which ones need more study before the proposal. The free SwissADME tool (http://www.swissadme.ch/index.php) was used to assess the findings\u0026apos; qualities, which were listed in \u003cstrong\u003eTable 5\u003c/strong\u003e for the ADMET conclusions.[29, 48\u0026ndash;50]\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003eThe authors would like to thank the Department of Chemistry, S. V. National Institute of Technology, Surat, Gujarat, India for its support. We also sincerely appreciate the Department of Chemistry, Saurashtra University, Rajkot, Gujarat, India, and the Department of Chemistry, IIT-Madras, Chennai, Tamil Nadu, India for the spectral characterization. Authors acknowledge the generous support from the Researchers Supporting project number (RSP 2025R122), King Saud University, Riyadh, Saudi Arabia.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRashid H ur, Martines MAU, Duarte AP, et al (2021) Research developments in the syntheses, anti-inflammatory activities and structure\u0026ndash;activity relationships of pyrimidines. RSC Adv 11:6060\u0026ndash;6098. https://doi.org/10.1039/D0RA10657G\u003c/li\u003e\n\u003cli\u003eFeckov\u0026aacute; M, le Poul P, Bure\u0026scaron; F, et al (2020) Nonlinear optical properties of pyrimidine chromophores. Dyes and Pigments 182:108659. https://doi.org/10.1016/j.dyepig.2020.108659\u003c/li\u003e\n\u003cli\u003eAchelle S, Rodr\u0026iacute;guez‐L\u0026oacute;pez J, Guen FR (2018) Photoluminescence Properties of Aryl‐, Arylvinyl‐, and Arylethynylpyrimidine Derivatives. 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Int J Health Sci (Qassim) 373\u0026ndash;392. https://doi.org/10.53730/ijhs.v6nS3.5190. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"},{"header":"Scheme ","content":"\u003cp\u003eScheme 1 is 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":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"monatshefte-fur-chemie-chemical-monthly","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mccm","sideBox":"Learn more about [Monatshefte für Chemie - Chemical Monthly](https://www.springer.com/journal/706)","snPcode":"706","submissionUrl":"https://www.editorialmanager.com/mccm/","title":"Monatshefte für Chemie - Chemical Monthly","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"thiazole-pyrimidine hybrids, ultra-sound, in-vitro PPA inhibition, Density functional theory, PPA isoenzyme II, MD simulation","lastPublishedDoi":"10.21203/rs.3.rs-5994323/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5994323/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis study gives structural information about the novel thiazole-pyrimidine hybrids (\u003cstrong\u003eP1 \u003c/strong\u003eto\u003cstrong\u003e P15\u003c/strong\u003e). The compounds were synthesized and yield optimized by sonochemistry, characterized using various spectroscopic techniques, including mass, \u003csup\u003e1\u003c/sup\u003eH-NMR, \u003csup\u003e13\u003c/sup\u003eC-NMR, and IR spectroscopy. The compounds were theoretically explored using the DFT approach with a B3LYP/6-311G (d, p) basis set, and their \u003cem\u003ein vitro\u003c/em\u003e porcine pancreatic α-amylase (PPA) enzyme screening was done. Compared to the standard acarbose (IC\u003csub\u003e50\u003c/sub\u003e = 0.34 mM), novel thiazole-pyrimidine hybrids (\u003cstrong\u003eP1 \u003c/strong\u003eto\u003cstrong\u003e P15\u003c/strong\u003e) demonstrated porcine pancreatic α-amylase inhibition ranging from IC\u003csub\u003e50\u003c/sub\u003e (0.33 to 0.73 mM). Molecular docking, MD simulation investigations, and ADMET were carried out to identify the active sites and explain the actions of the active substances by in silico molecular docking. The three active compounds \u003cstrong\u003eP3 \u003c/strong\u003e(IC\u003csub\u003e50\u003c/sub\u003e 0.33 mM, -10.6 kcal/mol\u003cstrong\u003e), P2 \u003c/strong\u003e(IC\u003csub\u003e50 \u003c/sub\u003e0.37 mM, -10.5 kcal/mol),\u003cstrong\u003e \u003c/strong\u003eand\u003cstrong\u003e P6 \u003c/strong\u003e(IC\u003csub\u003e50\u003c/sub\u003e 0.39 mM, -10.5 kcal/mol) were redocked at the active site of pig pancreatic alpha-amylase isoenzyme II (PDB ID:\u003cstrong\u003e1OSE\u003c/strong\u003e) to study the binding conformation and dynamics relevant to their activity. The binding interactions between \u003cstrong\u003eP2, P3, \u003c/strong\u003eand\u003cstrong\u003e P6\u003c/strong\u003e with porcine pancreatic α-amylase showed porcine pancreatic α-amylase's inhibitory potential.\u003c/p\u003e","manuscriptTitle":"An ultrasound-assisted synthesis of novel Thiazole-pyrimidine hybrids: in-vitro PPA enzyme inhibition, DFT analysis, Molecular docking, MD simulation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-18 12:13:17","doi":"10.21203/rs.3.rs-5994323/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-06-24T08:04:50+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-30T11:22:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-02-11T02:59:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"Monatshefte für Chemie - Chemical Monthly","date":"2025-02-10T14:10:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"monatshefte-fur-chemie-chemical-monthly","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mccm","sideBox":"Learn more about [Monatshefte für Chemie - Chemical Monthly](https://www.springer.com/journal/706)","snPcode":"706","submissionUrl":"https://www.editorialmanager.com/mccm/","title":"Monatshefte für Chemie - Chemical Monthly","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"10a4c63b-0546-4de5-8d06-efe458e0e80a","owner":[],"postedDate":"April 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2025-07-18T14:49:34+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-18 12:13:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5994323","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5994323","identity":"rs-5994323","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}