Potent α-glucosidase and α-amylase inhibitors for the treatment of diabetes mellitus: synthesis, in vitro and in silico studies of thiazole bearing sulfonamide derivatives

A new series of thiazole-bearing benzenesulfonamide derivatives (1–14) were synthesized and evaluated for in vitro inhibitory activity against α-glucosidase and α-amylase enzymes. All compounds displayed significant inhibitory potential as compared to the standard drug, acarbose (IC₅₀ = 38.45 ± 0.80 and 11.12 ± 0.15 µM, respectively). Compound 7 (3,4-dichlorophenyl derivative) showed the potent α-glucosidase inhibition (IC₅₀ = 11.80 ± 0.60 µM), while compound 1 (2-methoxy derivative) was the most potent α-amylase inhibitor (IC₅₀ = 5.30 ± 0.20 µM). Structure–activity relationship analyses revealed that chloro and nitro substituents, which are electron-withdrawing groups, enhanced inhibitory efficacy, particularly when positioned at specific locations on the aromatic ring. Molecular docking studies confirmed these findings, demonstrating strong interactions with key active site residues through hydrogen bonding and π-π stacking. These results highlight the potential of thiazole-sulfonamide hybrids as a promising lead for the development of effective dual α-glucosidase/α-amylase inhibitors for the treatment of diabetes mellitus.