Development of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and in silico insights

Hamdi, AbdelrahmanYaseen, MuhammadEwesa, Wafaa A.Bhat, Mashooq AhmadZiedan, NohaEl-Shafey, Hamed W.Mohamed, Ahmed A. B.Elnagar, Mohamed R.Haikalh, AbdullahOthmana, Dina I. A.Elgazari, Abdullah A.Abusabaaj, Ahmed H. A.Abdelrahman, Kamal S.Soltan, Osama M.Elbadawi, Mostafa M.2023-07-252023-07-252023-07-20Hamdi, A., Yaseen, M., Ewesa, W. A., Bhat, M. A., Ziedan, N., El-Shafey, H. W., Mohamed, A. A. B., Elnagar, M. R., Haikalh, A., Othmana, D. I. A., Elgazari, A. A., Abusabaaj, A. H. A., Abdelrahman, K. S., Soltan, O. M., & Elbadawi, M. M. (2023). Development of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and in silico insights. Journal of Enzyme Inhibition and Medicinal Chemistry, 38(1), Article-number: 2231170. https://doi.org/10.1080/14756366.2023.22311701475-636610.1080/14756366.2023.2231170http://hdl.handle.net/10034/627934This research study describes the development of new small molecules based on 2,4-thiazolidinedione (2,4-TZD) and their aldose reductase (AR) inhibitory activities. The synthesis of 17 new derivatives of 2,4-TZDs hybrids was feasible by incorporating two known bioactive scaffolds, benzothiazole heterocycle, and nitro phenacyl moiety. The most active hybrid (8b) was found to inhibit AR in a non-competitive manner (0.16 µM), as confirmed by kinetic studies and molecular docking simulations. Furthermore, the in vivo experiments demonstrated that compound 8b had a significant hypoglycaemic effect in mice with hyperglycaemia induced by streptozotocin. Fifty milligrams per kilogram dose of 8b produced a marked decrease in blood glucose concentration, and a lower dose of 5 mg/kg demonstrated a noticeable antihyperglycaemic effect. These outcomes suggested that compound 8b may be used as a promising therapeutic agent for the treatment of diabetic complications.Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttps://creativecommons.org/licenses/by-nc/4.0/Thiazolidinone-2,4-dionesBenzothiazoleAldose Reductase InhibitionAntihyperglycaemicDockingDevelopment of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and in silico insightsArticle1475-6374Journal of Enzyme Inhibition and Medicinal Chemistry