Computer-aided development of novel thiazolidinone-thiazole derivatives: multidimensional structure-activity relationships revealed by quantum chemical analysis, molecular docking and biological investigation.

Diabetes mellitus is a major global health challenge, highlighting the need for new inhibitors of the carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase. In this study, a series of thiazole-based thiazolidinone derivatives (1-10) was designed, synthesized, and structurally characterized using spectroscopic techniques. Among the synthesized compounds, 8 showed the strongest inhibitory activity against α-amylase and α-glucosidase, with IC50 values of 5.50 ± 0.40 and 5.90 ± 0.10 µM, respectively, and compared with 10.80 ± 0.50 and 11.10 ± 0.30 µM for acarbose. Molecular docking suggested that compound 8 can adopt a favorable binding orientation within the active sites of both enzymes through hydrogen-bonding and hydrophobic contacts. Enzyme kinetic studies further characterized its mode of inhibition. DFT calculations were performed to examine the electronic properties, frontier molecular orbitals, and molecular electrostatic potential of selected derivatives. ADMET analysis was also conducted to provide preliminary insight into their predicted pharmacokinetic and toxicity-related properties. Overall, the experimental and computational findings identify compound 8 as a promising lead structure for further investigation as an α-amylase and α-glucosidase inhibitor.