Synthesis and Biological Evaluation of Imidazo‐Thiadiazole‐Linked Benzisoxazole Hybrids as Dual α ‐Glucosidase and α ‐Amylase Inhibitors With Antioxidant Potential

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ABSTRACT Type 2 diabetes mellitus (T2DM) remains a major global health challenge, necessitating the discovery of novel therapeutics with improved safety and efficacy. In this study, a series of imidazo‐thiadiazole‐linked benzisoxazoles ( 1–20 ) was synthesized and evaluated for dual inhibitory activity against α ‐glucosidase and α ‐amylase enzymes. Most compounds showed potent enzyme inhibition, with compounds 3 and 4 exhibiting superior activity against α ‐glucosidase and α ‐amylase (IC 50 = 1.56 and 3.01 µM for compound 3 ; IC 50 = 3.24 and 5.82 µM for compound 4 ) compared to the standard drug acarbose (IC 50 = 14.85 and 15.25 µM). Enzyme kinetic studies revealed both competitive and uncompetitive modes of inhibition. Structure–activity relationship (SAR) analysis highlighted that para ‐substituted electron‐withdrawing groups significantly enhanced inhibitory potential. Antioxidant activity was assessed using cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), and 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) assays, with compound 2 displaying the strongest effect. Molecular docking supported the in vitro results, revealing favorable interactions with key catalytic residues of target enzymes. ADME/T profiling confirmed desirable pharmacokinetic properties and drug‐likeness. Overall, these findings suggest that the synthesized hybrids represent promising multifunctional candidates for T2DM therapy, combining potent enzyme inhibition, antioxidant activity, and favorable drug‐like profiles.

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