Discovery of benzimidazole-based selective α-glucosidase inhibitors with an uncompetitive mode of action: synthesis, biological assays and computational studies.

Abstract

A series of thirteen 1-(benzyloxy)-2-phenyl-1H-benzo[d]imidazole derivatives was designed, synthesized, and evaluated as α-glucosidase inhibitors. Structure-activity relationship analysis revealed that the presence of a chlorine atom at the C-6 position of the benzimidazole core, combined with suitable substituents on the pendant aromatic rings, was associated with relevant α-glucosidase inhibitory activity. Among the series, compounds 6 and 13 emerged as the most potent derivatives showing IC50 values of 32.35 μM and 15.70 μM, respectively, and greater potency than acarbose (IC50 = 139 μM) under the same experimental conditions. Importantly, the active compounds 6 and 13 did not appreciably inhibit α-amylase, thereby displaying a favorable selectivity profile over α-glucosidase. Kinetic studies highlighted an uncompetitive mechanism of inhibition for both compounds. Consistently, binding-site analysis and molecular docking suggested that they bind to a putative druggable pocket located at the entrance of the catalytic site, with chlorine substituents on the benzimidazole scaffold contributing to a more extensive network of hydrophobic interactions. Additional evaluation of antioxidant activity and cell viability reinforced the therapeutic promise of these compounds. Overall, these results identified this functionalized benzimidazole scaffold as a promising basis for the development of selective α-glucosidase inhibitors with potential application in the control of postprandial hyperglycemia.

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