Synthesis, Spectral Characterization, Molecular Docking and In-Vitro α-Amylase Inhibitory Evaluation of Novel Thiazolidin-3-yl-Benzamide Derivatives as Potential Antidiabetic Agents

Abstract

A novel series of ten thiazolidin-3-yl-benzamide derivatives (B1–B10) was designed and synthesized via a green, microwave-assisted, one-pot three-component condensation of benzohydrazide, substituted benzaldehydes and thioglycolic acid in absolute ethanol. The reaction proceeded efficiently at 110–130 °C within 20–60 minutes to afford the target compounds in good to excellent yields. All synthesized derivatives were characterized by melting point, Rf value, IR, ¹H NMR, ¹³C NMR and mass spectrometry, which confirmed the formation of the thiazolidinone ring and the benzamide linkage. In-silico molecular docking of the derivatives against α-amylase (PDB ID: 1HNY) using AutoDock Vina (PyRx 0.8) revealed binding energies ranging from –6.9 to –8.8 kcal/mol, with compound B5 (para-tolyl substituted) exhibiting the most favourable binding energy (–8.8 kcal/mol), nearly equivalent to the standard inhibitor Acarbose (–8.9 kcal/mol). In-vitro α-amylase inhibitory activity, assessed by the starch–iodine/DNS colorimetric method, showed IC50 values ranging from 36.10 to 66.35 µM. Compound B5 emerged as the most potent inhibitor (IC50 = 36.10 ± 0.34 µM), comparable to Acarbose (IC50 = 35.50 ± 0.04 µM), followed by B6, B3 and B4. A strong correlation was observed between the computational binding affinities and the experimental IC50 values, validating the reliability of the docking protocol. Structure–activity relationship analysis indicated that electron-donating alkyl/halogen substituents at the para-position of the 4-aryl ring favourably influenced α-amylase binding and inhibition. These findings suggest that the thiazolidin-3-yl-benzamide scaffold, particularly compound B5, represents a promising lead template for the design of new α-amylase inhibitors for the management of type 2 diabetes mellitus.