Synthesis and Biological Evaluations of New 4,5-Diphenyl-Imidazole-Indole-N-Phenylacetamide Derivatives Against ?-glucosidase and Acetylcholinesterase

Abstract

A novel series of 4,5-diphenyl-imidazole-indole-N-phenylacetamide derivatives (6a-m) was designed, synthesized, and evaluated for their inhibitory activities against alpha-glucosidase and acetylcholinesterase (AChE). Among the thirteen derivatives, nine were more potent than the standard alpha-glucosidase inhibitor (acarbose), and eleven showed higher potency than the standard AChE inhibitor (tacrine). The most effective compound against alpha-glucosidase was compound 6l, which demonstrated a 2.1-fold higher potency compared to acarbose. The best compound against AChE was compound 6j, which was 16.9-fold more potent than tacrine. Given that the compounds showed stronger inhibitory activity against AChE than against alpha-glucosidase, compound 6j, identified as the best AChE inhibitor, was selected for further investigation. Kinetic studies revealed that compound 6j is a competitive inhibitor of AChE. Molecular docking and dynamics simulations confirmed the stability of compound 6j within the active site of AChE. Additionally, compound 6j demonstrated no cytotoxicity at its effective dose against AChE in the normal cell line NIH-3T3, confirming its favorable safety profile at high concentrations.