Design, synthesis, and in silico studies of benzimidazole bearing phenoxyacetamide derivatives as α-glucosidase and α-amylase inhibitors

Abstract

Benzimidazole bearing phenoxyacetamide derivatives 7a-l were designed and synthesized as anti-diabetic agents. All derivatives were evaluated for in vitro α-glucosidase and α-amylase inhibition. Compounds 7a-l exhibited a varying degree of α-glucosidase inhibitory activity with IC50 values between 99.6 ± 3.1 - >750 µM compared with standard acarbose (IC50 = 750.0 ± 5.6 µM). Structure-activity relationships showed the important role of methoxy substituent on phenoxy linker to improve the potency. Also, the substitution of 4-F (7j) and 4-Cl (7k) moiety at the Y position improved the inhibitory activity. Enzyme kinetic studies of compound 7j proved that their inhibition was the competitive type with a Ki value of 67.0 µM. The results of α-amylase inhibitory activities indicated that most of the synthesized derivatives had moderate to weak inhibitory activities against α-amylase. Among them, compounds 7c (X = H; Y = 2-Br) and 7j (X = OMe; Y = 4-F) showed the strongest inhibition with 50.0% and 45.0% inhibition at 108 µM. Molecular docking studies were performed to understand the binding interaction of the compounds.