Elucidating the biological activities of thiadazole derivatives against Vibrio cholerae: Insights from DFT, spectroscopic studies, molecular docking and ADMET

Elucidating the biological activities of thiadazole derivatives against Vibrio cholerae: Insights from DFT, spectroscopic studies, molecular docking and ADMET | 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 Elucidating the biological activities of thiadazole derivatives against Vibrio cholerae: Insights from DFT, spectroscopic studies, molecular docking and ADMET Moses M. Edim, Bethel C. Ateb, Friday O. Izachi, Precious K. Assam, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4394391/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Cholera has become one of the major global health challenges, especially in sub-Saharan Africa, where there is poor hygiene and sanitation, and due to the emergence of a resistant strain of the causative agent of cholera, there is a need for new therapeutic agents. Thiadiazoles are organic compounds that have been reported to have various biological applications. This study comprehensively analysed the structural, electronic, and biological properties of N1,N10-bis(5-(2-oxo-2H-chromen-3yl)-1,3,4-thiadiazol-2-yl)-decane-diamide, a thiadiazole derivative (TDZD) as an agent against cholera via theoretical approaches. Computational analyses were conducted employing the B3LYP/6-311 + + 2d,2p level of theory, which provided substantial insights. Vibrational assignments via FT-IR spectroscopy confirmed the excellent agreement between the theoretical and reported experimental values, confirming the structural stability of the ligand. The electronic property analysis revealed slight variations in the electrophilicity index of the compound across solvents, with the highest (5.790 eV) in water and the lowest (5.753 eV) in the gas phase. Additionally, the high electronegativity values in all solvents, following the order of water (4.640 eV), DMSO (4.639 eV), ethanol (4.637 eV), and gas (4.584 eV), indicated ligand reactivity. Furthermore, molecular docking results indicated distinctive interactions between the ligand and the 1XTC and 6EHB cholera receptor proteins. A higher binding score was observed between the ligand and 1XTC, with a binding score of -7.6 kcal/mol, than between the ligand and 6EHB, with a binding score of -7.1 kcal/mol. Furthermore, the drug amoxicillin (AMOX) showed a comparable binding score of -7.8 kcal/mol for 1XTC and − 7.4 kcal/mol for 6EHB. The obtained results suggest the biological potential of TDZD as an anti-cholera agent and can be the foundation for further studies. DFT Vibrio cholerae Molecular docking ADMET Drug design Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1.0 Introduction Cholera, an endemic disease in many regions, particularly sub-Saharan Africa, is often spread through contaminated water, and poor sanitation has become one of the major global health challenges. This disease is caused mainly by the bacterium Vibrio cholerae [ 1 ]. It is among the oldest and most well understood epidemic-prone diseases. Cholera outbreaks have occurred throughout history, starting with the 19th century pandemic that originated in the Ganges delta [ 2 ]. Previous studies have reported that cholera mostly occurs in sub-Saharan Africa, and some parts of the Middle East region are endemic to approximately 69 countries; Asia, Africa and America, including sub-Saharan Africa, are more prone to this disease [ 3 ]. Reports by the World Health Organization estimated that a total of 2.8 million people contracted cholera, and approximately 91,000 people died [ 4 ]. Cholera is an enteric disease that has two distinctive epidemiological features: its ability to appear in explosive outbreaks and its ability to cause a true pandemic [ 5 ]. While most infected individuals experience no symptoms, others develop profuse watery diarrhea, vomiting, muscle cramps, weakness, and rapid heart rate [ 6 ]. The core mechanism by which Vibro cholorae initiates disease, which is responsible for the dehydration observed during cholera, is the secretion of CT, which is a protein complex [ 7 – 10 ]. After colonization by Vibrio cholorae , the bacteria secrete cholera enterotoxin, which interacts with the receptors in the intestinal epithelium, thereby leading to the manifestation of the symptoms mentioned earlier [ 11 ]. Studies have shown that a wide range of treatment options, including oral rehydration therapy, the use of antimicrobial agents, antibiotics and vaccines, are available, each of which depends on the severity of the patient’s cholera [ 11 ]. However, due to the development of new antibiotic-resistant strains of Vibrio cholerae , there is a need to develop more treatment options. Heterocycles are a very important class of organic compounds that have been reported to account for more than 50% of reported organic compounds [ 12 ]. They have been found to be essential components of hemoglobin, RNA, proteins, vitamins and other biologically active compounds, and they serve as precursors of a wide range of potential biological compounds [ 13 ]. Thiadiazoles, which are considered heterocyclic compounds over time, have received much attention, possibly due to their biological and pharmaceutical implications, which increase their availability for pharmaceutical and industrial applications as a result of the = N-C-S moiety [ 14 ]. Thiadiazoles are five-membered heterocyclic compounds that possess two nitrogen atoms and a sulfur atom as a part of the aromatic ring [ 15 ]. These compounds are azole compounds. There are approximately four isomeric forms of thiadiazoles. Among the four isomers, 1,3,4-thiadiazoles have been reported by previous studies to have a plethora of biological applications compared to the other isomers. Thiadiazoles have been employed as antibacterial, antimicrobial, and anticancer agents [ 16 ]. Some well-known drugs, including acetazolamide, scefazolin, megazol and methazolamine, which are currently in use, are thiadiazoles [ 17 ]. Several studies have reported the use of thiadiazole derivatives as compounds with biological activity using density functional theory (DFT), which is a computational method. Karaburun and colleagues [ 18 ] synthesized and characterized a series of 1,3,4-thiadiazole derivatives to obtain a novel bioactive compound with considerable antifungal activity. The in vitro antifungal activity of the synthesized compounds was determined against eight Candida species. Two active compounds, 3k and 3 l, showed antifungal effects. Docking studies on 14-α-sterol demethylase enzymes were also performed to investigate the inhibitory effects of the compounds on ergosterol biosynthesis. Theoretical absorption, distribution, metabolism, and excretion (ADME) predictions were calculated to determine the drug likeness of the final compounds. The results of the antifungal activity test, ergosterol biosynthesis assay, docking study, and ADME predictions indicated that the synthesized compounds are potential antifungal agents that inhibit ergosterol biosynthesis, probably by interacting with the fungal 14-α-sterol demethylase. Additionally, studies by Iyam et al . (2024) [ 19 ] explored thiadiazole derivatives for their potential as antibacterial agents against carbapenem-resistant Klebsiella pneumoniae and Pseudomonas aeruginosa . To achieve this goal, the compound under study was analysed both electronically and structurally using density functional theory. Their molecular docking results revealed the potential therapeutic efficacy of thiadiazole derivatives against carbapenem-resistant strains, suggesting that they are more favourable than conventional drugs in terms of binding affinity and interaction strength. Tunel et al . (2021) [ 20 ] synthesized thioether-bridged imidazo[2,1-b][ 1 , 3 , 4 ]thiadiazole derivatives. The synthesized structure was characterized using 1H NMR, FT-IR and 13C NMR, elemental analysis, mass spectrometry and X-ray diffraction analysis. The mycelial growth, mycelial growth inhibition, minimum inhibitory concentration, minimum fungicidal concentration, and lethal dose against various plant pathogenic fungi were determined for all of the target compounds synthesized in the study. The results from the test showed that the majority of the compounds had considerable antifungal activity. Furthermore, the absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters of the compounds were calculated, and it was also observed that all of the compounds met the general drug-likeness criteria. Finally, the molecular docking results showed that compounds 7h, 7i, 8h, and 8i displayed greater affinity for PDB ID:5TZ1, which is a CYP51 antifungal target structure. The main aim of this study was to determine the biological activity of a thiadiazole derivative (TDZD) against cholera using DFT and molecular docking, thereby contributing to the global effort to combat cholera and ultimately enhance human well-being. By propelling the boundaries of scientific understanding in this critical domain, this research holds promise for reshaping the trajectory of strategies against cholera and paves the way for more effective interventions in the future. 2.0 Methods 2.1 Experimental 2.1.1 Synthesis of N1,N10-Bis(5-(2-oxo-2H-chromen-3yl)-1,3,4-thiadiazol-2-yl)-decane-diamide This compound was synthesized and reported by Hamdy [ 21 ]. A mixture of 4 (0.446 g, 1 mmol), salicylaldehyde (0.244 g, 2 mmol) and 0.5 g of fused AcONa in AcOH (30 mL) was refluxed for 2 hours. After cooling, the formed product mass was collected, dried, and finally purified to afford this derivative. Figure 1 shows the proposed structure of the derivative. 2.1.2 Elemental analysis From the analytical data, the empirical formula of the studied compound was observed to be C 32 H 28 N 6 O 6 S 2 , which agrees with the values calculated for C, H, and N (see ref [ 21 ]). 2.2 Computational Methodology In this study, calculations were carried out at the DFT/B3LYP/6-311 + + G (d, p) level by employing Gaussian 09 software [ 22 ]. Compound geometry optimization was conducted via the same level of theory. To determine the electronic and structural properties of the derivative, various analyses were performed, including frontier molecular orbital (FMO) and natural bond orbital (NBO) analyses, electron localization function (ELF) studies, and noncovalent interaction (NCI) studies. To gain further insight into the stability of the studied compound, natural bond orbital (NBO) analysis was carried out using the NBO 7.0 program found in the Gaussian package. The system's reactivity and stability were analysed via frontier molecular orbital (FMO) analysis, and the visualized orbitals were obtained using Chemcraft [ 23 ]. In addition to findings concerning HOMO-LUMO interactions, supplementary quantum descriptors, including chemical hardness, chemical softness, electronegativity, chemical potential, and electrophilicity index, were computed. To provide additional validation for the insights gained from the HOMO-LUMO analysis, molecular electrostatic map analysis was carried out, and the results were visualized using Gaussview 6.0.16 software. 2.3 Molecular docking procedure The molecular docking process is a computational technique that predicts the binding mode and binding affinity of small molecules, such as drug candidates, to a target protein. Autodock tools and AutoDock Vina 1.5.6 [ 24 ] are widely used software tools for performing molecular docking simulations. In this study, TDZD was docked with two selected proteins, namely, IXTC and 6EHB, which are CTRs obtained from a protein database ( https://www.rcsb.org/ ). Carefully, these proteins were prepared for docking simulations by removing water, heteroatoms, and ligands and adding polar hydrogen using Biovia Discovery Studio software version 2021 [ 25 ]. The standard drug amoxicillin (AMOX) was also docked with the proteins to compare the binding affinity of the studied compound with that of the standard drug. The xyz coordinates of the 1XTC are x = 1.052620, y=-0.890880, z = 21.961832 and the radius is 21.000000 for 6EHB x=-4.269381, y = 51.699348, z = 92.021902 and the radius = 19.968170. 3.0 Results 3.1 Spectral characterization 3.1.1 Vibrational analysis Fourier transform infrared spectroscopy (FT-IR) provides insight into how molecules vibrate and the frequencies at which they are used. It also provides insight into the vibration of atoms in a molecule, which may be a result of polarization, and how they are linked together. The strength of the FT-IR measurement depends on how much the bonds that cause vibrations change their dipole moments. The full details of the FTIR theoretical results can be found in Table 1 . N-H Vibration The N-H functional group was theoretically observed in TDZD, as shown in Table 1 . The frequency in different solvents and the gas phase falls between 3553 and 3557 cm⁻¹ with the same vibration mode known as symmetrical stretching. The experimental frequency of falls was 3225 cm⁻¹, as reported by Hamdy [ 21 ]. All the solvents (TDZD-ethanol, TDZD-DMSO, and TDZD-water) exhibited the same theoretical value of 3553 cm⁻¹, while TDZD-Gas exhibited a different value at 3557 cm⁻¹. This result suggests the comprehensible stability of the compound in the gaseous phase and a slight difference in its stability in various solvents, which is attributed to solvation effects. This finding aligns with the reported literature [ 21 ]. C-H Vibration The C-H vibration characteristically falls within the range of 3002– 3184 cm⁻¹, as shown in Table 1 . However, this vibration occurs in two functional groups: CH and CH₂. The CH functional group has an experimental value of 3103 cm⁻¹ and portrays a symmetric stretching vibration. The solvents (TDZD-ethanol, TDZD-DMSO, and TDZD-water) exhibited the same theoretical values of 3184 cm⁻¹ and 3047 cm⁻¹, respectively, on the gas. In the same vein, the CH₂ functional group showed a symmetric stretching mode of vibration with an experimental value ranging from 2944–3042 cm⁻¹ and a theoretical value ranging from 3002–3043 cm⁻¹. This result therefore suggests the stability of the compound even when polar solvents are included, which is consistent with the reported literature [ 21 ]. C = O vibrations Vibration of this functional group was observed experimentally in the range of 1694–2861 cm⁻¹, a theoretical value ranging from 1707–3002 cm⁻¹, and a symmetric mode of vibration. It is also important to note that all the phases (TDZD-ethanol, TDZD-DMSO, TDZD-gas and TDZD-water) for each functional group exhibit the same theoretical value in accordance with the reported literature of this functional group, indicating the stability of the compound [ 23 ]. C = C Vibration This vibration displayed a symmetric stretching vibration. The experimental value was detected at 1616 cm⁻¹, whereas the theoretical stretching values for the examined compound in various solvents and the gas phase fell within the range of 1632–1645 cm⁻¹. These findings indicate that TDZD in DMSO and TDZD in water had a value of 1632 cm⁻¹, TDZD in ethanol had a value of 1645 cm⁻¹, and TDZD in gas had a value of 1640 cm⁻¹. In simpler terms, the compounds exhibited similar stabilities in the presence of TDZD in DMSO and in the presence of TDZD in water and different stabilities in the presence of ethanol and gas, suggesting that these compounds are less stable than the other phases [ 24 ]. Generally, the symmetric stretching and various identified functional groups highlighted in this context indicate good stability of the compound. Table 1 Vibrational analysis of the TDZD derivative FT-IR Frequency (cm − 1 ) Functional Group Vibration mode Exp. Theoretical DMSO TDZD DMSO TDZD Ethanol TDZD Gas TDZD Water 3225 3553 3553 3557 3553 NH Symmetric stretching 3103 3184 3184 3167 3184 CH Symmetric stretching 3042 3043 3043 3047 3043 CH 2 Symmetric stretching 2944 3006 3006 3002 3006 CH 2 Symmetric stretching 2861 3002 3002 2999 3002 C = O Symmetric stretching 1740 1738 1738 1751 3002 C = O Symmetric stretching 1694 1708 1709 1744 1707 C = O Symmetric stretching 1616 1632 1645 1640 1632 C = C Symmetric stretching 3.1.2 UV‒vis analysis The studied compounds were optimized at the B3LYP/6-311G++(2d, 2p) level of theory. Ultraviolet (UV) radiation is assimilated by a compound's molecules, prompting the transfer of electrons between different energy levels thus offering knowledge and understanding of the reactivity and stability of the compound [ 25 ]. According to Johann Wilhelm Ritter, each molecule exhibits a unique absorption spectrum that can be used to identify the molecule and characterize its chemical structure [ 26 – 27 ]. For instance, conjugated systems in organic molecules, such as those with double bonds or aromatic rings, often result in distinctive absorption bands in the UV‒vis spectrum. Hence, this analysis provides information about the reactivity and stability of TDZD by thoroughly examining the excitation of electrons following the absorption of UV light. Based on the results obtained (Table 2 ), in the gas phase, the electrons on the studied compound underwent excitation from the ground state (S 0 ) to the first state (S 1 ) at an energy of 3.427 eV and a wavelength of 362 nm. Conversely, the transition of electrons to the second excitation state (S 2 ) occurred at 3.548 eV and 349 nm. Upon shift to the third excited state (S 3 ), the electron underwent a transition at an energy level of 3.647 eV and a wavelength of 340 nm. Similarly, all transition in this context were captured to flow from the highest filled orbital (H) to the lowest unfilled orbital (L). Thus, it was observed that the energy increases as the electrons advance from the ground state first and beyond, indicating good stability, as electrons find it challenging to easily flow beyond the ground state. This behavior was consistent with the solvation effects of various solvents (DMSO, ethanol, and water). additionally, the introduction of DMSO, ethanol, and water into the studied compound results in a slightly lower excitation energy across all the excited states, indicating solvatochromism. This is due to the solvation effect on the molecules of the studied compound, as solute-solvent interactions can stabilize the excited state of the molecule, thereby reducing its excitation energy. Therefore, the studied compound exhibited a lower excitation energy in the solvent phase than in the gas phase, which indicates that the solvent environment plays a key role in modulating the electronic structure and properties of the compound. Comparatively, the studied compound has more reactive behavior in the gas phase than in the solvent phase. Table 2 UV‒vis analysis results for the studied derivative Compound Transition Type Energy (eV) Wavelength (nm) Oscillator strength ( f ) Percentage contribution (%) Transition DMSO S 0 -S 1 (171 \(\to\) 172) 3.438 361 0.7055 71 H \(\to\) L S 0 -S 2 (170 \(\to\) 173) 3.508 353 0.7362 74 H \(\to\) L + 2 S 0 -S 3 (169 \(\to\) 173) 3.628 342 0.0248 2.5 H \(\to\) L + 3 Ethanol S 0 -S 1 (171 \(\to\) 172) 3.443 360 0.6969 70 H \(\to\) L S 0 -S 2 (170 \(\to\) 173) 3.512 353 0.7266 73 H \(\to\) L + 2 S 0 -S 3 (169 \(\to\) 173) 3.627 342 0.0249 2.5 H \(\to\) L + 3 Gas S 0 -S 1 (169 \(\to\) 172) 3.427 362 0.0011 0.1 H \(\to\) L + 2 S 0 -S 2 (171 \(\to\) 173) 3.548 349 0.3542 35 H \(\to\) L + 2 S 0 -S 3 (170 \(\to\) 172) 3.647 340 0.3839 38 H \(\to\) L + 1 Water S 0 -S 1 (171 \(\to\) 172) 3.436 361 0.7094 71 H \(\to\) L S 0 -S 2 (170 \(\to\) 173) 3.506 353 0.7407 74 H \(\to\) L + 2 S 0 -S 3 (169 \(\to\) 173) 3.628 342 0.0248 2.5 H \(\to\) L + 3 3.2 Electronic properties 3.2.1 Frontier Molecular Orbital (FMO) studies The frontier molecular orbital (FMO), which encompasses the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), aids in understanding the electronic behavior of compounds or molecules [ 28 ]. Notably, the energy gap (E.g.) is an essential parameter obtained from the difference in the energies of the HOMO and LUMO, which represents the chemical reactivity, stability, and kinetics of a compound [ 29 ]. In line with previous research, lower values for E.g. indicate a less reactive and less stable compound, whereas higher values indicate more stable and less reactive compounds [ 30 ]. Additionally, the HOMO and LUMO values are used to compute the quantum descriptor results, viz., global hardness (ղ), softness (σ), electrophilicity (ω), chemical potential (µ), and electronegativity (χ ) . Interestingly, the reactivity of TDZD was determined in gas and solvent phases (DMSO, ethanol, and water). These solvents are considered polar due to the presence of polar functional groups in their structures [ 31 ]. Furthermore, the calculated results are shown in Table 3 , and a pictorial view of the HOMO and LUMO surface is displayed in Fig. 2 . According to the results presented in Table 3 , the energy gap of the compound TDZD in the gas phase is 3.653 eV, which is lower than that observed in the solvent phase. However, TDZD in ethanol is reported at 3.717 eV, which is lower than that observed for TDZD_Water and TDZD_DMSO, which are reported at 3.718 eV. Emphatically, we can say that in the solvent phases studied, the compounds exhibit similar reactivity, although TDZD is more reactive in the gas phase and more stable in the solvent phase (water and DMSO). Additionally, the values obtained for chemical hardness (ղ) and softness (σ) suggest that TDZD in all phases is biologically active. Table 3 Calculated results for the HOMO, LUMO, Eg, and quantum descriptors for the studied compounds Compound HOMO LUMO Eg (eV) ղ(eV) S (eV − 1 ) µ (eV) χ(eV) ω(eV) TDZD_Gas -6.411 -2.757 3.653 1.826 0.913 -4.584 4.584 5.753 TDZD_Water -6.499 -2.781 3.718 1.859 0.929 -4.640 4.640 5.790 TDZD_DMSO -6.498 -2.780 3.718 1.859 0.929 -4.639 4.639 5.788 TDZD_Ethanol -6.496 -2.779 3.717 1.858 0.929 -4.637 4.637 5.785 3.3 Natural Bond Orbitals (NBOs) NBO is an important approach used to explore the stability, charge transfer and hyperconjugative effects, inter- and intramolecular interactions of a compound and delocalization of electron density within a molecule [ 32 ]. NBO can be calculated based on the second-order perturbation energy; thus, the greater the stabilization energy is, the greater the interaction between the donor (occupied) and acceptor (unoccupied) orbitals [ 33 ]. The perturbation energy value measures the concentration of the interaction between the donor and acceptor. A higher perturbation (E 2 ) value indicates a strong interaction and enhanced stabilization of the molecular system [ 34 ]. There are different types of bonds of interest observed in NBO, such as sigma (σ), anti-sigma (σ*), pi-bond (π), anti-pi-bond (π*), and lone pair (LP) bonds. In this study, σ → σ* transitions occurred in the examination of the orbitals of TDZD. Based on our results presented in Table 4 , the gas phase had a maximum stabilization energy of 399.40 kcal/mol, which resulted from σC 45 -C 46 → σ*C 46 -H 73 and subsequently 370.34 kcal/mol from σC 45 -C 46 → σ*C 45 -H 71 , and the least stabilization energy was observed at 324.83 kcal/mol, which was derived from σC 45 -C 46 → σ*C 45 -H 72 . Similarly, the strongest donor-acceptor NBO interactions for water, DMSO, and ethanol from the scrutinized compound were observed at σC 45 -C 46 → σ*C 45 -H 72 , σC 45 -C 46 → σ*C 45 -H 72 , and σC 45 -C 46 → σ*C 45 -H 72 , with stabilization energies of 350.09 kcal/mol, 349.93 kcal/mol, and 349.58 kcal/mol, respectively, with no significant difference among the solvents. In the gas phase, the compound has the highest perturbation energy. The study compound has the potential to maintain stability, which is indicative of a good therapeutic agent. Table 4 Selected second-order perturbation energies for the studied compounds Compound Transition Type Donor Acceptor E (2) kcal/mol E(j)- E(i) F (I, j) Gas σ→ σ* σC 45 -C 46 σ*C 46 -H 73 399.40 1.09 0.592 σ→ σ* σC 45 -C 46 σ*C 45 -H 71 370.34 1.81 0.733 σ→ σ* σC 45 -C 46 σ*C 45 -H 72 324.83 0.75 0.442 Water σ→ σ* σC 45 -C 46 σ*C 45 -H 72 350.09 0.77 0.466 σ→ σ* σC 45 -C 46 σ*C 45 -H 71 309.97 1.98 0.702 σ→ σ* σC 45 -C 46 σ*C 46 -H 73 309.61 1.28 0.563 DMSO σ→ σ* σC 45 -C 46 σ*C 45 -H 72 349.93 0.77 0.466 σ→ σ* σC 45 -C 46 σ*C 45 -H 71 310.53 1.98 0.703 σ→ σ* σC 45 -C 46 σ*C 46 -H 73 310.39 1.28 0.564 Ethanol σ→ σ* σC 45 -C 46 σ*C 45 -H 72 349.58 0.77 0.465 σ→ σ* σC 45 -C 46 σ*C 46 -H 73 312.08 1.27 0.564 σ→ σ* σC 45 -C 46 σ*C 45 -H 71 311.76 1.98 0.703 3.4 Molecular electrostatic potential (MESP) MESP data are derived from a reliable quantum chemical method that has been widely used for the interpretation and prediction of various aspects of chemical reactivity [ 35 ]. To provide insight into the reactivity of electrophilic and nucleophilic site attack for TDZD, colours are used to demonstrate the colours of interest; red to yellow indicate electron-rich regions, while yellow indicates electron deficiency [ 36 ]. Figure 3 shows that the benzene ring is electrophilic in the region shown in blue and is electron deficient. On the right side of the compound, the pyran ring is nucleophilic at the lower part attached to oxygen, and the upper side is electrophilic. The thiadiazole ring is electron rich at the part attached to the nitrogen on the right side of the compound and electron deficient at the sulfur-attached part. The decane region is electron poor, but when it is attached to an oxygen atom, it becomes electron rich. 3.5 Noncovalent Interaction Analysis The study of noncovalent interactions (NCIs) is pivotal in drug development because it provides an understanding of the binding mechanisms and stability of molecular complexes. However, NCIs arise from different forces, including electrostatic interactions, weak interactions, and hydrogen bonding [ 37 ]. Electrostatic interactions are hinged on Coulomb's law and occur between charged particles where positively and negatively charged regions of molecules attract each other [ 38 ]. These interactions play a key role in understanding the binding of charged ligands to receptors in drug design. van der Waals interactions, including dispersion forces, arise from fluctuations in electron distributions within molecules [ 39 ]. Even though they are weaker than covalent bonds, van der Waals forces are significant in molecular recognition and binding. Hydrogen bonding occurs when hydrogen atoms covalently bond to electronegative atoms such as oxygen or nitrogen and interact with other electronegative atoms [ 39 ]. Hydrogen bonds contribute to the stability of protein structures, such as alpha helices and beta sheets, and are essential for molecular recognition and ligand binding [ 40 ]. Therefore, the behavior of the compound under study can be understood by closely examining its noncovalent interactions (NCIs), as it highlights some crucial forces, including van der Waals forces, repulsive forces, and hydrogen bonds. Understanding of some of these interactions is paramount for the development of new treatments and can provide key information on the behaviors of compounds and potential applications. Hence, from the results presented in Fig. 4 , two major types of force were captured at the surface of the compound, as indicated by green patches, which connote the van der Waal force of interaction, and red patches, indicating steric repulsion. The steric repulsion force was mostly attributed to the intramolecular nature of the benzene ring, thiadiazole, and pyran scaffold of the studied compound. The van der Waal force of interaction was noted around the region of the 1,3,4-thiadiazole ring, indicating the potential properties of the compound. In comparison to the various phases applied in this study, there was no significant variation observed for this analysis; hence, this compound remains consistent with the nature of its interactive properties, thereby indicating its potential as a promising drug. 3.6 Electron localization function (ELF) analysis ELF analysis is an important concept in the modelling of novel compounds because it is used to analyse the distribution of electrons in a compound. Additionally, it provides valuable insights into chemical bonding, molecular structure, and reactivity [ 41 ]. ELF analysis goes beyond traditional electron density calculations, offering a more detailed perspective on electron behavior. Moreover, the ELF measures the probability of finding a pair of electrons in a given region of space [ 42 ]. Unlike the electron density, which represents the total electron density, the ELF focuses specifically on the localization of electrons. High values of ELF indicate strong electron localization, suggesting the presence of covalent bonds or lone pairs, while low values correspond to delocalized or diffuse electron clouds, characteristic of nonbonding regions [ 41 , 42 ]. This analysis provides a clear visualization of chemical bonding, revealing regions of strong electron pairing associated with bonds and lone pairs. This information aids in the interpretation of molecular structures and the prediction of chemical reactivity [ 43 ]. Therefore, this technique can be very helpful in identifying the best candidate compounds for drug development. From the respective results illustrated in Fig. 5 , the atoms in the thiadiazole and benzene rings on both sides of the studied compound displayed dense electrons, thus highlighting the interaction regions. The delocalized region of electrons in this context was notably at the decane atoms. Despite the implementation of diverse phases (water, DMSO, gas, and ethanol), no significant variation in the localized and delocalized regions of the compound was observed. Therefore, understanding electron behavior in molecules provides insight into the structure-property relationships and reaction mechanisms of the studied compound. 3.7 Molecular docking In this section, we elucidate the biological activity of thiadiazole derivatives against the Vibrio cholerae -related proteins IXTC and 6EHB. IXTC and 6EHB are two proteins associated with Vibrio cholerae , the bacterium responsible for cholera [ 2 ]. For therapeutic intervention, targeting these proteins with the considered ligand is crucial because it can interfere with important biological processes, stop the progression of this disease, and possibly even result in the creation of new medicines for treating cholera. To achieve this goal, molecular docking enables us to understand the interaction mechanism and inhibition efficiency of the ligand against proteins, and the results based on high negative binding affinity, short distances and the presence of hydrogen bonds, van der Waals interactions, hydrophobic interactions or other kinds of interactions demonstrate the potential of the ligands for investigating proteins [ 44 ]. The docking results of the ligand were compared to those of the recommended drug amoxicillin, and the obtained results are shown in Table 5 . The graphical representations showing ligand interactions within the amino acid pockets of the protein and the distance of interaction are displayed in Fig. 6 . For example, utilizing molecular docking, Owen and colleagues [ 45 ] showed that semicarbazine derivatives exhibited a binding affinity of -5.4 kcal/mol for the protein 1XTC. Using molecular docking, Ubah et al. [ 46 ] demonstrated the potency of aminoresin derivatives against Vibrio cholerae proteins. In our study, the protein 1XTC, when docked against the studied thiadiaazole derivative, showed a binding affinity of -7.6 kcal/mol, which is comparable to the value of -7.8 kcal/mol obtained for the standard drug amoxicillin. Moreover, both the standard drug and the studied ligand were docked into the pockets of the following amino acids: lysine, arginine and aspartate, which are essential amino acids. The thiadiazole derivative (TDZD) interacted with the amino acids LYS284, PRO285, GLN254, TYR282, and LYS251, yielding a binding score of -7.1 kcal/mol. Similarly, the standard drug amoxicillin interacted with ARG220, LYS9, PHE257, and TYR250, resulting in a binding score of -7.4 kcal/mol. The findings from these studies suggest the potential of TDZD as a drug candidate for treating cholera, as it exhibits activity comparable to that of standard drugs against selected proteins. Table 5 Binding scores for the studied ligands against the selected proteins: 1XTC and TDZD Interactions Binding affinity (Kcal/mol) Amino acid residues TDZD + 1XTC -7.6 LYS63, LYS237, LYS62, ARG67, ASP238 AMOX + 1XTC -7.8 LYS63, LYS237, LYS63, ASP70 TDZD + 6EHB -7.1 LYS284, PRO285, GLN254, TYR282, LYS251 AMOX + 6EHB -7.4 ARG220, LYS9, PHE257, TYR250 3.8 ADMET studies Absorption, distribution, metabolism, excretion, and toxicity (ADMET) play key roles in drug discovery and development. High-quality drug candidates should not only have sufficient efficacy against therapeutic targets but also show appropriate ADMET properties at therapeutic doses [ 47 ]. The prediction of the fate of a drug and the effects caused by a drug inside the body, such as how the drug is absorbed if administered orally and how much is absorbed in the gastrointestinal tract, is a vital part of drug identification [ 48 ]. Poor absorption of a drug may affect its distribution and metabolism, thereby leading to neurotoxicity and nephrotoxicity. Interestingly, the pharmacokinetic properties of the studied compound were evaluated to gain insight into its therapeutic effects on living organisms. From this interpretation, TDZD is suggested to have a proper permeability because its value is -6.012 log cm/s, which is correct according to the predicted value of >-5.15 log cm/s [ 49 ]. The mechanism of plasma protein binding (PPB) involves the uptake and distribution of a drug, and the binding of a drug to a protein strongly influences its pharmacodynamic behavior [ 50 ]. PPB can directly influence oral bioavailability. According to the empirical decision for drug interpretation, the predicted value is ≤ 90%, while the results from this study indicate that 99.907% of the drugs are highly protein bound and may exhibit a low therapeutic index [ 48 – 50 ]. Drugs that act in the CNS need to cross the BBB to reach their molecular target. The pragmatic decision results should be within the range of 0-0.7 cm/s; from this study, the result is shown to be greater than the decision result and indicates that it is poor [ 51 ]. Cytochrome P450 is an important detoxification enzyme in the body. Many drugs are deactivated by cytochrome P450 isoforms, while some can be activated by them. As shown in Table 6 , the cyclopeptides CYP1A2, CYP2C19 and CYP2D6 are predicted not to be P450 inhibitors in any isoform, except for CYP2C9 and CYP3A4, which implies that the ability of the body to detoxify these inhibitors is slightly lower [ 52 – 53 ]. The clearance of a drug emphasizes the volume of distribution alongside the half-life and the frequency of dosing of a drug and is an important pharmacokinetic parameter. Pragmatic decisions show that clearance should be ≥ 5 ml/min/kg for excellent clearance, while the prediction of this clearance is 1.300 ml/min/kg because of poor clearance [ 50 – 51 ]. Additionally, toxicity is said to be the degree of damage a drug or compound can cause to an organism. Drug toxicity is dose dependent and can affect the entire body [ 54 ]. From the toxicity parameters determining the hepatotoxicity of the drug, it is noteworthy that this drug can cause damage to the liver at a predicted range of 0.69, which is a low active value. In terms of cytotoxicity, this drug did not induce cell death, as the predicted result was an inactive value of P = 0.97; in this case, immunotoxicity was active, with a value of P = 0.96, which indicates an adverse effect on the immune system resulting from exposure to the drug. An inactive carcinogenic value of P = 0.62 shows that this drug will not have a tendency to induce tumors or cause cancer in the body [ 51 – 55 ]. Mutagenicity is the ability to cause genetic mutations in cells or eggs and sperm, with an inactive mutagenic value of P = 0.97 indicating the opposite [ 53 ]. From the toxicity study, we ascertained that TDZD has potential for use as a drug agent against cholera. Table 6 displays the ADMET properties of the studied compounds. Table 6 ADMET study on the biological activity of TDZD PHYSICOCHEMICAL PROPERTIES Formular C 32 H 28 N 6 O 6 S 2 Molecular weight 656.73 g/mol Num. of heavy atoms 46 TPSA 93.12 Ų ABSORPTION Caco-2 Permeability -6.012 cm/s MDCK Permeability 2.2e-06 cm/s P-gp substrate Yes DISTRIBUTION PPB 99.907% VD 2.743 L /kg BBB PENETRATION No METABOLISM GI absorption High CYP1A2 inhibitor No CYP2C19 inhibitor No CYP2C9 inhibitor Yes CYP2D6 inhibitor No CYP3A4 inhibitor YES EXCRETION CL 1.300 ml/min/kg T 1/2 0.001 sec TOXICITY Hepatotoxicity Active (P = 0.69) Cytotoxicity Inactive (P = 0.97) Immunotoxicity Active (P = 0.96) Carcinogenicity Inactive (P = 0.62) Mutagenicity Inactive (P = 0.97) DRUG-LIKENESS Lipinski No; 2 violations: MW > 500, NorO > 10 Ghose No; 3 violations: MW > 480, MR > 130 Veber No; 1 violation: Rotors > 10 Egan Yes Muegge No; 3 violations: MW > 600, XLOGP3 > 5, H-acc > 10 Bioavailability score 0.17 4.0 Conclusion This study theoretically determined the potential of a thiadiazole derivative (TDZD) as an agent for the treatment of cholera. The DFT/B3LYP/6-311 + + 2d,2p level of theory was used for the computational studies to obtain substantial information on the various theoretical analyses reported in the study. Notably, this study used a multidimensional approach to determine the properties of TDZD in various solvent environments. Vibrational assignments using FT-IR spectroscopy showed strong agreement between the theoretical and experimental values for the C-H, N-H, C = C, and C = O stretching vibrations in different solvents. This consistency suggests that the ligand is structurally stable across various environments. UV/vis excitation analysis showed that the introduction of DMSO, ethanol, and water into the studied compound resulted in a slightly lower excitation energy across all the excited states. Furthermore, the electronic property analysis revealed that TDZD demonstrated a lower energy gap of 3.653 eV compared to that obtained from ethanol, water and DMSO, with values of 3.717 eV and 3.718, respectively. The chemical hardness of the compound tended to change from that of ethanol to that of methanol, with values of 1.859 eV, 1.858 eV, and 1.826 eV for DMSO, water, ethanol and gas, respectively. This sequence signifies a reduced reactivity of TDZD from the water to gas phase. The docking results revealed distinct interactions between TDZD and target proteins. Furthermore, molecular docking results indicated distinctive interactions between the ligand and the 1XTC and 6EHB cholera receptor proteins. A higher binding score was observed between the ligand and 1XTC, with a score of -7.6 kcal/mol, than between the ligand and 6EHB, with a binding score of -7.1 kcal/mol. Furthermore, the drug amoxicillin (AMOX) displayed a comparable binding score of -7.8 kcal/mol for 1XTC and − 7.4 kcal/mol for 6EHB. This study reveals the potential of TDZD as a potent agent against cholera and can be subjected to further experimental studies to further confirm this claim. Declarations Ethics approval and consent to participate Not applicable Consent for publication Not applicable Availability of data and material All data are contained within the manuscript and manuscript supporting information. Competing Interests All authors declare no conflicts of interest. Funding This research did not receive funding from any source. Authors' contributions Moses M. Edim : Project conceptualization, design, supervision. Alpha O. Gulack : Project administration, Methodology, and supervision. Bethel C. Ateb, Precious L. Assam, and Friday O. Izachi : Writing, editing, analysis, and Manuscript draft. Anna Imojara and Fidelis E. Abeng : Writing, proofreading, validation and editing. Prince J. Nna : Visualization, Validation, and Supervision. References Basu I, Mukhopadhyay C. Insights Into Binding Of Cholera Toxin To Gm1 Containing Membrane. (2014): Langmuir 30; 1544-15252 Cdc (Center for Disease Control and Prevention). Cholera –Vibro Cholerae Infection.(2018). Http://Www.Cdc.Gov\Cholera\Treatment\Index.Html. Accessed 23 October 2018. Sears Cl, Kaper Jb.(2000). Enteric Bacterial Toxins: Mechanisms Of Action And Linkage To Intestinal Secretion. Microbiol Rev.(2001);60; 167-215. World Health Organization. (2020). Report Of The First Meeting Of The Who Diagnostic Technical Advisory Group For Neglected Tropical Diseases: Geneva, Switzerland , 30–31 October. Sawasvirojwong S,(2013). An Adult Mouse Model of Vibrio cholerae-induced Diarrhea for Studying Pathogenesis and Potential Cholera Therapy Plos Negltrop Dis 7; E2293 Bhuiyan Na, Nusrins , Alam M , Morita M, Watanabe H ,Ramanurthy T , Cravioto A. Nair Gb (2009). Changing Genotyopes of Cholera Toxin (Ct). Fems Immunol Med Microbiol 57; 136 -141. Waldor Mk , Mekalanos Jj (2000). Lysogenic Conversion By A Filamentous Phage Encoding Cholera Toxin . Science 272; 1910-1914. Davis Bm, Moyer Ke , Boyd Ef, Weldor Mk, (2000) Ctx Prophages In Classical Biotype Vibro Cholorae ; Functional Phage Genes However, Dysfunctional Phage Genome. J Bacteriol 182-6992-6998. Spangler Bd (2003), Structure And Function Of Cholera Toxin And The Related Escherichia Coli Heat – Liable Entero Toxin . Microbiol Rev 56; 622 – 647. Mekakanos Jj,(2004) Cholera Toxin ; Genetic Analysis , Regulation And Role In Pathogenesis . Curr Top Microbiol Ummunol 118;97-118 Francisca B.M Souse, Isavela R.S.G. Noleto, Leticla S. Chaves,Gabriella Pacheco,Ana P . Oliveira, Milkhail M.V. Fonseca And Jand V.R. Medeiros.(2020).A Comprehensive Review Of Therapeutic Approaches Available For The Treatment Of Cholera. Journal Of Pharmacy And Pharmacology,72; 1715-1731. Chinchilla, R., Nájera, C., & Yus, M. (2004). Metalated heterocycles and their applications in synthetic organic chemistry. Chemical reviews , 104 (5), 2667-2722. Eftekhari-Sis, B., Zirak, M., & Akbari, A. (2013). Arylglyoxals in synthesis of heterocyclic compounds. Chemical reviews , 113 (5), 2958-3043. Holownia, A. E. (2020). Investigating the Synthesis and Reactivity of Boron Carbonyl Compounds (Doctoral dissertation, University of Toronto (Canada)). Sonawane, R. K., & Mohite, S. K. (2021). Heterocyclic Bridgehead Nitrogen Atom System: Review on [1, 2, 4] Triazolo [3,4-b][1, 3, 4] thiadiazole and Its Pharmacological Screening. Hu, Y., Li, C. Y., Wang, X. M., Yang, Y. H., & Zhu, H. L. (2014). 1, 3,4-Thiadiazole: synthesis, reactions, and applications in medicinal, agricultural, and materials chemistry. Chemical reviews , 114 (10), 5572-5610. Zyad H.J. Ai – Qaisi, Zahraa S,Ai – Garawi, Ahmed Jasim M, Ai –Karawi , Ali Jasim Hammood ,Abanoub Mosaad Abdallah, William, Gehad G. Mohamed. (2022). Antiureolytic Activity Of New Water Soluble Thiadiazole Derivatives: Spectroscopic, Dft, And Molecular Docking Studies. Spectrochimica Acta Part A: Molecular And Bimolecular Spectroscopy 272;120971. Karaburun, A. Ç., Acar Çevik, U., Osmaniye, D., Sağlık, B. N., Kaya Çavuşoğlu, B., Levent, S., ... & Kaplancıklı, Z. A. (2018). Synthesis and evaluation of new 1, 3,4-thiadiazole derivatives as potent antifungal agents. Molecules , 23 (12), 3129. Iyam, S. O., Ogbodo, S. E., Okafor, E. R., Runde, M., Gulack, A. O., Odey, M. O., ... & Louis, H. (2024). Elucidating the antibacterial efficacy of thiadiazol derivative against carbapenem-resistant Klebsiella pneumoniae and Pseudomonas aeruginosa : An in-silico perspective. Chemical Physics Impact , 8 , 100466. Tunel, H., Er, M., Alici, H., Onaran, A., Karakurt, T., & Tahtaci, H. (2021). Synthesis, structural characterization, biological activity, and theoretical studies of some novel thioether‐bridged 2, 6‐disubstituted imidazothiadiazole analogues. Journal of Heterocyclic Chemistry , 58 (6), 1321-1343. Thabet, H. K. (2020). Sebacoyl Isothiocyanate in the Synthesis of Bis (1, 3,4-thiadiazole, 1, 3,4-thiadiazolo [3,2-a] pyridine, 4-thiazolidinone, Chromenes, and Naphtho [1,2-b][1, 4] oxazine) Derivatives. Oriental Journal of Chemistry , 36 (2). Frisch, A. (2009). Gaussian 09 W Reference. Wallingford, USA, 25p , 470 . Zhurko, G. A., & Zhurko, D. A. (2013). Chemcraft graphical program for working with quantum chemistry results. Chemcraft , 1 , 2008. T.M. Almutairi, N. Rezki, M.R. Aouad, M. Hagar, B.A. Bakr, M.T. Hamed, E. A. Moneer, (2022). Exploring The Anti Parasitic Activity Of Tris-1, 3,4-Thiadiazoles Against Toxoplasma Gondii-Infected Mice, Molecules 27 (7) 2246. Sharma, S., Sharma, A., & Gupta, U. (2021). Molecular Docking studies on the Anti-fungal activity of Allium sativum (Garlic) against Mucormycosis (black fungus) by BIOVIA discovery studio visualizer 21.1. 0.0. Balzani, V., Bergamini, G., Campagna, S., & Puntoriero, F. (2007). Photochemistry and photophysics of coordination compounds: overview and general concepts (pp. 1-36). Springer Berlin Heidelberg. Gorretta, N., Gowen, A. A., Holden, N. M., Wolfe, M. L., Ogejo, J. A., & Cummins, E. J. (2020). Visible and near infrared optical spectroscopic sensors for biosystems engineering. Visible Near - Infrared Opt. Spectrosc. Sensors Biosyst. Eng , 10 . Kumar, A., Deval, V., Tandon, P., Gupta, A., & D’silva, E. D. (2014). Experimental and theoretical (FT-IR, FT-Raman, UV–vis, NMR) spectroscopic analysis and first order hyperpolarizability studies of nonlinear optical material:(2E)-3-[4-(methylsulfanyl) phenyl]-1-(4-nitrophenyl) prop-2-en-1-one using density functional theory. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy , 130 , 41-53. Liu, C., Li, Y., Takao, M., Toyao, T., Maeno, Z., Kamachi, T., ... & Shimizu, K. I. (2020). Frontier molecular orbital based analysis of solid–adsorbate interactions over group 13 metal oxide surfaces. The Journal of Physical Chemistry C , 124 (28), 15355-15365. Morales-Bayuelo, A., Sánchez-Márquez, J., Jana, G., & Chattaraj, P. K. (2020). Conceptual DFT analysis of the plausible mechanism of some pericyclic reactions. Structural Chemistry , 31 (5), 1745-1756. Dos Santos, R. B., Rivelino, R., de Brito Mota, F., Kakanakova-Georgieva, A., & Gueorguiev, G. K. (2015). Feasibility of novel (H 3 C) n X (SiH 3) 3− n compounds (X= B, Al, Ga, In): structure, stability, reactivity, and Raman characterization from ab initio calculations. Dalton Transactions , 44 (7), 3356-3366. Finney, J. L., & Soper, A. K. (1994). Chemical and biological importance of solvent structure and perturbations in solutions. Chemical Society Reviews , 23 (1), 1-10. Prashanth, J., Ramesh, G., Naik, J. L., Ojha, J. K., & Reddy, B. V. (2016). Molecular geometry, NBO analysis, hyperpolarizability and HOMO-LUMO energies of 2-azido-1-phenylethanone determined via quantum chemical calculations. Materials Today: Proceedings , 3 (10), 3761-3769. Halim, S. A., & Ibrahim, M. A. (2017). Synthesis, DFT calculations, electronic structure, electronic absorption spectra, natural bond orbital (NBO) and nonlinear optical (NLO) analysis of the novel 5-methyl-8H-benzo [h] chromeno [2,3-b][1, 6] naphthyridine-6 (5H), 8-dione (MBCND). Journal of Molecular Structure , 1130 , 543-558. Riley, K. E., Pitonák, M., Jurecka, P., & Hobza, P. (2010). Stabilization and structure calculations for noncovalent interactions in extended molecular systems based on wave function and density functional theories. Chemical Reviews , 110 (9), 5023-5063. Suresh, C. H., Remya, G. S., & Anjalikrishna, P. K. (2022). Molecular electrostatic potential analysis: A powerful tool to interpret and predict chemical reactivity. Wiley Interdisciplinary Reviews: Computational Molecular Science , 12 (5), e1601. Ojha, J. K., Ramesh, G., & Reddy, B. V. (2023). Structure, chemical reactivity, NBO, MEP analysis and thermodynamic parameters of pentamethyl benzene using DFT study. Chemical Physics Impact , 7 , 100280. Haque, A., Alenezi, K. M., Khan, M. S., Wong, W. Y., & Raithby, P. R. (2023). Noncovalent interactions (NCIs) in π-conjugated functional materials: advances and perspectives. Chemical Society Reviews , 52 (2), 454-472. Mahmood, E. A., Poor Heravi, M. R., Khanmohammadi, A., Mohammadi-Aghdam, S., Ebadi, A. G., & Habibzadeh, S. (2022). DFT calculations, structural analysis, solvent effects, and noncovalent interaction study on the para-aminosalicylic acid complex as a tuberculosis drug: AIM, NBO, and NMR analyses. Journal of Molecular Modelling , 28 (10), 297. Della Volpe, C., & Siboni, S. (2022). From van der Waals equation to acid‒base theory of surfaces: a chemical-mathematical journey. Reviews of Adhesion and Adhesives , (1), 47-97. Hubbard, R. E., & Haider, M. K. (2010). Hydrogen bonds in proteins: role and strength. eLS . Poater, J., Duran, M., Sola, M., & Silvi, B. (2005). Theoretical evaluation of electron delocalization in aromatic molecules by means of atoms in molecules (AIM) and electron localization function (ELF) topological approaches. Chemical reviews , 105 (10), 3911-3947. Prasana, J. C., Muthu, S., & Abraham, C. S. (2019). Molecular docking studies, charge transfer excitation and wave function analyses (ESP, ELF, LOL) on valacyclovir: a potential antiviral drug. Computational biology and chemistry , 78 , 9-17. Janani, S., Rajagopal, H., Muthu, S., Aayisha, S., & Raja, M. (2021). Molecular structure, spectroscopic (FT-IR, FT-Raman, NMR), HOMO-LUMO, chemical reactivity, AIM, ELF, LOL and Molecular docking studies on 1-Benzyl-4-(N-Boc-amino) piperidine. Journal of Molecular Structure , 1230 , 129657. Mierzwa, G., Gordon, A. J., & Berski, S. (2020). The nature of multiple boron-nitrogen bonds studied using electron localization function (ELF), electron density (AIM), and natural bond orbital (NBO) methods. Journal of molecular modelling , 26 , 1-23. Owen, A. E., Anyambula, I. A., Benson, C. U., Ojumola, F. O., Alawa, J. A., Benjamin, I., ... & Louis, H. (2024). Exploration of semicarbazone derivatives as promising agents against cholera: Insights from spectroscopic analysis, reactivity studies (ELF, HOMO-LUMO, NBO), solvation effects, and molecular docking investigations. Chemical Physics Impact, 8, 100438. Ubah, C. B., Mujafarkani, N., Sundaravadivelu, A., Narendran, N., Godfrey, O. C., Ogbodo, S. E., ... & Louis, H. (2024). Derivative of aminoresin as potent anti-virulence agent: Synthesis, spectral (FT-IR, UV, NMR) analysis, molecular docking, effect of polar solvation dynamics, and quantum chemical investigation. Journal of Molecular Structure, 1295, 136744. Tsaioun, K., Blaauboer, B. J., & Hartung, T. (2016). Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods. ALTEX-Alternatives to animal experimentation , 33 (4), 343-358. Vinarov, Z., Abdallah, M., Agundez, J. A., Allegaert, K., Basit, A. W., Braeckmans, M., ... & Augustijns, P. (2021). Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review. European Journal of Pharmaceutical Sciences , 162 , 105812. Hassan, A. S., Morsy, N. M., Aboulthana, W. M., & Ragab, A. (2023). Exploring novel derivatives of isatin-based Schiff bases as multitarget agents: design, synthesis, in vitro biological evaluation, and in silico ADMET analysis with molecular modelling simulations. RSC advances , 13 (14), 9281-9303. Lambrinidis, G., Vallianatou, T., & Tsantili-Kakoulidou, A. (2015). In vitro, in silico and integrated strategies for the estimation of plasma protein binding. A review. Advanced drug delivery reviews , 86 , 27-45. Mikitsh, J. L., & Chacko, A. M. (2014). Pathways for small molecule delivery to the central nervous system across the blood‒brain barrier. Perspectives in medicinal chemistry , 6 , PMC-S13384. Naglah, A. M., Moustafa, G. O., Elhenawy, A. A., Mounier, M. M., El-Sayed, H., Al-Omar, M. A., ... & Bhat, M. A. (2021). Nα-1,3-benzenedicarbonyl-bis-(Amino acid) and dipeptide candidates: synthesis, cytotoxic, antimicrobial and molecular docking investigation. Drug Design, Development and Therapy , 1315-1332. Billat, P. A., Roger, E., Faure, S., & Lagarce, F. (2017). Models for drug absorption from the small intestine: where are we and where are we going?. Drug Discovery Today , 22 (5), 761-775. Saganuwan, S. A. (2017). Toxicity studies of drugs and chemicals in animals: an overview. Bulgarian Journal of Veterinary Medicine , 20 (4). Rahmouni, F., Badraoui, R., Ben-Nasr, H., Bardakci, F., Elkahoui, S., Siddiqui, A. J., ... & Rebai, T. (2022). Pharmacokinetics and therapeutic potential of Teucrium polium against liver damage associated hepatotoxicity and oxidative injury in rats: Computational, biochemical and histological studies. Life , 12 (7). Cite Share Download PDF Status: Posted Version 1 posted 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-4394391","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":302334525,"identity":"a35c0e1a-13ea-434c-8631-60cdeb704b66","order_by":0,"name":"Moses M. Edim","email":"","orcid":"","institution":"Cross River State University of Technology: Cross River University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Moses","middleName":"M.","lastName":"Edim","suffix":""},{"id":302334526,"identity":"76bdd40a-9c18-44d5-89e4-0497eb9c8d10","order_by":1,"name":"Bethel C. Ateb","email":"","orcid":"","institution":"University of Calabar","correspondingAuthor":false,"prefix":"","firstName":"Bethel","middleName":"C.","lastName":"Ateb","suffix":""},{"id":302334527,"identity":"ed35f34b-2f9c-4960-a62c-6685b0bdf60e","order_by":2,"name":"Friday O. Izachi","email":"","orcid":"","institution":"Cross River State University of Technology: Cross River University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Friday","middleName":"O.","lastName":"Izachi","suffix":""},{"id":302334528,"identity":"cb973e5a-53b9-4c18-bbb0-3e2e3c4a177c","order_by":3,"name":"Precious K. Assam","email":"","orcid":"","institution":"Cross River State University of Technology: Cross River University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Precious","middleName":"K.","lastName":"Assam","suffix":""},{"id":302334529,"identity":"72d36d3f-1890-4030-a742-3a5612d700be","order_by":4,"name":"Alpha O. Gulack","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIie3RPwrCMBQG8ITA6/Js15ZqvUKL4CLoYYS6uDmJg4Kgi3qcXCCQLh6g4OKf1cVBqKJgap0T3ATzDck35EfyCCE2Nr8Yh0C51QkBulcFXSNhFUFFWFwW+IaAXzYj8eY1uS/uAr2lTMfXYbcOhB2OuYb4wh0k641Af5vKXYP31cOg1RrqrhHY9msrgSR3FruAM0UQQh1pKhI8FWkqMgr41ExiRUIsBMY5SHrhwkwS4aZhYzbAZJv2Q8ozBGaYJcrWMjg/OlGUyeRy45Oe58wPJ+345Y/QRVUZvlft8Q8hj6rSwnjaxsbG5h/zAlB9QcpqdbskAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0009-0008-3243-2832","institution":"University of Calabar","correspondingAuthor":true,"prefix":"","firstName":"Alpha","middleName":"O.","lastName":"Gulack","suffix":""},{"id":302334530,"identity":"914e3749-bc9c-43b6-bbd4-9e635f37978f","order_by":5,"name":"Anna Imojara","email":"","orcid":"","institution":"University of Calabar","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Imojara","suffix":""},{"id":302334531,"identity":"ae501d59-b6e3-465c-9e6e-c45fad07eebb","order_by":6,"name":"Fidelis E. Abeng","email":"","orcid":"","institution":"Cross River State University of Technology: Cross River University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Fidelis","middleName":"E.","lastName":"Abeng","suffix":""},{"id":302334532,"identity":"c95f39e7-eccc-43c6-8bc8-e99d07eab076","order_by":7,"name":"Prince J. Nna","email":"","orcid":"","institution":"Ignatius Ajuru University of Education","correspondingAuthor":false,"prefix":"","firstName":"Prince","middleName":"J.","lastName":"Nna","suffix":""}],"badges":[],"createdAt":"2024-05-09 10:08:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4394391/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4394391/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56989337,"identity":"85abe8e7-e0b3-4be8-89db-0a867988d97c","added_by":"auto","created_at":"2024-05-23 05:56:49","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":498742,"visible":true,"origin":"","legend":"\u003cp\u003eChemical structure of N1,N10-bis(5-(2-oxo-2H-chromen-3yl)-1,3,4-thiadiazol-2-yl)-decane-diamide\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4394391/v1/59c677baeea4db4e9884f390.jpeg"},{"id":56989340,"identity":"2b77601e-332c-47be-9048-30a6ba07b235","added_by":"auto","created_at":"2024-05-23 05:56:50","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":867832,"visible":true,"origin":"","legend":"\u003cp\u003eA pictorial display of the HOMO and LUMO surface for the studied derivative\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4394391/v1/d0d72c65e0cf6def73792b2e.jpeg"},{"id":56989339,"identity":"4f4ad74c-288d-4590-898b-9a4d4e4bc3e4","added_by":"auto","created_at":"2024-05-23 05:56:50","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":633859,"visible":true,"origin":"","legend":"\u003cp\u003eVisualizationof the electrophilic and nucleophilic regions of the studied compound\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4394391/v1/62c3fa597c106c89bb6cab2a.jpeg"},{"id":56989952,"identity":"5ce95cd8-c49c-4265-9636-d6460c6fe546","added_by":"auto","created_at":"2024-05-23 06:04:49","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":606103,"visible":true,"origin":"","legend":"\u003cp\u003ePictorial demonstration of the noncovalent interaction of the studied compound\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4394391/v1/1e3640531f77b94c20402b75.jpeg"},{"id":56989341,"identity":"11d595fd-0f69-4c33-92d0-629262e5c91a","added_by":"auto","created_at":"2024-05-23 05:56:50","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1030775,"visible":true,"origin":"","legend":"\u003cp\u003eElectron localization function plot of the studied compound\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4394391/v1/fe2dcd9378749d32da5512b2.jpeg"},{"id":56989342,"identity":"e0817c28-52d5-4d3a-a77e-0c1f0df59da8","added_by":"auto","created_at":"2024-05-23 05:56:50","extension":"jpeg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1054432,"visible":true,"origin":"","legend":"\u003cp\u003e2D and 3D molecular interactions between the studied compound, amoxicillin and targeted \u003cem\u003eV. cholerae\u003c/em\u003eproteins\u003c/p\u003e","description":"","filename":"floatimage6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4394391/v1/6c8cc1ac51234a8c108e9cc5.jpeg"},{"id":62604248,"identity":"6aff6b63-a14c-47a5-a25a-5f1b779480a7","added_by":"auto","created_at":"2024-08-16 10:32:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5753672,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4394391/v1/bb511b68-1d40-47e6-9011-b1dcb47ba7e6.pdf"}],"financialInterests":"","formattedTitle":"Elucidating the biological activities of thiadazole derivatives against Vibrio cholerae: Insights from DFT, spectroscopic studies, molecular docking and ADMET","fulltext":[{"header":"1.0 Introduction","content":"\u003cp\u003eCholera, an endemic disease in many regions, particularly sub-Saharan Africa, is often spread through contaminated water, and poor sanitation has become one of the major global health challenges. This disease is caused mainly by the bacterium \u003cem\u003eVibrio cholerae\u003c/em\u003e [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. It is among the oldest and most well understood epidemic-prone diseases. Cholera outbreaks have occurred throughout history, starting with the 19th century pandemic that originated in the Ganges delta [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Previous studies have reported that cholera mostly occurs in sub-Saharan Africa, and some parts of the Middle East region are endemic to approximately 69 countries; Asia, Africa and America, including sub-Saharan Africa, are more prone to this disease [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Reports by the World Health Organization estimated that a total of 2.8\u0026nbsp;million people contracted cholera, and approximately 91,000 people died [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Cholera is an enteric disease that has two distinctive epidemiological features: its ability to appear in explosive outbreaks and its ability to cause a true pandemic [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. While most infected individuals experience no symptoms, others develop profuse watery diarrhea, vomiting, muscle cramps, weakness, and rapid heart rate [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The core mechanism by which \u003cem\u003eVibro cholorae\u003c/em\u003e initiates disease, which is responsible for the dehydration observed during cholera, is the secretion of CT, which is a protein complex [\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. After colonization by \u003cem\u003eVibrio cholorae\u003c/em\u003e, the bacteria secrete cholera enterotoxin, which interacts with the receptors in the intestinal epithelium, thereby leading to the manifestation of the symptoms mentioned earlier [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Studies have shown that a wide range of treatment options, including oral rehydration therapy, the use of antimicrobial agents, antibiotics and vaccines, are available, each of which depends on the severity of the patient\u0026rsquo;s cholera [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, due to the development of new antibiotic-resistant strains of \u003cem\u003eVibrio cholerae\u003c/em\u003e, there is a need to develop more treatment options.\u003c/p\u003e \u003cp\u003eHeterocycles are a very important class of organic compounds that have been reported to account for more than 50% of reported organic compounds [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. They have been found to be essential components of hemoglobin, RNA, proteins, vitamins and other biologically active compounds, and they serve as precursors of a wide range of potential biological compounds [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Thiadiazoles, which are considered heterocyclic compounds over time, have received much attention, possibly due to their biological and pharmaceutical implications, which increase their availability for pharmaceutical and industrial applications as a result of the =\u0026thinsp;N-C-S moiety [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Thiadiazoles are five-membered heterocyclic compounds that possess two nitrogen atoms and a sulfur atom as a part of the aromatic ring [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. These compounds are azole compounds. There are approximately four isomeric forms of thiadiazoles. Among the four isomers, 1,3,4-thiadiazoles have been reported by previous studies to have a plethora of biological applications compared to the other isomers. Thiadiazoles have been employed as antibacterial, antimicrobial, and anticancer agents [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Some well-known drugs, including acetazolamide, scefazolin, megazol and methazolamine, which are currently in use, are thiadiazoles [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral studies have reported the use of thiadiazole derivatives as compounds with biological activity using density functional theory (DFT), which is a computational method. Karaburun and colleagues [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] synthesized and characterized a series of 1,3,4-thiadiazole derivatives to obtain a novel bioactive compound with considerable antifungal activity. The in vitro antifungal activity of the synthesized compounds was determined against eight Candida species. Two active compounds, 3k and 3 l, showed antifungal effects. Docking studies on 14-α-sterol demethylase enzymes were also performed to investigate the inhibitory effects of the compounds on ergosterol biosynthesis. Theoretical absorption, distribution, metabolism, and excretion (ADME) predictions were calculated to determine the drug likeness of the final compounds. The results of the antifungal activity test, ergosterol biosynthesis assay, docking study, and ADME predictions indicated that the synthesized compounds are potential antifungal agents that inhibit ergosterol biosynthesis, probably by interacting with the fungal 14-α-sterol demethylase. Additionally, studies by Iyam \u003cem\u003eet al\u003c/em\u003e. (2024) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] explored thiadiazole derivatives for their potential as antibacterial agents against carbapenem-resistant \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e and \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e. To achieve this goal, the compound under study was analysed both electronically and structurally using density functional theory. Their molecular docking results revealed the potential therapeutic efficacy of thiadiazole derivatives against carbapenem-resistant strains, suggesting that they are more favourable than conventional drugs in terms of binding affinity and interaction strength. Tunel \u003cem\u003eet al\u003c/em\u003e. (2021) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] synthesized thioether-bridged imidazo[2,1-b][\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]thiadiazole derivatives. The synthesized structure was characterized using 1H NMR, FT-IR and 13C NMR, elemental analysis, mass spectrometry and X-ray diffraction analysis. The mycelial growth, mycelial growth inhibition, minimum inhibitory concentration, minimum fungicidal concentration, and lethal dose against various plant pathogenic fungi were determined for all of the target compounds synthesized in the study. The results from the test showed that the majority of the compounds had considerable antifungal activity. Furthermore, the absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters of the compounds were calculated, and it was also observed that all of the compounds met the general drug-likeness criteria. Finally, the molecular docking results showed that compounds 7h, 7i, 8h, and 8i displayed greater affinity for PDB ID:5TZ1, which is a CYP51 antifungal target structure. The main aim of this study was to determine the biological activity of a thiadiazole derivative (TDZD) against cholera using DFT and molecular docking, thereby contributing to the global effort to combat cholera and ultimately enhance human well-being. By propelling the boundaries of scientific understanding in this critical domain, this research holds promise for reshaping the trajectory of strategies against cholera and paves the way for more effective interventions in the future.\u003c/p\u003e"},{"header":"2.0 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Experimental\u003c/h2\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003e2.1.1 Synthesis of N1,N10-Bis(5-(2-oxo-2H-chromen-3yl)-1,3,4-thiadiazol-2-yl)-decane-diamide\u003c/h2\u003e \u003cp\u003eThis compound was synthesized and reported by Hamdy [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A mixture of 4 (0.446 g, 1 mmol), salicylaldehyde (0.244 g, 2 mmol) and 0.5 g of fused AcONa in AcOH (30 mL) was refluxed for 2 hours. After cooling, the formed product mass was collected, dried, and finally purified to afford this derivative. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the proposed structure of the derivative.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003e2.1.2 Elemental analysis\u003c/h2\u003e \u003cp\u003eFrom the analytical data, the empirical formula of the studied compound was observed to be C\u003csub\u003e32\u003c/sub\u003eH\u003csub\u003e28\u003c/sub\u003eN\u003csub\u003e6\u003c/sub\u003eO\u003csub\u003e6\u003c/sub\u003eS\u003csub\u003e2\u003c/sub\u003e, which agrees with the values calculated for C, H, and N (see ref [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Computational Methodology\u003c/h2\u003e \u003cp\u003eIn this study, calculations were carried out at the DFT/B3LYP/6-311\u0026thinsp;+\u0026thinsp;+\u0026thinsp;G (d, p) level by employing Gaussian 09 software [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Compound geometry optimization was conducted via the same level of theory. To determine the electronic and structural properties of the derivative, various analyses were performed, including frontier molecular orbital (FMO) and natural bond orbital (NBO) analyses, electron localization function (ELF) studies, and noncovalent interaction (NCI) studies. To gain further insight into the stability of the studied compound, natural bond orbital (NBO) analysis was carried out using the NBO 7.0 program found in the Gaussian package. The system's reactivity and stability were analysed via frontier molecular orbital (FMO) analysis, and the visualized orbitals were obtained using Chemcraft [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In addition to findings concerning HOMO-LUMO interactions, supplementary quantum descriptors, including chemical hardness, chemical softness, electronegativity, chemical potential, and electrophilicity index, were computed. To provide additional validation for the insights gained from the HOMO-LUMO analysis, molecular electrostatic map analysis was carried out, and the results were visualized using Gaussview 6.0.16 software.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Molecular docking procedure\u003c/h2\u003e \u003cp\u003eThe molecular docking process is a computational technique that predicts the binding mode and binding affinity of small molecules, such as drug candidates, to a target protein. Autodock tools and AutoDock Vina 1.5.6 [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] are widely used software tools for performing molecular docking simulations. In this study, TDZD was docked with two selected proteins, namely, IXTC and 6EHB, which are CTRs obtained from a protein database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.rcsb.org/\u003c/span\u003e\u003cspan address=\"https://www.rcsb.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Carefully, these proteins were prepared for docking simulations by removing water, heteroatoms, and ligands and adding polar hydrogen using Biovia Discovery Studio software version 2021 [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The standard drug amoxicillin (AMOX) was also docked with the proteins to compare the binding affinity of the studied compound with that of the standard drug. The xyz coordinates of the 1XTC are x\u0026thinsp;=\u0026thinsp;1.052620, y=-0.890880, z\u0026thinsp;=\u0026thinsp;21.961832 and the radius is 21.000000 for 6EHB x=-4.269381, y\u0026thinsp;=\u0026thinsp;51.699348, z\u0026thinsp;=\u0026thinsp;92.021902 and the radius\u0026thinsp;=\u0026thinsp;19.968170.\u003c/p\u003e \u003c/div\u003e"},{"header":"3.0 Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Spectral characterization\u003c/h2\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e3.1.1 Vibrational analysis\u003c/h2\u003e \u003cp\u003eFourier transform infrared spectroscopy (FT-IR) provides insight into how molecules vibrate and the frequencies at which they are used. It also provides insight into the vibration of atoms in a molecule, which may be a result of polarization, and how they are linked together. The strength of the FT-IR measurement depends on how much the bonds that cause vibrations change their dipole moments. The full details of the FTIR theoretical results can be found in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eN-H Vibration\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe N-H functional group was theoretically observed in TDZD, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The frequency in different solvents and the gas phase falls between 3553 and 3557 cm⁻\u0026sup1; with the same vibration mode known as symmetrical stretching. The experimental frequency of falls was 3225 cm⁻\u0026sup1;, as reported by Hamdy [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. All the solvents (TDZD-ethanol, TDZD-DMSO, and TDZD-water) exhibited the same theoretical value of 3553 cm⁻\u0026sup1;, while TDZD-Gas exhibited a different value at 3557 cm⁻\u0026sup1;. This result suggests the comprehensible stability of the compound in the gaseous phase and a slight difference in its stability in various solvents, which is attributed to solvation effects. This finding aligns with the reported literature [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cb\u003eC-H Vibration\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe C-H vibration characteristically falls within the range of 3002\u0026ndash; 3184 cm⁻\u0026sup1;, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. However, this vibration occurs in two functional groups: CH and CH₂. The CH functional group has an experimental value of 3103 cm⁻\u0026sup1; and portrays a symmetric stretching vibration. The solvents (TDZD-ethanol, TDZD-DMSO, and TDZD-water) exhibited the same theoretical values of 3184 cm⁻\u0026sup1; and 3047 cm⁻\u0026sup1;, respectively, on the gas. In the same vein, the CH₂ functional group showed a symmetric stretching mode of vibration with an experimental value ranging from 2944\u0026ndash;3042 cm⁻\u0026sup1; and a theoretical value ranging from 3002\u0026ndash;3043 cm⁻\u0026sup1;. This result therefore suggests the \u003cb\u003estability\u003c/b\u003e of the compound even when polar solvents are included, which is consistent with the reported literature [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cb\u003eC\u0026thinsp;=\u0026thinsp;O vibrations\u003c/b\u003e \u003c/p\u003e \u003cp\u003eVibration of this functional group was observed experimentally in the range of 1694\u0026ndash;2861 cm⁻\u0026sup1;, a theoretical value ranging from 1707\u0026ndash;3002 cm⁻\u0026sup1;, and a symmetric mode of vibration. It is also important to note that all the phases (TDZD-ethanol, TDZD-DMSO, TDZD-gas and TDZD-water) for each functional group exhibit the same theoretical value in accordance with the reported literature of this functional group, indicating the stability of the compound [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cb\u003eC\u0026thinsp;=\u0026thinsp;C Vibration\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThis vibration displayed a symmetric stretching vibration. The experimental value was detected at 1616 cm⁻\u0026sup1;, whereas the theoretical stretching values for the examined compound in various solvents and the gas phase fell within the range of 1632\u0026ndash;1645 cm⁻\u0026sup1;. These findings indicate that TDZD in DMSO and TDZD in water had a value of 1632 cm⁻\u0026sup1;, TDZD in ethanol had a value of 1645 cm⁻\u0026sup1;, and TDZD in gas had a value of 1640 cm⁻\u0026sup1;. In simpler terms, the compounds exhibited similar stabilities in the presence of TDZD in DMSO and in the presence of TDZD in water and different stabilities in the presence of ethanol and gas, suggesting that these compounds are less stable than the other phases [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Generally, the symmetric stretching and various identified functional groups highlighted in this context indicate good stability of the compound.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eVibrational analysis of the TDZD derivative\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eFT-IR Frequency (cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFunctional Group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eVibration mode\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExp.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eTheoretical\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDMSO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTDZD DMSO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTDZD Ethanol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTDZD Gas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTDZD Water\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3225\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3553\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3553\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3557\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3553\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSymmetric stretching\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3167\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSymmetric stretching\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3042\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3043\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3043\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3047\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3043\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSymmetric stretching\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2944\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSymmetric stretching\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2861\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC\u0026thinsp;=\u0026thinsp;O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSymmetric stretching\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1740\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1738\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1738\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1751\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC\u0026thinsp;=\u0026thinsp;O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSymmetric stretching\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1694\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1708\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1709\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1744\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1707\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC\u0026thinsp;=\u0026thinsp;O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSymmetric stretching\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1616\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1632\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1645\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1640\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1632\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC\u0026thinsp;=\u0026thinsp;C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSymmetric stretching\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003e3.1.2 UV‒vis analysis\u003c/h2\u003e \u003cp\u003eThe studied compounds were optimized at the B3LYP/6-311G++(2d, 2p) level of theory. Ultraviolet (UV) radiation is assimilated by a compound's molecules, prompting the transfer of electrons between different energy levels thus offering knowledge and understanding of the reactivity and stability of the compound [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. According to Johann Wilhelm Ritter, each molecule exhibits a unique absorption spectrum that can be used to identify the molecule and characterize its chemical structure [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. For instance, conjugated systems in organic molecules, such as those with double bonds or aromatic rings, often result in distinctive absorption bands in the UV‒vis spectrum. Hence, this analysis provides information about the reactivity and stability of TDZD by thoroughly examining the excitation of electrons following the absorption of UV light. Based on the results obtained (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), in the gas phase, the electrons on the studied compound underwent excitation from the ground state (S\u003csub\u003e0\u003c/sub\u003e) to the first state (S\u003csub\u003e1\u003c/sub\u003e) at an energy of 3.427 eV and a wavelength of 362 nm. Conversely, the transition of electrons to the second excitation state (S\u003csub\u003e2\u003c/sub\u003e) occurred at 3.548 eV and 349 nm. Upon shift to the third excited state (S\u003csub\u003e3\u003c/sub\u003e), the electron underwent a transition at an energy level of 3.647 eV and a wavelength of 340 nm. Similarly, all transition in this context were captured to flow from the highest filled orbital (H) to the lowest unfilled orbital (L). Thus, it was observed that the energy increases as the electrons advance from the ground state first and beyond, indicating good stability, as electrons find it challenging to easily flow beyond the ground state. This behavior was consistent with the solvation effects of various solvents (DMSO, ethanol, and water). additionally, the introduction of DMSO, ethanol, and water into the studied compound results in a slightly lower excitation energy across all the excited states, indicating solvatochromism. This is due to the solvation effect on the molecules of the studied compound, as solute-solvent interactions can stabilize the excited state of the molecule, thereby reducing its excitation energy. Therefore, the studied compound exhibited a lower excitation energy in the solvent phase than in the gas phase, which indicates that the solvent environment plays a key role in modulating the electronic structure and properties of the compound. Comparatively, the studied compound has more reactive behavior in the gas phase than in the solvent phase.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUV‒vis analysis results for the studied derivative\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompound\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTransition Type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEnergy (eV)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWavelength (nm)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOscillator strength (\u003cem\u003ef\u003c/em\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePercentage contribution (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eTransition\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDMSO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eS\u003csub\u003e0\u003c/sub\u003e-S\u003csub\u003e1\u003c/sub\u003e(171 \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e172)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.438\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e361\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.7055\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eH \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eS\u003csub\u003e0\u003c/sub\u003e-S\u003csub\u003e2\u003c/sub\u003e (170 \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e173)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.508\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e353\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.7362\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eH \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e L\u0026thinsp;+\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eS\u003csub\u003e0\u003c/sub\u003e-S\u003csub\u003e3\u003c/sub\u003e (169 \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e173)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.628\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e342\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0248\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eH \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e L\u0026thinsp;+\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEthanol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eS\u003csub\u003e0\u003c/sub\u003e-S\u003csub\u003e1\u003c/sub\u003e(171 \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e172)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.443\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e360\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.6969\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eH \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eS\u003csub\u003e0\u003c/sub\u003e-S\u003csub\u003e2\u003c/sub\u003e (170 \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e173)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.512\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e353\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.7266\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eH \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e L\u0026thinsp;+\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eS\u003csub\u003e0\u003c/sub\u003e-S\u003csub\u003e3\u003c/sub\u003e (169 \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e173)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.627\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e342\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0249\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eH \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e L\u0026thinsp;+\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eS\u003csub\u003e0\u003c/sub\u003e-S\u003csub\u003e1\u003c/sub\u003e(169 \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e172)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.427\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e362\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eH \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e L\u0026thinsp;+\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eS\u003csub\u003e0\u003c/sub\u003e-S\u003csub\u003e2\u003c/sub\u003e (171 \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e173)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.548\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e349\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.3542\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eH \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e L\u0026thinsp;+\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eS\u003csub\u003e0\u003c/sub\u003e-S\u003csub\u003e3\u003c/sub\u003e (170 \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e172)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.647\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e340\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.3839\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eH \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e L\u0026thinsp;+\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWater\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eS\u003csub\u003e0\u003c/sub\u003e-S\u003csub\u003e1\u003c/sub\u003e(171 \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e172)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.436\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e361\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.7094\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eH \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eS\u003csub\u003e0\u003c/sub\u003e-S\u003csub\u003e2\u003c/sub\u003e (170 \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e173)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.506\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e353\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.7407\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eH \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e L\u0026thinsp;+\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eS\u003csub\u003e0\u003c/sub\u003e-S\u003csub\u003e3\u003c/sub\u003e (169 \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e173)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.628\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e342\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0248\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eH \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\to\\)\u003c/span\u003e\u003c/span\u003e L\u0026thinsp;+\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Electronic properties\u003c/h2\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003e3.2.1 Frontier Molecular Orbital (FMO) studies\u003c/h2\u003e \u003cp\u003eThe frontier molecular orbital (FMO), which encompasses the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), aids in understanding the electronic behavior of compounds or molecules [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Notably, the energy gap (E.g.) is an essential parameter obtained from the difference in the energies of the HOMO and LUMO, which represents the chemical reactivity, stability, and kinetics of a compound [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In line with previous research, lower values for E.g. indicate a less reactive and less stable compound, whereas higher values indicate more stable and less reactive compounds [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Additionally, the HOMO and LUMO values are used to compute the quantum descriptor results, viz., global hardness (ղ), softness (σ), electrophilicity (ω), chemical potential (\u0026micro;), and electronegativity (χ\u003cb\u003e)\u003c/b\u003e. Interestingly, the reactivity of TDZD was determined in gas and solvent phases (DMSO, ethanol, and water). These solvents are considered polar due to the presence of polar functional groups in their structures [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Furthermore, the calculated results are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, and a pictorial view of the HOMO and LUMO surface is displayed in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. According to the results presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, the energy gap of the compound TDZD in the gas phase is 3.653 eV, which is lower than that observed in the solvent phase. However, TDZD in ethanol is reported at 3.717 eV, which is lower than that observed for TDZD_Water and TDZD_DMSO, which are reported at 3.718 eV. Emphatically, we can say that in the solvent phases studied, the compounds exhibit similar reactivity, although TDZD is more reactive in the gas phase and more stable in the solvent phase (water and DMSO). Additionally, the values obtained for chemical hardness (ղ) and softness (σ) suggest that TDZD in all phases is biologically active.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCalculated results for the HOMO, LUMO, Eg, and quantum descriptors for the studied compounds\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompound\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHOMO\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLUMO\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEg (eV)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eղ(eV)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eS\u003c/em\u003e (eV\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026micro; (eV)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eχ(eV)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eω(eV)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTDZD_Gas\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-6.411\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.757\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.653\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.826\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.913\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-4.584\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.584\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e5.753\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTDZD_Water\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-6.499\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.781\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.718\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.859\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.929\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-4.640\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.640\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e5.790\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTDZD_DMSO\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-6.498\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.780\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.718\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.859\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.929\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-4.639\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.639\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e5.788\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTDZD_Ethanol\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-6.496\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.779\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.717\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.858\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.929\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-4.637\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.637\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e5.785\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e\u003cb\u003e3.3 Natural Bond Orbitals (NBOs)\u003c/b\u003e\u003c/h2\u003e \u003cp\u003eNBO is an important approach used to explore the stability, charge transfer and hyperconjugative effects, inter- and intramolecular interactions of a compound and delocalization of electron density within a molecule [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. NBO can be calculated based on the second-order perturbation energy; thus, the greater the stabilization energy is, the greater the interaction between the donor (occupied) and acceptor (unoccupied) orbitals [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. The perturbation energy value measures the concentration of the interaction between the donor and acceptor. A higher perturbation (E\u003csup\u003e2\u003c/sup\u003e) value indicates a strong interaction and enhanced stabilization of the molecular system [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. There are different types of bonds of interest observed in NBO, such as sigma (σ), anti-sigma (σ*), pi-bond (π), anti-pi-bond (π*), and lone pair (LP) bonds. In this study, σ \u0026rarr; σ* transitions occurred in the examination of the orbitals of TDZD. Based on our results presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, the gas phase had a maximum stabilization energy of 399.40 kcal/mol, which resulted from σC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u0026rarr; σ*C\u003csub\u003e46\u003c/sub\u003e-H\u003csub\u003e73\u003c/sub\u003e and subsequently 370.34 kcal/mol from σC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u0026rarr; σ*C\u003csub\u003e45\u003c/sub\u003e-H\u003csub\u003e71\u003c/sub\u003e, and the least stabilization energy was observed at 324.83 kcal/mol, which was derived from σC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u0026rarr; σ*C\u003csub\u003e45\u003c/sub\u003e-H\u003csub\u003e72\u003c/sub\u003e. Similarly, the strongest donor-acceptor NBO interactions for water, DMSO, and ethanol from the scrutinized compound were observed at σC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u0026rarr; σ*C\u003csub\u003e45\u003c/sub\u003e-H\u003csub\u003e72\u003c/sub\u003e, σC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u0026rarr; σ*C\u003csub\u003e45\u003c/sub\u003e-H\u003csub\u003e72\u003c/sub\u003e, and σC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u0026rarr; σ*C\u003csub\u003e45\u003c/sub\u003e-H\u003csub\u003e72\u003c/sub\u003e, with stabilization energies of 350.09 kcal/mol, 349.93 kcal/mol, and 349.58 kcal/mol, respectively, with no significant difference among the solvents. In the gas phase, the compound has the highest perturbation energy. The study compound has the potential to maintain stability, which is indicative of a good therapeutic agent.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSelected second-order perturbation energies for the studied compounds\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompound\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTransition Type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDonor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAcceptor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eE \u003csup\u003e(2)\u003c/sup\u003e kcal/mol\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eE(j)- E(i)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eF (I, j)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGas\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eσ\u0026rarr; σ*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eσC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eσ*C\u003csub\u003e46\u003c/sub\u003e-H\u003csub\u003e73\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e399.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.592\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eσ\u0026rarr; σ*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eσC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eσ*C\u003csub\u003e45\u003c/sub\u003e-H\u003csub\u003e71\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e370.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.733\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eσ\u0026rarr; σ*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eσC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eσ*C\u003csub\u003e45\u003c/sub\u003e-H\u003csub\u003e72\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e324.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.442\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWater\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eσ\u0026rarr; σ*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eσC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eσ*C\u003csub\u003e45\u003c/sub\u003e-H\u003csub\u003e72\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e350.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.466\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eσ\u0026rarr; σ*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eσC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eσ*C\u003csub\u003e45\u003c/sub\u003e-H\u003csub\u003e71\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e309.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.702\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eσ\u0026rarr; σ*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eσC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eσ*C\u003csub\u003e46\u003c/sub\u003e-H\u003csub\u003e73\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e309.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.563\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDMSO\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eσ\u0026rarr; σ*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eσC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eσ*C\u003csub\u003e45\u003c/sub\u003e-H\u003csub\u003e72\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e349.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.466\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eσ\u0026rarr; σ*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eσC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eσ*C\u003csub\u003e45\u003c/sub\u003e-H\u003csub\u003e71\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e310.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.703\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eσ\u0026rarr; σ*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eσC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eσ*C\u003csub\u003e46\u003c/sub\u003e-H\u003csub\u003e73\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e310.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.564\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEthanol\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eσ\u0026rarr; σ*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eσC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eσ*C\u003csub\u003e45\u003c/sub\u003e-H\u003csub\u003e72\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e349.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.465\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eσ\u0026rarr; σ*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eσC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eσ*C\u003csub\u003e46\u003c/sub\u003e-H\u003csub\u003e73\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e312.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.564\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eσ\u0026rarr; σ*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eσC\u003csub\u003e45\u003c/sub\u003e-C\u003csub\u003e46\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eσ*C\u003csub\u003e45\u003c/sub\u003e-H\u003csub\u003e71\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e311.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.703\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Molecular electrostatic potential (MESP)\u003c/h2\u003e \u003cp\u003eMESP data are derived from a reliable quantum chemical method that has been widely used for the interpretation and prediction of various aspects of chemical reactivity [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. To provide insight into the reactivity of electrophilic and nucleophilic site attack for TDZD, colours are used to demonstrate the colours of interest; red to yellow indicate electron-rich regions, while yellow indicates electron deficiency [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows that the benzene ring is electrophilic in the region shown in blue and is electron deficient. On the right side of the compound, the pyran ring is nucleophilic at the lower part attached to oxygen, and the upper side is electrophilic. The thiadiazole ring is electron rich at the part attached to the nitrogen on the right side of the compound and electron deficient at the sulfur-attached part. The decane region is electron poor, but when it is attached to an oxygen atom, it becomes electron rich.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Noncovalent Interaction Analysis\u003c/h2\u003e \u003cp\u003eThe study of noncovalent interactions (NCIs) is pivotal in drug development because it provides an understanding of the binding mechanisms and stability of molecular complexes. However, NCIs arise from different forces, including electrostatic interactions, weak interactions, and hydrogen bonding [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Electrostatic interactions are hinged on Coulomb's law and occur between charged particles where positively and negatively charged regions of molecules attract each other [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. These interactions play a key role in understanding the binding of charged ligands to receptors in drug design. van der Waals interactions, including dispersion forces, arise from fluctuations in electron distributions within molecules [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Even though they are weaker than covalent bonds, van der Waals forces are significant in molecular recognition and binding. Hydrogen bonding occurs when hydrogen atoms covalently bond to electronegative atoms such as oxygen or nitrogen and interact with other electronegative atoms [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Hydrogen bonds contribute to the stability of protein structures, such as alpha helices and beta sheets, and are essential for molecular recognition and ligand binding [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Therefore, the behavior of the compound under study can be understood by closely examining its noncovalent interactions (NCIs), as it highlights some crucial forces, including van der Waals forces, repulsive forces, and hydrogen bonds. Understanding of some of these interactions is paramount for the development of new treatments and can provide key information on the behaviors of compounds and potential applications. Hence, from the results presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, two major types of force were captured at the surface of the compound, as indicated by green patches, which connote the van der Waal force of interaction, and red patches, indicating steric repulsion. The steric repulsion force was mostly attributed to the intramolecular nature of the benzene ring, thiadiazole, and pyran scaffold of the studied compound. The van der Waal force of interaction was noted around the region of the 1,3,4-thiadiazole ring, indicating the potential properties of the compound. In comparison to the various phases applied in this study, there was no significant variation observed for this analysis; hence, this compound remains consistent with the nature of its interactive properties, thereby indicating its potential as a promising drug.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e3.6 Electron localization function (ELF) analysis\u003c/h2\u003e \u003cp\u003eELF analysis is an important concept in the modelling of novel compounds because it is used to analyse the distribution of electrons in a compound. Additionally, it provides valuable insights into chemical bonding, molecular structure, and reactivity [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. ELF analysis goes beyond traditional electron density calculations, offering a more detailed perspective on electron behavior. Moreover, the ELF measures the probability of finding a pair of electrons in a given region of space [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Unlike the electron density, which represents the total electron density, the ELF focuses specifically on the localization of electrons. High values of ELF indicate strong electron localization, suggesting the presence of covalent bonds or lone pairs, while low values correspond to delocalized or diffuse electron clouds, characteristic of nonbonding regions [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. This analysis provides a clear visualization of chemical bonding, revealing regions of strong electron pairing associated with bonds and lone pairs. This information aids in the interpretation of molecular structures and the prediction of chemical reactivity [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Therefore, this technique can be very helpful in identifying the best candidate compounds for drug development. From the respective results illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, the atoms in the thiadiazole and benzene rings on both sides of the studied compound displayed dense electrons, thus highlighting the interaction regions. The delocalized region of electrons in this context was notably at the decane atoms. Despite the implementation of diverse phases (water, DMSO, gas, and ethanol), no significant variation in the localized and delocalized regions of the compound was observed. Therefore, understanding electron behavior in molecules provides insight into the structure-property relationships and reaction mechanisms of the studied compound.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e3.7 Molecular docking\u003c/h2\u003e \u003cp\u003eIn this section, we elucidate the biological activity of thiadiazole derivatives against the \u003cem\u003eVibrio cholerae\u003c/em\u003e-related proteins IXTC and 6EHB. IXTC and 6EHB are two proteins associated with \u003cem\u003eVibrio cholerae\u003c/em\u003e, the bacterium responsible for cholera [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. For therapeutic intervention, targeting these proteins with the considered ligand is crucial because it can interfere with important biological processes, stop the progression of this disease, and possibly even result in the creation of new medicines for treating cholera. To achieve this goal, molecular docking enables us to understand the interaction mechanism and inhibition efficiency of the ligand against proteins, and the results based on high negative binding affinity, short distances and the presence of hydrogen bonds, van der Waals interactions, hydrophobic interactions or other kinds of interactions demonstrate the potential of the ligands for investigating proteins [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. The docking results of the ligand were compared to those of the recommended drug amoxicillin, and the obtained results are shown in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. The graphical representations showing ligand interactions within the amino acid pockets of the protein and the distance of interaction are displayed in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e. For example, utilizing molecular docking, Owen and colleagues [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e] showed that semicarbazine derivatives exhibited a binding affinity of -5.4 kcal/mol for the protein 1XTC. Using molecular docking, Ubah \u003cem\u003eet al.\u003c/em\u003e [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e] demonstrated the potency of aminoresin derivatives against \u003cem\u003eVibrio cholerae\u003c/em\u003e proteins. In our study, the protein 1XTC, when docked against the studied thiadiaazole derivative, showed a binding affinity of -7.6 kcal/mol, which is comparable to the value of -7.8 kcal/mol obtained for the standard drug amoxicillin. Moreover, both the standard drug and the studied ligand were docked into the pockets of the following amino acids: lysine, arginine and aspartate, which are essential amino acids. The thiadiazole derivative (TDZD) interacted with the amino acids LYS284, PRO285, GLN254, TYR282, and LYS251, yielding a binding score of -7.1 kcal/mol. Similarly, the standard drug amoxicillin interacted with ARG220, LYS9, PHE257, and TYR250, resulting in a binding score of -7.4 kcal/mol. The findings from these studies suggest the potential of TDZD as a drug candidate for treating cholera, as it exhibits activity comparable to that of standard drugs against selected proteins.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBinding scores for the studied ligands against the selected proteins: 1XTC and TDZD\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInteractions\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBinding affinity (Kcal/mol)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAmino acid residues\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTDZD\u0026thinsp;+\u0026thinsp;1XTC\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-7.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLYS63, LYS237, LYS62, ARG67, ASP238\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAMOX\u0026thinsp;+\u0026thinsp;1XTC\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-7.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLYS63, LYS237, LYS63, ASP70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTDZD\u0026thinsp;+\u0026thinsp;6EHB\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-7.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLYS284, PRO285, GLN254, TYR282, LYS251\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAMOX\u0026thinsp;+\u0026thinsp;6EHB\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-7.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eARG220, LYS9, PHE257, TYR250\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e3.8 ADMET studies\u003c/h2\u003e \u003cp\u003eAbsorption, distribution, metabolism, excretion, and toxicity (ADMET) play key roles in drug discovery and development. High-quality drug candidates should not only have sufficient efficacy against therapeutic targets but also show appropriate ADMET properties at therapeutic doses [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. The prediction of the fate of a drug and the effects caused by a drug inside the body, such as how the drug is absorbed if administered orally and how much is absorbed in the gastrointestinal tract, is a vital part of drug identification [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Poor absorption of a drug may affect its distribution and metabolism, thereby leading to neurotoxicity and nephrotoxicity. Interestingly, the pharmacokinetic properties of the studied compound were evaluated to gain insight into its therapeutic effects on living organisms. From this interpretation, TDZD is suggested to have a proper permeability because its value is -6.012 log cm/s, which is correct according to the predicted value of \u0026gt;-5.15 log cm/s [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. The mechanism of plasma protein binding (PPB) involves the uptake and distribution of a drug, and the binding of a drug to a protein strongly influences its pharmacodynamic behavior [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. PPB can directly influence oral bioavailability. According to the empirical decision for drug interpretation, the predicted value is \u0026le;\u0026thinsp;90%, while the results from this study indicate that 99.907% of the drugs are highly protein bound and may exhibit a low therapeutic index [\u003cspan additionalcitationids=\"CR49\" citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. Drugs that act in the CNS need to cross the BBB to reach their molecular target. The pragmatic decision results should be within the range of 0-0.7 cm/s; from this study, the result is shown to be greater than the decision result and indicates that it is poor [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. Cytochrome P450 is an important detoxification enzyme in the body. Many drugs are deactivated by cytochrome P450 isoforms, while some can be activated by them. As shown in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, the cyclopeptides CYP1A2, CYP2C19 and CYP2D6 are predicted not to be P450 inhibitors in any isoform, except for CYP2C9 and CYP3A4, which implies that the ability of the body to detoxify these inhibitors is slightly lower [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. The clearance of a drug emphasizes the volume of distribution alongside the half-life and the frequency of dosing of a drug and is an important pharmacokinetic parameter. Pragmatic decisions show that clearance should be \u0026ge;\u0026thinsp;5 ml/min/kg for excellent clearance, while the prediction of this clearance is 1.300 ml/min/kg because of poor clearance [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. Additionally, toxicity is said to be the degree of damage a drug or compound can cause to an organism. Drug toxicity is dose dependent and can affect the entire body [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. From the toxicity parameters determining the hepatotoxicity of the drug, it is noteworthy that this drug can cause damage to the liver at a predicted range of 0.69, which is a low active value. In terms of cytotoxicity, this drug did not induce cell death, as the predicted result was an inactive value of P\u0026thinsp;=\u0026thinsp;0.97; in this case, immunotoxicity was active, with a value of P\u0026thinsp;=\u0026thinsp;0.96, which indicates an adverse effect on the immune system resulting from exposure to the drug. An inactive carcinogenic value of P\u0026thinsp;=\u0026thinsp;0.62 shows that this drug will not have a tendency to induce tumors or cause cancer in the body [\u003cspan additionalcitationids=\"CR52 CR53 CR54\" citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. Mutagenicity is the ability to cause genetic mutations in cells or eggs and sperm, with an inactive mutagenic value of P\u0026thinsp;=\u0026thinsp;0.97 indicating the opposite [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. From the toxicity study, we ascertained that TDZD has potential for use as a drug agent against cholera. Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e displays the ADMET properties of the studied compounds.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eADMET study on the biological activity of TDZD\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePHYSICOCHEMICAL PROPERTIES\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC\u003csub\u003e32\u003c/sub\u003eH\u003csub\u003e28\u003c/sub\u003eN\u003csub\u003e6\u003c/sub\u003eO\u003csub\u003e6\u003c/sub\u003eS\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMolecular weight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e656.73 g/mol\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNum. of heavy atoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTPSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93.12 \u0026Aring;\u0026sup2;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eABSORPTION\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCaco-2 Permeability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-6.012 cm/s\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMDCK Permeability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.2e-06 cm/s\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP-gp substrate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDISTRIBUTION\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePPB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e99.907%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.743 \u003csub\u003eL\u003c/sub\u003e/kg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBBB PENETRATION\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMETABOLISM\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGI absorption\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCYP1A2 inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCYP2C19 inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCYP2C9 inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCYP2D6 inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCYP3A4 inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEXCRETION\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.300 ml/min/kg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e1/2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.001 sec\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTOXICITY\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatotoxicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eActive (P\u0026thinsp;=\u0026thinsp;0.69)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCytotoxicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInactive (P\u0026thinsp;=\u0026thinsp;0.97)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunotoxicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eActive (P\u0026thinsp;=\u0026thinsp;0.96)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCarcinogenicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInactive (P\u0026thinsp;=\u0026thinsp;0.62)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMutagenicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInactive (P\u0026thinsp;=\u0026thinsp;0.97)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDRUG-LIKENESS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLipinski\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo; 2 violations: MW\u0026thinsp;\u0026gt;\u0026thinsp;500, NorO\u0026thinsp;\u0026gt;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGhose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo; 3 violations: MW\u0026thinsp;\u0026gt;\u0026thinsp;480, MR\u0026thinsp;\u0026gt;\u0026thinsp;130\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVeber\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo; 1 violation: Rotors\u0026thinsp;\u0026gt;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEgan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMuegge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo; 3 violations: MW\u0026thinsp;\u0026gt;\u0026thinsp;600, XLOGP3\u0026thinsp;\u0026gt;\u0026thinsp;5, H-acc\u0026thinsp;\u0026gt;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBioavailability score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4.0 Conclusion","content":"\u003cp\u003eThis study theoretically determined the potential of a thiadiazole derivative (TDZD) as an agent for the treatment of cholera. The DFT/B3LYP/6-311\u0026thinsp;+\u0026thinsp;+\u0026thinsp;2d,2p level of theory was used for the computational studies to obtain substantial information on the various theoretical analyses reported in the study. Notably, this study used a multidimensional approach to determine the properties of TDZD in various solvent environments. Vibrational assignments using FT-IR spectroscopy showed strong agreement between the theoretical and experimental values for the C-H, N-H, C\u0026thinsp;=\u0026thinsp;C, and C\u0026thinsp;=\u0026thinsp;O stretching vibrations in different solvents. This consistency suggests that the ligand is structurally stable across various environments. UV/vis excitation analysis showed that the introduction of DMSO, ethanol, and water into the studied compound resulted in a slightly lower excitation energy across all the excited states. Furthermore, the electronic property analysis revealed that TDZD demonstrated a lower energy gap of 3.653 eV compared to that obtained from ethanol, water and DMSO, with values of 3.717 eV and 3.718, respectively. The chemical hardness of the compound tended to change from that of ethanol to that of methanol, with values of 1.859 eV, 1.858 eV, and 1.826 eV for DMSO, water, ethanol and gas, respectively. This sequence signifies a reduced reactivity of TDZD from the water to gas phase.\u003c/p\u003e \u003cp\u003eThe docking results revealed distinct interactions between TDZD and target proteins. Furthermore, molecular docking results indicated distinctive interactions between the ligand and the 1XTC and 6EHB cholera receptor proteins. A higher binding score was observed between the ligand and 1XTC, with a score of -7.6 kcal/mol, than between the ligand and 6EHB, with a binding score of -7.1 kcal/mol. Furthermore, the drug amoxicillin (AMOX) displayed a comparable binding score of -7.8 kcal/mol for 1XTC and \u0026minus;\u0026thinsp;7.4 kcal/mol for 6EHB. This study reveals the potential of TDZD as a potent agent against cholera and can be subjected to further experimental studies to further confirm this claim.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data are contained within the manuscript and manuscript supporting information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare\u0026nbsp;no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive funding from any source.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMoses M. Edim\u003c/strong\u003e: Project conceptualization, design, supervision. \u003cstrong\u003eAlpha O. Gulack\u003c/strong\u003e: Project administration, Methodology, and supervision.\u0026nbsp;\u003cstrong\u003eBethel C. Ateb, Precious L. Assam, and Friday O. Izachi\u003c/strong\u003e: Writing, editing, analysis, and Manuscript draft.\u0026nbsp;\u003cstrong\u003eAnna Imojara and Fidelis E. Abeng\u003c/strong\u003e: Writing, proofreading, validation and editing. \u003cstrong\u003ePrince J. Nna\u003c/strong\u003e: Visualization, Validation, and Supervision.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBasu I, Mukhopadhyay C. Insights Into Binding Of Cholera Toxin To Gm1 Containing Membrane. (2014): Langmuir 30; 1544-15252\u003c/li\u003e\n\u003cli\u003eCdc (Center for Disease Control and Prevention). Cholera \u0026ndash;Vibro Cholerae Infection.(2018). Http://Www.Cdc.Gov\\Cholera\\Treatment\\Index.Html. Accessed 23 October 2018.\u003c/li\u003e\n\u003cli\u003eSears Cl, Kaper Jb.(2000). Enteric Bacterial Toxins: Mechanisms Of Action And Linkage To Intestinal Secretion. Microbiol Rev.(2001);60; 167-215.\u003c/li\u003e\n\u003cli\u003eWorld Health Organization. (2020). Report Of The First Meeting Of The Who Diagnostic Technical Advisory Group For Neglected Tropical Diseases: Geneva, Switzerland\u003cem\u003e,\u003c/em\u003e 30\u0026ndash;31 October.\u003c/li\u003e\n\u003cli\u003eSawasvirojwong S,(2013). An Adult Mouse Model of Vibrio cholerae-induced Diarrhea for Studying Pathogenesis and Potential Cholera Therapy Plos Negltrop Dis 7; E2293\u003c/li\u003e\n\u003cli\u003eBhuiyan Na, Nusrins , Alam M , Morita M, Watanabe H ,Ramanurthy T , Cravioto A. Nair Gb (2009). Changing Genotyopes of Cholera Toxin (Ct). Fems Immunol Med Microbiol 57; 136 -141.\u003c/li\u003e\n\u003cli\u003eWaldor Mk , Mekalanos Jj (2000). Lysogenic Conversion By A Filamentous Phage Encoding Cholera Toxin . Science 272; 1910-1914.\u003c/li\u003e\n\u003cli\u003eDavis Bm, Moyer Ke , Boyd Ef, Weldor Mk, (2000) Ctx Prophages In Classical Biotype \u003cem\u003eVibro Cholorae \u003c/em\u003e; Functional Phage Genes However, Dysfunctional Phage Genome. J Bacteriol 182-6992-6998.\u003c/li\u003e\n\u003cli\u003eSpangler Bd (2003), Structure And Function Of Cholera Toxin And The Related \u003cem\u003eEscherichia Coli \u003c/em\u003eHeat \u0026ndash; Liable Entero Toxin . Microbiol Rev 56; 622 \u0026ndash; 647.\u003c/li\u003e\n\u003cli\u003eMekakanos Jj,(2004) Cholera Toxin ; Genetic Analysis , Regulation And Role In Pathogenesis . Curr Top Microbiol Ummunol 118;97-118\u003c/li\u003e\n\u003cli\u003eFrancisca B.M Souse, Isavela R.S.G. Noleto, Leticla S. Chaves,Gabriella Pacheco,Ana P . Oliveira, Milkhail M.V. Fonseca And Jand V.R. Medeiros.(2020).A Comprehensive Review Of Therapeutic Approaches Available For The Treatment Of Cholera. Journal Of Pharmacy And Pharmacology,72; 1715-1731.\u003c/li\u003e\n\u003cli\u003eChinchilla, R., N\u0026aacute;jera, C., \u0026amp; Yus, M. (2004). Metalated heterocycles and their applications in synthetic organic chemistry. \u003cem\u003eChemical reviews\u003c/em\u003e, \u003cem\u003e104\u003c/em\u003e(5), 2667-2722. \u003c/li\u003e\n\u003cli\u003eEftekhari-Sis, B., Zirak, M., \u0026amp; Akbari, A. (2013). Arylglyoxals in synthesis of heterocyclic compounds. \u003cem\u003eChemical reviews\u003c/em\u003e, \u003cem\u003e113\u003c/em\u003e(5), 2958-3043.\u003c/li\u003e\n\u003cli\u003eHolownia, A. E. (2020). \u003cem\u003eInvestigating the Synthesis and Reactivity of Boron Carbonyl Compounds\u003c/em\u003e (Doctoral dissertation, University of Toronto (Canada)). \u003c/li\u003e\n\u003cli\u003eSonawane, R. K., \u0026amp; Mohite, S. K. (2021). Heterocyclic Bridgehead Nitrogen Atom System: Review on [1, 2, 4] Triazolo [3,4-b][1, 3, 4] thiadiazole and Its Pharmacological Screening. \u003c/li\u003e\n\u003cli\u003eHu, Y., Li, C. Y., Wang, X. M., Yang, Y. H., \u0026amp; Zhu, H. L. (2014). 1, 3,4-Thiadiazole: synthesis, reactions, and applications in medicinal, agricultural, and materials chemistry. \u003cem\u003eChemical reviews\u003c/em\u003e, \u003cem\u003e114\u003c/em\u003e(10), 5572-5610. \u003c/li\u003e\n\u003cli\u003eZyad H.J. Ai \u0026ndash; Qaisi, Zahraa S,Ai \u0026ndash; Garawi, Ahmed Jasim M, Ai \u0026ndash;Karawi , Ali Jasim Hammood ,Abanoub Mosaad Abdallah, William, Gehad G. Mohamed. (2022). Antiureolytic Activity Of New Water Soluble Thiadiazole Derivatives: Spectroscopic, Dft, And Molecular Docking Studies. \u003cem\u003eSpectrochimica Acta Part A: Molecular And Bimolecular Spectroscopy \u003c/em\u003e272;120971.\u003c/li\u003e\n\u003cli\u003eKaraburun, A. \u0026Ccedil;., Acar \u0026Ccedil;evik, U., Osmaniye, D., Sağlık, B. N., Kaya \u0026Ccedil;avuşoğlu, B., Levent, S., ... \u0026amp; Kaplancıklı, Z. A. (2018). Synthesis and evaluation of new 1, 3,4-thiadiazole derivatives as potent antifungal agents. \u003cem\u003eMolecules\u003c/em\u003e, \u003cem\u003e23\u003c/em\u003e(12), 3129.\u003c/li\u003e\n\u003cli\u003eIyam, S. O., Ogbodo, S. E., Okafor, E. R., Runde, M., Gulack, A. O., Odey, M. O., ... \u0026amp; Louis, H. (2024). Elucidating the antibacterial efficacy of thiadiazol derivative against carbapenem-resistant \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e and \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e: An in-silico perspective. \u003cem\u003eChemical Physics Impact\u003c/em\u003e, \u003cem\u003e8\u003c/em\u003e, 100466.\u003c/li\u003e\n\u003cli\u003eTunel, H., Er, M., Alici, H., Onaran, A., Karakurt, T., \u0026amp; Tahtaci, H. (2021). Synthesis, structural characterization, biological activity, and theoretical studies of some novel thioether‐bridged 2, 6‐disubstituted imidazothiadiazole analogues. \u003cem\u003eJournal of Heterocyclic Chemistry\u003c/em\u003e, \u003cem\u003e58\u003c/em\u003e(6), 1321-1343.\u003c/li\u003e\n\u003cli\u003eThabet, H. K. (2020). Sebacoyl Isothiocyanate in the Synthesis of Bis (1, 3,4-thiadiazole, 1, 3,4-thiadiazolo [3,2-a] pyridine, 4-thiazolidinone, Chromenes, and Naphtho [1,2-b][1, 4] oxazine) Derivatives. \u003cem\u003eOriental Journal of Chemistry\u003c/em\u003e, \u003cem\u003e36\u003c/em\u003e(2).\u003c/li\u003e\n\u003cli\u003eFrisch, A. (2009). Gaussian 09 W Reference. \u003cem\u003eWallingford, USA, 25p\u003c/em\u003e, \u003cem\u003e470\u003c/em\u003e. \u003c/li\u003e\n\u003cli\u003eZhurko, G. A., \u0026amp; Zhurko, D. A. (2013). Chemcraft graphical program for working with quantum chemistry results. \u003cem\u003eChemcraft\u003c/em\u003e, \u003cem\u003e1\u003c/em\u003e, 2008. \u003c/li\u003e\n\u003cli\u003eT.M. Almutairi, N. Rezki, M.R. Aouad, M. Hagar, B.A. Bakr, M.T. Hamed, E. A. Moneer, (2022). Exploring The Anti Parasitic Activity Of Tris-1, 3,4-Thiadiazoles Against Toxoplasma Gondii-Infected Mice, \u003cem\u003eMolecules\u003c/em\u003e 27 (7) 2246. Sharma, S., Sharma, A., \u0026amp; Gupta, U. (2021). Molecular Docking studies on the Anti-fungal activity of Allium sativum (Garlic) against Mucormycosis (black fungus) by BIOVIA discovery studio visualizer 21.1. 0.0.\u003c/li\u003e\n\u003cli\u003eBalzani, V., Bergamini, G., Campagna, S., \u0026amp; Puntoriero, F. (2007). \u003cem\u003ePhotochemistry and photophysics of coordination compounds: overview and general concepts\u003c/em\u003e (pp. 1-36). Springer Berlin Heidelberg.\u003c/li\u003e\n\u003cli\u003eGorretta, N., Gowen, A. A., Holden, N. M., Wolfe, M. L., Ogejo, J. A., \u0026amp; Cummins, E. J. (2020). Visible and near infrared optical spectroscopic sensors for biosystems engineering. \u003cem\u003eVisible Near\u003c/em\u003e\u003cem\u003e-\u003c/em\u003e\u003cem\u003eInfrared Opt. Spectrosc. Sensors Biosyst. Eng\u003c/em\u003e, \u003cem\u003e10\u003c/em\u003e.\u003c/li\u003e\n\u003cli\u003eKumar, A., Deval, V., Tandon, P., Gupta, A., \u0026amp; D\u0026rsquo;silva, E. D. (2014). Experimental and theoretical (FT-IR, FT-Raman, UV\u0026ndash;vis, NMR) spectroscopic analysis and first order hyperpolarizability studies of nonlinear optical material:(2E)-3-[4-(methylsulfanyl) phenyl]-1-(4-nitrophenyl) prop-2-en-1-one using density functional theory. \u003cem\u003eSpectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy\u003c/em\u003e, \u003cem\u003e130\u003c/em\u003e, 41-53.\u003c/li\u003e\n\u003cli\u003eLiu, C., Li, Y., Takao, M., Toyao, T., Maeno, Z., Kamachi, T., ... \u0026amp; Shimizu, K. I. (2020). Frontier molecular orbital based analysis of solid\u0026ndash;adsorbate interactions over group 13 metal oxide surfaces. \u003cem\u003eThe Journal of Physical Chemistry C\u003c/em\u003e, \u003cem\u003e124\u003c/em\u003e(28), 15355-15365.\u003c/li\u003e\n\u003cli\u003eMorales-Bayuelo, A., S\u0026aacute;nchez-M\u0026aacute;rquez, J., Jana, G., \u0026amp; Chattaraj, P. K. (2020). Conceptual DFT analysis of the plausible mechanism of some pericyclic reactions. \u003cem\u003eStructural Chemistry\u003c/em\u003e, \u003cem\u003e31\u003c/em\u003e(5), 1745-1756.\u003c/li\u003e\n\u003cli\u003eDos Santos, R. B., Rivelino, R., de Brito Mota, F., Kakanakova-Georgieva, A., \u0026amp; Gueorguiev, G. K. (2015). Feasibility of novel (H 3 C) n X (SiH 3) 3\u0026minus; n compounds (X= B, Al, Ga, In): structure, stability, reactivity, and Raman characterization from ab initio calculations. \u003cem\u003eDalton Transactions\u003c/em\u003e, \u003cem\u003e44\u003c/em\u003e(7), 3356-3366.\u003c/li\u003e\n\u003cli\u003eFinney, J. L., \u0026amp; Soper, A. K. (1994). Chemical and biological importance of solvent structure and perturbations in solutions. \u003cem\u003eChemical Society Reviews\u003c/em\u003e, \u003cem\u003e23\u003c/em\u003e(1), 1-10.\u003c/li\u003e\n\u003cli\u003ePrashanth, J., Ramesh, G., Naik, J. L., Ojha, J. K., \u0026amp; Reddy, B. V. (2016). Molecular geometry, NBO analysis, hyperpolarizability and HOMO-LUMO energies of 2-azido-1-phenylethanone determined via quantum chemical calculations. \u003cem\u003eMaterials Today: Proceedings\u003c/em\u003e, \u003cem\u003e3\u003c/em\u003e(10), 3761-3769.\u003c/li\u003e\n\u003cli\u003eHalim, S. A., \u0026amp; Ibrahim, M. A. (2017). Synthesis, DFT calculations, electronic structure, electronic absorption spectra, natural bond orbital (NBO) and nonlinear optical (NLO) analysis of the novel 5-methyl-8H-benzo [h] chromeno [2,3-b][1, 6] naphthyridine-6 (5H), 8-dione (MBCND). \u003cem\u003eJournal of Molecular Structure\u003c/em\u003e, \u003cem\u003e1130\u003c/em\u003e, 543-558.\u003c/li\u003e\n\u003cli\u003eRiley, K. E., Piton\u0026aacute;k, M., Jurecka, P., \u0026amp; Hobza, P. (2010). Stabilization and structure calculations for noncovalent interactions in extended molecular systems based on wave function and density functional theories. \u003cem\u003eChemical Reviews\u003c/em\u003e, \u003cem\u003e110\u003c/em\u003e(9), 5023-5063.\u003c/li\u003e\n\u003cli\u003eSuresh, C. H., Remya, G. S., \u0026amp; Anjalikrishna, P. K. (2022). Molecular electrostatic potential analysis: A powerful tool to interpret and predict chemical reactivity. \u003cem\u003eWiley Interdisciplinary Reviews: Computational Molecular Science\u003c/em\u003e, \u003cem\u003e12\u003c/em\u003e(5), e1601.\u003c/li\u003e\n\u003cli\u003eOjha, J. K., Ramesh, G., \u0026amp; Reddy, B. V. (2023). Structure, chemical reactivity, NBO, MEP analysis and thermodynamic parameters of pentamethyl benzene using DFT study. \u003cem\u003eChemical Physics Impact\u003c/em\u003e, \u003cem\u003e7\u003c/em\u003e, 100280.\u003c/li\u003e\n\u003cli\u003eHaque, A., Alenezi, K. M., Khan, M. S., Wong, W. Y., \u0026amp; Raithby, P. R. (2023). Noncovalent interactions (NCIs) in \u0026pi;-conjugated functional materials: advances and perspectives. \u003cem\u003eChemical Society Reviews\u003c/em\u003e, \u003cem\u003e52\u003c/em\u003e(2), 454-472.\u003c/li\u003e\n\u003cli\u003eMahmood, E. A., Poor Heravi, M. R., Khanmohammadi, A., Mohammadi-Aghdam, S., Ebadi, A. G., \u0026amp; Habibzadeh, S. (2022). DFT calculations, structural analysis, solvent effects, and noncovalent interaction study on the para-aminosalicylic acid complex as a tuberculosis drug: AIM, NBO, and NMR analyses. \u003cem\u003eJournal of Molecular Modelling\u003c/em\u003e, \u003cem\u003e28\u003c/em\u003e(10), 297.\u003c/li\u003e\n\u003cli\u003eDella Volpe, C., \u0026amp; Siboni, S. (2022). From van der Waals equation to acid‒base theory of surfaces: a chemical-mathematical journey. \u003cem\u003eReviews of Adhesion and Adhesives\u003c/em\u003e, (1), 47-97.\u003c/li\u003e\n\u003cli\u003eHubbard, R. E., \u0026amp; Haider, M. K. (2010). Hydrogen bonds in proteins: role and strength. \u003cem\u003eeLS\u003c/em\u003e.\u003c/li\u003e\n\u003cli\u003ePoater, J., Duran, M., Sola, M., \u0026amp; Silvi, B. (2005). Theoretical evaluation of electron delocalization in aromatic molecules by means of atoms in molecules (AIM) and electron localization function (ELF) topological approaches. \u003cem\u003eChemical reviews\u003c/em\u003e, \u003cem\u003e105\u003c/em\u003e(10), 3911-3947.\u003c/li\u003e\n\u003cli\u003ePrasana, J. C., Muthu, S., \u0026amp; Abraham, C. S. (2019). Molecular docking studies, charge transfer excitation and wave function analyses (ESP, ELF, LOL) on valacyclovir: a potential antiviral drug. \u003cem\u003eComputational biology and chemistry\u003c/em\u003e, \u003cem\u003e78\u003c/em\u003e, 9-17.\u003c/li\u003e\n\u003cli\u003eJanani, S., Rajagopal, H., Muthu, S., Aayisha, S., \u0026amp; Raja, M. (2021). Molecular structure, spectroscopic (FT-IR, FT-Raman, NMR), HOMO-LUMO, chemical reactivity, AIM, ELF, LOL and Molecular docking studies on 1-Benzyl-4-(N-Boc-amino) piperidine. \u003cem\u003eJournal of Molecular Structure\u003c/em\u003e, \u003cem\u003e1230\u003c/em\u003e, 129657.\u003c/li\u003e\n\u003cli\u003eMierzwa, G., Gordon, A. J., \u0026amp; Berski, S. (2020). The nature of multiple boron-nitrogen bonds studied using electron localization function (ELF), electron density (AIM), and natural bond orbital (NBO) methods. \u003cem\u003eJournal of molecular modelling\u003c/em\u003e, \u003cem\u003e26\u003c/em\u003e, 1-23.\u003c/li\u003e\n\u003cli\u003eOwen, A. E., Anyambula, I. A., Benson, C. U., Ojumola, F. O., Alawa, J. A., Benjamin, I., ... \u0026amp; Louis, H. (2024). Exploration of semicarbazone derivatives as promising agents against cholera: Insights from spectroscopic analysis, reactivity studies (ELF, HOMO-LUMO, NBO), solvation effects, and molecular docking investigations. Chemical Physics Impact, 8, 100438.\u003c/li\u003e\n\u003cli\u003eUbah, C. B., Mujafarkani, N., Sundaravadivelu, A., Narendran, N., Godfrey, O. C., Ogbodo, S. E., ... \u0026amp; Louis, H. (2024). Derivative of aminoresin as potent anti-virulence agent: Synthesis, spectral (FT-IR, UV, NMR) analysis, molecular docking, effect of polar solvation dynamics, and quantum chemical investigation. Journal of Molecular Structure, 1295, 136744.\u003c/li\u003e\n\u003cli\u003eTsaioun, K., Blaauboer, B. J., \u0026amp; Hartung, T. (2016). Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods. \u003cem\u003eALTEX-Alternatives to animal experimentation\u003c/em\u003e, \u003cem\u003e33\u003c/em\u003e(4), 343-358.\u003c/li\u003e\n\u003cli\u003eVinarov, Z., Abdallah, M., Agundez, J. A., Allegaert, K., Basit, A. W., Braeckmans, M., ... \u0026amp; Augustijns, P. (2021). Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review. \u003cem\u003eEuropean Journal of Pharmaceutical Sciences\u003c/em\u003e, \u003cem\u003e162\u003c/em\u003e, 105812.\u003c/li\u003e\n\u003cli\u003eHassan, A. S., Morsy, N. M., Aboulthana, W. M., \u0026amp; Ragab, A. (2023). Exploring novel derivatives of isatin-based Schiff bases as multitarget agents: design, synthesis, in vitro biological evaluation, and in silico ADMET analysis with molecular modelling simulations. \u003cem\u003eRSC advances\u003c/em\u003e, \u003cem\u003e13\u003c/em\u003e(14), 9281-9303.\u003c/li\u003e\n\u003cli\u003eLambrinidis, G., Vallianatou, T., \u0026amp; Tsantili-Kakoulidou, A. (2015). In vitro, in silico and integrated strategies for the estimation of plasma protein binding. A review. \u003cem\u003eAdvanced drug delivery reviews\u003c/em\u003e, \u003cem\u003e86\u003c/em\u003e, 27-45.\u003c/li\u003e\n\u003cli\u003eMikitsh, J. L., \u0026amp; Chacko, A. M. (2014). Pathways for small molecule delivery to the central nervous system across the blood‒brain barrier. \u003cem\u003ePerspectives in medicinal chemistry\u003c/em\u003e, \u003cem\u003e6\u003c/em\u003e, PMC-S13384.\u003c/li\u003e\n\u003cli\u003eNaglah, A. M., Moustafa, G. O., Elhenawy, A. A., Mounier, M. M., El-Sayed, H., Al-Omar, M. A., ... \u0026amp; Bhat, M. A. (2021). N\u0026alpha;-1,3-benzenedicarbonyl-bis-(Amino acid) and dipeptide candidates: synthesis, cytotoxic, antimicrobial and molecular docking investigation. \u003cem\u003eDrug Design, Development and Therapy\u003c/em\u003e, 1315-1332.\u003c/li\u003e\n\u003cli\u003eBillat, P. A., Roger, E., Faure, S., \u0026amp; Lagarce, F. (2017). Models for drug absorption from the small intestine: where are we and where are we going?. \u003cem\u003eDrug Discovery Today\u003c/em\u003e, \u003cem\u003e22\u003c/em\u003e(5), 761-775.\u003c/li\u003e\n\u003cli\u003eSaganuwan, S. A. (2017). Toxicity studies of drugs and chemicals in animals: an overview. \u003cem\u003eBulgarian Journal of Veterinary Medicine\u003c/em\u003e, \u003cem\u003e20\u003c/em\u003e(4).\u003c/li\u003e\n\u003cli\u003eRahmouni, F., Badraoui, R., Ben-Nasr, H., Bardakci, F., Elkahoui, S., Siddiqui, A. J., ... \u0026amp; Rebai, T. (2022). Pharmacokinetics and therapeutic potential of Teucrium polium against liver damage associated hepatotoxicity and oxidative injury in rats: Computational, biochemical and histological studies. \u003cem\u003eLife\u003c/em\u003e, \u003cem\u003e12\u003c/em\u003e(7).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"DFT, Vibrio cholerae, Molecular docking, ADMET, Drug design","lastPublishedDoi":"10.21203/rs.3.rs-4394391/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4394391/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCholera has become one of the major global health challenges, especially in sub-Saharan Africa, where there is poor hygiene and sanitation, and due to the emergence of a resistant strain of the causative agent of cholera, there is a need for new therapeutic agents. Thiadiazoles are organic compounds that have been reported to have various biological applications. This study comprehensively analysed the structural, electronic, and biological properties of N1,N10-bis(5-(2-oxo-2H-chromen-3yl)-1,3,4-thiadiazol-2-yl)-decane-diamide, a thiadiazole derivative (TDZD) as an agent against cholera via theoretical approaches. Computational analyses were conducted employing the B3LYP/6-311\u0026thinsp;+\u0026thinsp;+\u0026thinsp;2d,2p level of theory, which provided substantial insights. Vibrational assignments via FT-IR spectroscopy confirmed the excellent agreement between the theoretical and reported experimental values, confirming the structural stability of the ligand. The electronic property analysis revealed slight variations in the electrophilicity index of the compound across solvents, with the highest (5.790 eV) in water and the lowest (5.753 eV) in the gas phase. Additionally, the high electronegativity values in all solvents, following the order of water (4.640 eV), DMSO (4.639 eV), ethanol (4.637 eV), and gas (4.584 eV), indicated ligand reactivity. Furthermore, molecular docking results indicated distinctive interactions between the ligand and the 1XTC and 6EHB cholera receptor proteins. A higher binding score was observed between the ligand and 1XTC, with a binding score of -7.6 kcal/mol, than between the ligand and 6EHB, with a binding score of -7.1 kcal/mol. Furthermore, the drug amoxicillin (AMOX) showed a comparable binding score of -7.8 kcal/mol for 1XTC and \u0026minus;\u0026thinsp;7.4 kcal/mol for 6EHB. The obtained results suggest the biological potential of TDZD as an anti-cholera agent and can be the foundation for further studies.\u003c/p\u003e","manuscriptTitle":"Elucidating the biological activities of thiadazole derivatives against Vibrio cholerae: Insights from DFT, spectroscopic studies, molecular docking and ADMET","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-23 05:56:45","doi":"10.21203/rs.3.rs-4394391/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"40bd6735-bd78-41e8-a2b6-f3b305cec4df","owner":[],"postedDate":"May 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-16T10:24:41+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-23 05:56:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4394391","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4394391","identity":"rs-4394391","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}