Investigation of Aldose Reductase Inhibitory Potential by Theoretical and Computational Analysis of 2-((4-fluorobenzyl)thio)-6-(4-methoxyphenyl)Imidazo[2,1-b][1,3,4]Thiadiazol

Abstract

In this study, the structural and biological properties of 2-((4-fluorobenzyl)thio)-6-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole were investigated in detail using theoretical and computational methods. Within the scope of the calculations, the molecule’s natural bond orbital analysis, molecular electrostatic potential surface mapping, nonlinear optical properties, highest occupied molecular orbital and lowest unoccupied molecular orbital energy levels, optimized molecular geometry, and Mulliken atomic charge distribution were obtained in detail using the PBEPBE and B3LYP methods with the 6-31G(d,p) basis set. The biological activity of the molecule was investigated by molecular docking on the crystal structures of the aldose reductase enzymes 4ICC and 4IGS. Docking results revealed binding energies of -9.50 kcal/mol for 4ICC and -10.00 kcal/mol for 4IGS, demonstrating a strong inhibitory effect, particularly against the 4IGS structure. Absorption, Distribution, Metabolism, Excretion, and Toxicity analyses demonstrated that the molecule conforms to Lipinski's rules and has high oral bioavailability. The results suggest that FTMT is structurally stable, biologically active, and a potential therapeutic candidate, particularly for diabetes-related diseases.

Keywords

• Natural bond orbital
• nonlinear optical properties
• molecular docking
• mulliken atomic charge
• molecular electrostatic potential surface mapping

References

1. Albert, V., Piendl, G., Yousseff, D., Lammert, H., Hummel, M., Ortmann, O., Jagla, W., Gaumann, A., Wege, A.K., Brockhoff, G., 2022. Protein kinase C targeting of luminal (T-47D), luminal/HER2-positive (BT474), and triple negative (HCC1806) breast cancer cells in-vitro with AEB071 (Sotrastaurin) is efficient but mediated by subtype specific molecular effects. Arch Gynecol Obstet. 306, 1197-1210. 10.1007/s00404-022-06434-2
2. AlRabiah, H., Muthu, S., Al-Omary, F., Al-Tamimi, A.-M., Raja, M., Muhamed, R.R., El-Emam, A.A.-R., 2017. Molecular structure, vibrational spectra, NBO, Fukui function, HOMO-LUMO analysis and molecular docking study of 6-[(2-methylphenyl) sulfanyl]-5-propylpyrimidine-2,4-(1H, 3H)-dione. Macedonian Journal of Chemistry and Chemical Engineering. 36, 59-80.
3. Bağlan, M., Gören, K., Çakmak, İ., 2022. Theoretical Investigation of 1H and 13C NMR Spectra of Diethanol Amine Dithiocarbamate RAFT Agent. Journal of the Institute of Science and Technology. 12, 1677-1689. https://doi.org/10.21597/jist.1103750
4. Bağlan, M., Gören, K., Yıldıko, Ü., 2023a. DFT Computations and Molecular Docking Studies of 3-(6-(3-aminophenyl)thiazolo[1,2,4]triazol-2-yl)-2H-chromen-2-one(ATTC) Molecule. Hittite Journal of Science and Engineering. 10, 11-19. https://doi.org/10.17350/HJSE19030000286
5. Bağlan, M., Gören, K., Yıldıko, Ü., 2023b. HOMO–LUMO, NBO, NLO, MEP analysis and molecular docking using DFT calculations in DFPA molecule. International Journal of Chemistry and Technology. 7, 38-47. https://doi.org/10.32571/ijct.1135173
6. Bağlan, M., Yıldıko, Ü., Gören, K., 2022. Computational Investigation of 5.5'',7''-trihydroxy-3,7-dimethoxy-4'-4'''-O-biflavone from Flavonoids Using DFT Calculations and Molecular Docking. Adıyaman University Journal of Science. 12, 283-298. https://doi.org/10.37094/adyujsci.1121018
7. Bağlan, M., Yıldıko, Ü., Gören, K., 2023. DFT Calculations and Molecular Docking Study in 6-(2”-Pyrrolidinone-5”-Yl)-(-) Epicatechin Molecule from Flavonoids. Eskişehir Teknik Üniversitesi Bilim ve Teknoloji Dergisi B-Teorik Bilimler. 11, 43-55. https://doi.org/10.20290/estubtdb.1126604
8. Baig, M.M., GholamHosseini, H., Moqeem, A.A., Mirza, F., Lindén, M., 2019. Clinical decision support systems in hospital care using ubiquitous devices: Current issues and challenges. Health Informatics J. 25, 1091-1104. 10.1177/1460458217740722

9. Bakal, R.L., Jawarkar, R.D., Manwar, J.V., Jaiswal, M.S., Ghosh, A., Gandhi, A., Zaki, M.E.A., Al-Hussain, S., Samad, A., Masand, V.H., Mukerjee, N., Nasir Abbas Bukhari, S., Sharma, P., Lewaa, I., 2022. Identification of potent aldose reductase inhibitors as antidiabetic (Anti-hyperglycemic) agents using QSAR based virtual Screening, molecular Docking, MD simulation and MMGBSA approaches. Saudi Pharm J. 30, 693-710. 10.1016/j.jsps.2022.04.003
10. Burley, S.K., Berman, H.M., Bhikadiya, C., Bi, C., Chen, L., Di Costanzo, L., Christie, C., Dalenberg, K., Duarte, J.M., Dutta, S., 2019. RCSB Protein Data Bank: biological macromolecular structures enabling research and education in fundamental biology, biomedicine, biotechnology and energy. Nucleic acids research. 47, D464-D474. https://doi.org/10.1093/nar/gky1004
11. Çimen, E., Gören, K., Tahiroğlu, V., Yıldıko, Ü., 2025. The Theoretical Calculations by DFT Method and Analysis ADME, Molecular Docking of 1-(1-(4-hydroxybutyl)-6-methyl-4-phenyl-2-thioxohexahydropyrimidin-5-yl)ethan-1-one (pyrimidine-thiones) Compound. Osmaniye Korkut Ata Üniversitesi Fen Bilimleri Enstitüsü Dergisi. 8, 1129-1145.
12. Çimen, E.,Tahiroğlu, V., 2024. 3-[1-(5-Amino-[1, 3, 4] tiadiazol-2-il)-2-(1H-imidazol-4-il)-etilimino]-2,3-dihidro-indol-2-on Molekülün Teoriksel İncelenmesi. Türk Doğa ve Fen Dergisi. 13, 6-13.
13. Er, M., Ahmadov, F., Karakurt, T., Direkel, Ş., Tahtaci, H., 2019. A Novel Class Substituted Imidazo [2, 1‐b][1,3,4] thiadiazole Derivatives: Synthesis, Characterization, In Vitro Biological Activity, and Potential Inhibitors Design Studies. ChemistrySelect. 4, 14281-14290.
14. G.W.T. M.J. Frisch, H.B.S., G.E. Scuseria, M.A. Robb, J.R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G.A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H.P. Hratchian, A.F. Izmaylov, J. Bloino, G. Zheng, J.L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J.A. Montgomery Jr., J.E. Peralta, F. Ogliaro, M. Bearpark, J.J. Heyd, E. Brothers, K.N. Kudin, V.N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.C. Burant, S.S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J.M. Millam, M. Klene, J.E. Knox, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, R.L. Martin, K. Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador, J.J. Dannenberg, S. Dapprich, A.D. Daniels, Ö. Farkas, J.B. Foresman, J.V. Ortiz, J. Cioslowski, D.J. Fox. (2009). Gaussian 09. In (Version Revision A.02)
15. Gifty, V.,Jothy, V.B., 2023. Experimental and theoretical vibrational spectral Investigations, structural conformations, DFT estimations and docking studies of antibacterial drug Nitrilotriaceticacid. Journal of Molecular Liquids. 386, 122380.
16. Gökce, H., Alpaslan, Y.B., Zeyrek, C.T., Ağar, E., Güder, A., Özdemir, N., Alpaslan, G., 2019. Structural, spectroscopic, radical scavenging activity, molecular docking and DFT studies of a synthesized Schiff base compound. Journal of Molecular Structure. 1179, 205-215.
17. Gören, K.,Bağlan, M., 2023. Inflammation and Anti-Inflammatory Drugs. New Frontiers In Health Sciences. 59. Gören, K., Bağlan, M., Tahiroğlu, V., Yıldıko, Ü., 2024. Theoretical Calculations and Molecular Docking Analysis of 4-(2-(4-bromophenyl)hydrazineylidene)-3,5-diphenyl-4H-pyrazole Molecule. Journal of Advanced Research in Natural and Applied Sciences. 10, 786-802. https://doi.org/10.28979/jarnas.1516154
18. Gören, K., Bağlan, M., Yıldıko, Ü., 2024a. Antimicrobial, and Antitubercular Evaluation with ADME and Molecular Docking Studies and DFT Calculatıons of (Z)-3-((1-(5-amino-1,3,4-thiadiazol-2-yl)-2-Phenylethyl)imino)-5-nitroindolin-2-one Schiff Base. Karadeniz Fen Bilimleri Dergisi. 14, 1694-1708. https://doi.org/10.31466/kfbd.1423367
19. Gören, K., Bağlan, M., Yıldıko, Ü., 2024b. Melanoma Cancer Evaluation with ADME and Molecular Docking Analysis, DFT Calculations of (E)-methyl 3-(1-(4-methoxybenzyl)-2,3-dioxoindolin-5-yl)-acrylate Molecule. Journal of the Institute of Science and Technology. 14, 1186-1199. https://doi.org/10.21597/jist.1467666
20. Gören, K., Bağlan, M., Yıldıko, Ü., 2025. Analysis by DFT, ADME and Docking Studies of N'-(4-hydroxy-3-methoxybenzylidene)naphtho[2,3-b]furan-2-carbohydrazide. Eskişehir Teknik Üniversitesi Bilim ve Teknoloji Dergisi B-Teorik Bilimler.13,7-23.
21. Gören, K., Kotan, G., Manap, S., Yüksek, H., 2024. Synthesis, Antimicrobial and Antioxidant Activities of 3-Alkyl(aryl)-4-(3-methoxy-4-hydroxybenzylideneamino)-4,5-dihydro-1H-1,2,4-triazol-5-one Derivatives. Chemistry Africa. 7, 5273-5289. https://doi.org/10.1007/s42250-024-01139-2
22. Gören, K.,Yıldıko, Ü., 2024. Aldose Reductase Evaluation against Diabetic Complications Using ADME and Molecular Docking Studies and DFT Calculations of Spiroindoline Derivative Molecule. Süleyman Demirel Üniversitesi Fen Bilimleri Enstitüsü Dergisi. 28, 281-292. https://doi.org/10.19113/sdufenbed.1474689
23. Güller, P., Taşer, B., Özkan, H., 2025. Exploring the Antibacterial and Enzyme Inhibitory Potential of Selected β-Carboline Derivatives: In Vitro and In Silico Insights. International Journal of Chemistry and Technology. 9, 13-24. 10.32571/ijct.1648820
24. Hagar, M., Ahmed, H.A., Aljohani, G., Alhaddad, O.A., 2020. Investigation of some antiviral N-heterocycles as COVID 19 drug: molecular docking and DFT calculations. International Journal of Molecular Sciences. 21, 3922. https://doi.org/10.3390/ijms21113922
25. Hajam, T.A., Saleem, H., Syed Ali Padhusha, M., Mohammed Ameen, K., 2022. Quantum mechanical study, spectroscopic (FT-IR, FT-Raman and UV-Vis) study, NBO, NLO analysis and molecular docking studies of 2-ethoxy-4-(pyridine-2yliminomethyl)-phenol. Polycyclic Aromatic Compounds. 42, 4819-4842.
26. Hassan, S.A., Aziz, D.M., Kader, D.A., Rasul, S.M., Muhamad, M.A., Muhammedamin, A.A., 2025. Design, synthesis, and computational analysis (molecular docking, DFT, MEP, RDG, ELF) of diazepine and oxazepine sulfonamides: biological evaluation for in vitro and in vivo anti-inflammatory, antimicrobial, and cytotoxicity predictions. Molecular Diversity. 29, 2367-2389. https://doi.org/10.1007/s11030-024-10996-5
27. Kaya, B., Acar Çevik, U., Necip, A., Duran, H.E., Çiftçi, B., Işık, M., Soyer, P., Bostancı, H.E., Kaplancıklı, Z.A., Beydemir, Ş., 2025. Design, Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel 1,3,4-thiadiazole derivatives targeting both aldose reductase and α-glucosidase for diabetes mellitus. ACS Omega. 10, 18812-18828. 10.1021/acsomega.5c00566
28. Kredzielak-Manikowska, I., Traczyk, Z., Ceglarek, B., Sikorska, A., Brycz-Witkowska, J., Stańczak, H., Wozniak, J., Konopka, L., 2000. [Chronic eosinophilic leukemia]. Pol Arch Med Wewn. 103, 67-71.
29. Kumar, B., Devi, J., Dubey, A., Tufail, N., Khurana, D., 2024. Thiosemicarbazone ligands based transition metal complexes: a multifaceted investigation of antituberculosis, anti‐inflammatory, antibacterial, antifungal activities, and molecular docking, density functional theory, molecular electrostatic potential, absorption, distribution, metabolism, excretion, and toxicity studies. Applied Organometallic Chemistry. 38, e7345. https://doi.org/10.1002/aoc.7345
30. Lee, Y.S., Chen, Z., Kador, P.F., 1998. Molecular modeling studies of the binding modes of aldose reductase inhibitors at the active site of human aldose reductase. Bioorg Med Chem. 6, 1811-1819. 10.1016/s0968-0896(98)00139-4
31. Li, X., Keady, J., Ward, R., 2021. Neighbourhoods and dementia: An updated realist review of the qualitative literature to inform contemporary practice and policy understanding. Dementia (London). 20, 2957-2981. 10.1177/14713012211023649
32. Lin, J., Sahakian, D.C., De Morais, S., Xu, J.J., Polzer, R.J., Winter, S.M., 2003. The role of absorption, distribution, metabolism, excretion and toxicity in drug discovery. Current topics in medicinal chemistry. 3, 1125-1154.
33. Liu, N.Q., Cao, M., Frédérich, M., Choi, Y.H., Verpoorte, R., van der Kooy, F., 2010. Metabolomic investigation of the ethnopharmacological use of Artemisia afra with NMR spectroscopy and multivariate data analysis. J Ethnopharmacol. 128, 230-235. 10.1016/j.jep.2010.01.020
34. Nishida, A., Kubota, T., Yamada, Y., Higashi, K., Kitamura, K., Nakahara, K., Iga, T., 2002. Thiopurine S-methyltransferase activity in Japanese subjects: metabolic activity of 6-mercaptopurine 6-methylation in different TPMT genotypes. Clin Chim Acta. 323, 147-150. 10.1016/s0009-8981(02)00184-5
35. Noureddine, O., Issaoui, N., Al-Dossary, O., 2021. DFT and molecular docking study of chloroquine derivatives as antiviral to coronavirus COVID-19. Journal of King Saud University-Science. 33, 101248. https://doi.org/10.1016/j.jksus.2020.101248
36. Patel, H.M., Noolvi, M.N., Sethi, N.S., Gadad, A.K., Cameotra, S.S., 2017. Synthesis and antitubercular evaluation of imidazo [2,1-b][1,3,4] thiadiazole derivatives. Arabian Journal of Chemistry. 10, S996-S1002. https://doi.org/10.1016/j.ejmech.2015.03.024
37. Ramprasad, J., Nayak, N., Dalimba, U., Yogeeswari, P., Sriram, D., Peethambar, S., Achur, R., Kumar, H.S., 2015. Synthesis and biological evaluation of new imidazo [2,1-b][1,3,4] thiadiazole-benzimidazole derivatives. European journal of medicinal chemistry. 95, 49-63.
38. Release, S., 2019. 3: Maestro, Schrödinger, LLC: New York, NY, USA. 2019.
39. Romagnoli, R., Baraldi, P.G., Prencipe, F., Balzarini, J., Liekens, S., Estévez, F., 2015. Design, synthesis and antiproliferative activity of novel heterobivalent hybrids based on imidazo [2,1-b][1,3,4] thiadiazole and imidazo [2,1-b][1,3] thiazole scaffolds. European journal of medicinal chemistry. 101, 205-217.
40. Sakthivel, S., Alagesan, T., Muthu, S., Abraham, C.S., Geetha, E., 2018. Quantum mechanical, spectroscopic study (FT-IR and FT-Raman), NBO analysis, HOMO-LUMO, first order hyperpolarizability and docking studies of a non-steroidal anti-inflammatory compound. Journal of Molecular Structure. 1156, 645-656. https://doi.org/10.1016/j.molstruc.2017.12.024
41. Saravanan, R., Seshadri, S., Gunasekaran, S., Mendoza-Meroño, R., García-Granda, S., 2015. Conformational analysis, X-ray crystallographic, FT-IR, FT-Raman, DFT, MEP and molecular docking studies on 1-(1-(3-methoxyphenyl)ethylidene) thiosemicarbazide. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 139, 321-328.
42. Satheeshkumar, R., Prabha, K., Vennila, K.N., Sayin, K., Güney, E., Kaminsky, W., Acevedo, R., 2022. Spectroscopic (FT-IR, NMR, single crystal XRD) and DFT studies including FMO, Mulliken charges, and Hirshfeld surface analysis, molecular docking and ADME analyses of 2-amino-4′-fluorobenzophenone (FAB). Journal of Molecular Structure. 1267, 133552. https://doi.org/10.1016/j.molstruc.2022.133552
43. Shahabi, D.,Tavakol, H., 2017. DFT, NBO and molecular docking studies of the adsorption of fluoxetine into and on the surface of simple and sulfur-doped carbon nanotubes. Applied Surface Science. 420, 267-275. https://doi.org/10.1016/j.apsusc.2017.05.068
44. Shalaby, M.A., Fahim, A.M., Rizk, S.A., 2023. Microwave-assisted synthesis, antioxidant activity, docking simulation, and DFT analysis of different heterocyclic compounds. Scientific Reports. 13, 4999.
45. Srivastava, V., Yadav, A., Sarkar, P., 2022. Molecular docking and ADMET study of bioactive compounds of Glycyrrhiza glabra against main protease of SARS-CoV2. Materials Today: Proceedings. 49, 2999-3007. https://doi.org/10.1016/j.matpr.2020.10.055
46. Systèmes, D., 2016. Biovia, discovery studio modeling environment. Dassault Systèmes Biovia: San Diego, CA, USA. Tahiroğlu, V., Gören, K., Bağlan, M., 2025. In Silico drug evaluation by molecular docking, ADME studies and DFT calculations of 2-(6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide. BMC Pharmacology and Toxicology. 26, 116. https://doi.org/10.1186/s40360-025-00958-4
47. Tahiroğlu, V., Gören, K., Bağlan, M., Yıldıko, Ü., 2024. Molecular Docking and DFT Analysis of Thiazolidinone-Bis Schiff Base for anti-Cancer and anti-Urease Activity. Journal of the Institute of Science and Technology. 14, 822-834. https://doi.org/10.21597/jist.1416223
48. Tahiroğlu, V., Gören, K., Çimen, E., Yıldıko, Ü., 2024. Moleculer Docking and Theoretical Analysis of the (E)-5-((Z)-4-methylbenzylidene)-2-(((E)-4-methylbenzylidene)hydrazineylidene)-3-phenylthiazolidin-4-one Molecule. Bitlis Eren Üniversitesi Fen Bilimleri Dergisi. 13, 659-672. https://doi.org/10.17798/bitlisfen.1471235
49. Tahiroğlu, V., Gören, K., Kotan, G., Yüksek, H., 2025. In silico drug evaluation by molecular docking, ADME studies and synthesis, characterization, biological activities, DFT, SAR analysis of the novel Mannich bases. BMC Chemistry. 19, 249. https://doi.org/10.1186/s13065-025-01615-x
50. Tahiroğlu, V., Gören, K., Yıldıko, Ü., Bağlan, M., 2024. IInvestigation, Structural Characterization and Evaluation of the Biological Potency by Molecular Docking of Amoxicillin Analogue of a Schiff Base Molecule. International Journal of Chemistry and Technology. 8, 190-199. https://doi.org/10.32571/ijct.1410570
51. Umamaheswari, M., Aji, C., Asokkumar, K., Sivsshanmugam, T., Subhadradevi, V., Jagannath, P., Madeswaran, A., 2012. Docking studies: In silico aldose reductase inhibitory activity of commercially available flavonoids. Bangladesh Journal of Pharmacology. 7, 108-113.
52. Uzzaman, M., Hasan, M.K., Mahmud, S., Yousuf, A., Islam, S., Uddin, M.N., Barua, A., 2021. Physicochemical, spectral, molecular docking and ADMET studies of Bisphenol analogues; A computational approach. Informatics in medicine unlocked. 25, 100706. https://doi.org/10.1016/j.imu.2021.100706
53. Yadav, D.K., Kumar, S., Saloni, Singh, H., Kim, M.-h., Sharma, P., Misra, S., Khan, F., 2017. Molecular docking, QSAR and ADMET studies of withanolide analogs against breast cancer. Drug Design, Development and Therapy. 1859-1870. https://doi.org/10.2147/DDDT.S130601
54. Zaki, Y.H., Abdelhamid, A.O., Sayed, A.R., Mohamed, H.S., 2023. Synthesis of 1, 3, 4-thiadiazole derivatives using hydrazonoyl bromide: Molecular docking and computational studies. Polycyclic Aromatic Compounds. 43, 1364-1377.