New Quinazolin-4(3H)-One-Thiazolidine-2,4-Dione Hybrids as Dual Inhibitors of α-Glycosidase and Aldose Reductase: The Synthetic, In Vitro, and In Silico Approaches.

The impact of diabetes and its complications on individuals is profound, leading to severe health issues and reduced quality of life. This study aimed the design, synthesis, and evaluation of new quinazolin-4(3H)-one-thiazolidine-2,4-dione hybrids as dual inhibitors targeting α-glycosidase (α-Gly) and aldose reductase (ALR2), two key enzymes implicated in type 2 diabetes mellitus (T2DM) and its complications. Thirteen compounds were synthesized and characterized using FTIR, NMR, and HRMS. In vitro assays revealed potent inhibition of α-Gly and ALR2, with compound 9 (phenethyl substituted) emerging as the most potent inhibitor for both enzymes (α-Gly K = 0.355 µM, ALR2 Ki = 0.106 µM). Molecular docking and dynamics simulations confirmed the stable binding of compound 9 in the active sites of both enzymes, with key interactions such as hydrogen bonds and π-π stacking contributing to its potency. The docking score of compound 9 was calculated as -11.120 kcal/mol for α-Gly and -10.713 kcal/mol for ALR2. Additionally, cytotoxicity studies showed that the compounds exhibited low toxicity towards human healthy cell lines, indicating their potential for therapeutic use. ADME-T predictions further supported their drug-like properties, with compounds 8 (cyclohexyl substituted) and 9 demonstrating favorable pharmacokinetic profiles. Overall, this study identifies compound 9 as a promising candidate for further optimization and development as a dual-target inhibitor for T2DM and its complications.