New benzimidazole-indole-amide derivatives as potent α-glucosidase and acetylcholinesterase inhibitors.

New derivatives 6a-m with benzimidazole-indole-amide scaffold were developed, synthesized, and assessed for potential inhibitory effects on α-glucosidase and acetylcholinesterase (AChE). These compounds were synthesized by various amine derivatives. With the exception of two compounds, the α-glucosidase inhibitory activities of the title derivatives were more than that of the positive control acarbose. Moreover, the anti-AChE activity of these compounds, with the exception of one compound, was better than that of tacrine (standard inhibitor). The most potent compound against α-glucosidase was 3-methylphenyl derivative 6i and the most potent compound against AChE was 3,4-dimethoxyphenethyl derivative 6m. All the synthesized compounds were placed in the active sites of α-glucosidase and AChE by in silico docking method and the obtained binding energies were approximately in agreement with the in vitro observed data. Interaction modes of the most potent compounds 6i and 6m demonstrated that these compounds interacted with important residues of their target enzymes. Molecular dynamics simulation was conducted specifically on compound 6i in complex with α-glucosidase to obtain deeper insights into the behavior of this molecule. Furthermore, in silico pharmacokinetic and toxicity studies on the most potent compound predicted that these compounds have good profiles in terms of oral absorption and toxicity.