Design, Synthesis, in Vitro and in Silico Evaluation of Thiazole-Hydrazone Hybrids as Potent and Safe α-Glucosidase Inhibitors

Abstract

Diabetes mellitus (DM) is a growing global health issue. Therefore, the development of novel antidiabetic agents with minimal adverse effects is urgently needed. Inhibition of the alpha-glucosidase enzyme, which plays a key role in carbohydrate digestion and glucose absorption, remains a promising therapeutic strategy. This study focused on the design, synthesis, biological evaluation, and molecular modeling of novel thiazole-hydrazone hybrids as potential alpha-glucosidase inhibitors. A two-step synthetic route was employed to obtain twelve new compounds, which were structurally characterized via NMR (1H and 13C), and HRMS techniques. The alpha-glucosidase inhibitory activity was assessed in vitro using Saccharomyces cerevisiae-derived enzyme, and cytotoxicity was evaluated on CCD-34Lu human lung fibroblast cells via MTT assay. Except for compound 10, all compounds exhibited stronger alpha-glucosidase inhibitory activity than acarbose (IC50 = 240.50 +/- 21.21 mu M) with the IC50 values ranging from 1.01 +/- 0.15 to 4.57 +/- 0.23 mu M. Compound 1 emerged as the most active compound and was selected for further enzyme kinetics and in silico studies. Based on enzyme kinetics, the compound showed a mixed-type inhibition mechanism with a Ki value of 0.33 mu M, suggesting a higher affinity for the free enzyme. Docking and molecular dynamics simulations confirmed high affinity and stability of compound 1 at the allosteric site, surpassing acarbose. Moreover, none of the compounds showed cytotoxicity at their effective concentrations. These findings suggest that the synthesized thiazole-hydrazone hybrids, particularly compound 1, are promising lead compounds for the development of safer and more effective alpha-glucosidase inhibitors in the management of type 2 diabetes mellitus (T2DM).