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

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 alpha-glucosidase (alpha-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 (Ki = 0.106 mu M) approximately nine times more effective than the standard epalrestat (EPR) (Ki = 0.967 mu M) and alpha-Glu inhibition (Ki = 0.648 mu M) about six times stronger than acarbose (ACR) (Ki = 0.3.775 mu M). 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.

Journal

ARCHIV DER PHARMAZIE

Year

2025

Volume

358

Issue

6

ISSN

0365-6233

eISSN

1521-4184

DOI

10.1002/ardp.70033

WoS UID

WOS:001519771300006