Quinazolin‐4(3<i>H</i>)‐One‐Based New Glitazones as Dual Inhibitors of α‐Glucosidase and Aldose Reductase: Comprehensive Approaches for Managing Diabetes Mellitus and Its Complications

Abstract

A series of novel glitazones containing thiazolidine-2,4-dione and quinazolin-4(3H)-one moieties were synthesized to explore their potential as dual inhibitors of aldose reductase (ALR2) and α-glucosidase (α-Glu), two key enzymes involved in diabetes and its complications. In vitro assays revealed that compounds 8 (cyclohexyl substituted), 9 (phenethyl substituted), and 11 (phenyl substituted) exhibited potent inhibitory effects on both enzymes, with 11 being the most active, showing an ALR2 inhibition (K_i = 0.106 µM) approximately nine times more effective than the standard epalrestat (EPR) (K_i = 0.967 µM) and α-Glu inhibition (K_i = 0.648 µM) about six times stronger than acarbose (ACR) (K_i = 0.3.775 µM). Molecular docking and molecular dynamics simulations showed that compound 11 formed strong interactions with residues Trp-20, Gln-183, and Asp-43 for ALR2 and residues Arg-200, Arg-400, and Glu-271 for Phe-297. Cytotoxicity assays performed on healthy cell lines (HUVEC and BEAS-B2) revealed that the tested compounds were nontoxic at inhibitory concentrations. These findings highlight the potential of compound 11 as a promising dual inhibitor for managing diabetes and its complications, providing a foundation for further optimization and therapeutic exploration.