Design, synthesis, in vitro and in silico evaluation of thiazole-hydrazone hybrids as potent and safe α-glucosidase inhibitors

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 α-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 α-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 α-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 α-glucosidase inhibitory activity than acarbose (IC₅₀ = 240.50 ± 21.21 μM) with the IC₅₀ values ranging from 1.01 ± 0.15 to 4.57 ± 0.23 μM. 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 K_i value of 0.33 μM, 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 α-glucosidase inhibitors in the management of type 2 diabetes mellitus (T2DM).

Anti-diabetic activity; Enzyme kinetics; In silico; Molecular docking; Thiazole-hydrazone hybrids; α-Glucosidase inhibitors.