Novel phthalimido-benzenesulfonamide hybrid as a potent α-glucosidase inhibitor: synthesis, biological evaluation, molecular docking and in silico ADME prediction

Year 2025, Volume: 4 Issue: 3, 1 - 10

Şirin Uysal Ol , Zeynep Soyer

https://doi.org/10.55971/EJLS.1772928

Abstract

Diabetes mellitus is a global health crisis, recognized as one of the 21st century’s most significant challenges. Therapeutic strategies for managing Type 2 Diabetes mellitus (T2DM) frequently involve α-glucosidase inhibitors (AGIs), which mitigate postprandial glucose excursions by delaying carbohydrate digestion. This study focuses on the synthesis, characterization, and in vitro α-glucosidase inhibitory evaluation of a novel phthalimido-benzenesulfonamide hybrid compound, specifically 4-phthalimido-N-(5-chloro-2-pyridylamino)benzenesulfonamide. Additionally, enzyme kinetics and molecular docking studies were performed on this compound to reveal enzyme inhibition models and ligand-enzyme binding interactions. Furthermore, we used the PreADMET web service to calculate the ADME/Tox properties of the compound. According to the biological activity data, the target compound exhibited α-glucosidase inhibition (IC50 = 1240.52 ± 316.98 µM) comparable to the reference drug acarbose (IC50 = 1210.96 ± 0.17 μM), positioning it as a promising scaffold for future antidiabetic drug development efforts. Molecular docking studies provided informative clues for the ligand-enzyme binding interactions to estimate allosteric cavities (A1-A5) of the homology model of α-glucosidase. Kinetic analysis revealed an uncompetitive inhibition, with reduced Kₘ and Vₘₐₓ, confirming an allosteric mechanism. In silico ADME/Tox predictions suggested that the compound had favorable ADME/Tox properties. Overall, this hybrid compound represents a promising lead for next-generation AGIs with reduced side effects.

Keywords

Allosteric inhibition , α-glucosidase inhibitor , diabetes , molecular docking , phthalimido-benzenesulfonamide

Ethical Statement

Not applicable, because this article does not contain any studies with human or animal subjects.

Supporting Institution

This research received no grant from any funding agency/sector.

Project Number

-

Thanks

The authors gratefully acknowledge Dr. Güneş Çoban and MSc. Merve ARI for performing molecular docking and enzyme kinetic studies, respectively. Authors also thank to the Pharmaceutical Sciences Research Centre (FABAL) at Ege University, Faculty of Pharmacy for spectral analyses of the compounds.

References

• Lyu F., Wu D., Wei C., Wu A. Vascular cognitive impairment and dementia in type 2 diabetes mellitus: an overview. Life Sci. 2020;254:117771. https://doi.org/10.1016/j.lfs.2020.117771
• Kumar A., Gangwar R., Zargar A.A., Kumar R., Sharma A. Prevalence of diabetes in India: a review of IDF Diabetes Atlas 10th Edition. Curr Diabetes Rev. 2024;20(1):e130423215752.https://doi.org/10.2174/1573399819666230413094200
• Mushtaq A., Azam U., Mehreen S., Naseer M.M. Synthetic α glucosidase inhibitors as promising anti diabetic agents: recent developments and future challenges. Eur J Med Chem. 2023;249:115119. https://doi.org/10.1016/j.ejmech.2023.115119
• Mehanna A. Antidiabetic agents: past, present and future. Future Med Chem. 2013;5(4):411 430. https://doi.org/10.4155/fmc.13.13
• Lu H., Xie T., Wu Q., Hu Z., Luo Y., Luo F. Alpha glucosidase inhibitory peptides: sources, preparations, identifications, and action mechanisms. Nutrients. 2023;15(19):4267. https://doi.org/10.3390/nu15194267
• Dhameja M., Gupta P. Synthetic heterocyclic candidates as promising α glucosidase inhibitors: an overview. Eur J Med Chem. 2019;176:343 377. https://doi.org/10.1016/j.ejmech.2019.04.025
• Viegas Junior C., Danuello A., da Silva Bolzani V., Barreiro E.J., Fraga C.A. Molecular hybridization: a useful tool in the design of new drug prototypes. Curr Med Chem. 2007;14(17):1829 1852. https://doi.org/10.2174/092986707781058805
• Soyer Z., Uysal S., Parlar S., Tarikogullari Dogan A.H., Alptüzün V. Synthesis and molecular docking studies of some 4 phthalimidobenzenesulfonamide derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors. J Enzyme Inhib Med Chem. 2017;32(1):13 19. https://doi.org/10.1080/14756366.2016.1226298
• Sou S., Mayumi S., Takahashi H., Yamasaki R., Kadoya S., Sodeoka M., Hashimoto Y. Novel alpha glucosidase inhibitors with a tetrachlorophthalimide skeleton. Bioorg Med Chem Lett. 2000;10(10):1081 1084. https://doi.org/10.1016/S0960 894X(00)00161 X
• Pascale R., Carocci A., Catalano A., Lentini G., Spagnoletta A., Cavalluzzi M.M., De Santis F., De Palma A., Scalera V., Franchini C. New N (phenoxydecyl)phthalimide derivatives displaying potent inhibition activity towards alpha glucosidase. Bioorg Med Chem. 2010;18(16):5903 5914. https://doi.org/10.1016/j.bmc.2010.06.088
• Mahapatra S., Singh J., Raju R., Maiti B., Maity T. Evaluation of some synthesized novel substituted phthalimide derivatives as potent antidiabetic agents. Asian J Chem. 2011;23(4):1581 1584.
• Bian X., Wang Q., Ke C., Zhao G., Li Y. A new series of N2 substituted 5 (p toluenesulfonylamino)phthalimide analogues as α glucosidase inhibitors. Bioorg Med Chem Lett. 2013;23(7):2022 2026. https://doi.org/10.1016/j.bmcl.2013.02.011
• Sherafati M., Mohammadi Khanaposhtani M., Moradi S., Asgari M.S., Najafabadipour N., Faramarzi M.A., Mahdavi M., Biglar M., Larijani B., Hamedifar H., Hajimiri M.H. Design, synthesis and biological evaluation of novel phthalimide Schiff base coumarin hybrids as potent α glucosidase inhibitors. Chem Pap. 2020;74:4379 4388. https://doi.org/10.1007/s11696 020 01246 7
• Türkeş C., Akocak S., Işık M., Lolak N., Taslimi P., Durgun M., Gülçin İ., Budak Y., Beydemir Ş. Novel inhibitors with sulfamethazine backbone: synthesis and biological study of multi target cholinesterases and α glucosidase inhibitors. J Biomol Struct Dyn. 2022;40(19):8752 8764. https://doi.org/10.1080/07391102.2021.1916599
• Apaydın Ç.B., Hasbal Çelikok G., Yılmaz Özden T., Cihan Üstündağ G. Design, synthesis and biological evaluation of novel sulfonamide hydrazones as α glucosidase and α amylase inhibitors. İstanbul J Pharm. 2022;52(2):108 113. https://doi.org/10.26650/IstanbulJPharm.2022.1018698
• aha M., Imran S., Salahuddin M., Iqbal N., Rahim F., Uddin N., Shehzad A., Khalid Farooq R., Alomari M., Mohammed Khan K. Evaluation and docking of indole sulfonamide as a potent inhibitor of α glucosidase enzyme in streptozotocin induced diabetic albino Wistar rats. Bioorg Chem. 2021;110:104808. https://doi.org/10.1016/j.bioorg.2021.104808
• Abbasi M.A., Islam M., Aziz ur Rehman, Rasool S., Rubab K., Hussain G., Ahmad I., Ashraf M., Shahid M., Shah S.A.A. Synthesis, characterization, antibacterial, α glucosidase inhibition and hemolytic studies on some new N (2,3 dimethylphenyl)benzenesulfonamide derivatives. Trop J Pharm Res. 2016;15(3):591 598. https://doi.org/10.4314/tjpr.v15i3.22
• Seo W.D., Kim J.H., Kang J.E., Ryu H.W., Curtis Long M.J., Lee H.S., Yang M.S., Park K.H. Sulfonamide chalcone as a new class of alpha glucosidase inhibitors. Bioorg Med Chem Lett. 2005;15(24):5514 5516. https://doi.org/10.1016/j.bmcl.2005.08.087
• Uysal S., Soyer Z., Saylam M., Tarikogullari A.H., Yilmaz S., Kirmizibayrak P.B. Design, synthesis and biological evaluation of novel naphthoquinone 4 aminobenzensulfonamide/carboxamide derivatives as proteasome inhibitors. Eur J Med Chem. 2021;209:112890. https://doi.org/10.1016/j.ejmech.2020.112890
• Santos J.L., Yamasaki P.R., Chin C.M., Takashi C.H., Pavan F.R., Leite C.Q. Synthesis and in vitro anti Mycobacterium tuberculosis activity of a series of phthalimide derivatives. Bioorg Med Chem. 2009;17(11):3795 3799. https://doi.org/10.1016/j.bmc.2009.04.042
• Ayan E.K., Çoban G., Soyer Z. Design, synthesis, biological evaluation, and molecular modeling studies of some quinazolin 4(3H) one benzenesulfonamide hybrids as potential α glucosidase inhibitors. J Biomol Struct Dyn. 2024;14:1 21. https://doi.org/10.1080/07391102.2024.2427373
• Webb B, Sali A. Comparative protein structure modeling using modeller. In: Current Protocols in Bioinformatics. John Wiley & Sons, Inc.; (2016). p. 5.6.1-5.6.37.
• Pettersen E.F., Goddard T.D., Huang C.C., Couch G.S., Greenblatt D.M., Meng E.C., Ferrin T.E. UCSF Chimera —a visualization system for exploratory research and analysis. J Comput Chem. 2004;25(13):1605 1612. https://doi.org/10.1002/jcc.20084
• Jakalian A., Jack D.B., Bayly C.I. Fast, efficient generation of high quality atomic charges. AM1 BCC model: II. Parameterization and validation. J Comput Chem. 2002;23(16):1623 1641. https://doi.org/10.1002/jcc.10128
• Wang J., Wolf R.M., Caldwell J.W., Kollman P.A., Case D.A. Development and testing of a general amber force field. J Comput Chem. 2004;25(9):1157 1174. https://doi.org/10.1002/jcc.20035
• Case DA, Aktulga HM, Belfon K, Ben-Shalom IY, Brozell SR, ... Kollman PA. Amber 2021. San Francisco: University of California; (2021).
• He X., Man V.H., Yang W., Lee T.S., Wang J. A fast and high quality charge model for the next generation general AMBER force field. J Chem Phys. 2020;153(11):114502. https://doi.org/10.1063/5.0019056
• Molecular Operating Environment (MOE 2020.09). Montreal: Chemical Computing Group Inc.; (2020)
• Lee SK, Chang GS, Lee IH, Chung JE, Sung KY, No KT. PreADME: PC-based program for batch prediction of ADME properties. 15th European Symposium on Quantitative Structure – Activity relationships & Molecular Modeling (EuroQSAR 2004); September 5-11, 2004; İstanbul, Türkiye.
• Hesse M, Meier H, Zeeh B. Spectroscopic methods in organic chemistry. 2nd ed. Stuttgart: Thieme; (2014). ISBN:9783131791320
• Nakanishi K, Solomon PH. Infrared absorption spectroscopy. 2nd ed. San Francisco: Holden-Day Inc; (1977). ISBN: 9780816262519.