Synthesis, characterization, and molecular docking analysis of novel benzimidazole derivatives as cholinesterase inhibitors

• Novel benzimidazoles which gave better cholinesterase inhibition than Rivastigmine.
• Inhibition potency related to 2-position substitution of the benzimidazole core.
• Benzimidazoles interact with receptor due to hydrophobic and mild polar interaction.
• Benzimidazoles as potential drug treatment for Alzheimer’s disease.

Two series of novel acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors containing benzimidazole core structure were synthesized by a four-step reaction pathway starting from 4-fluoro-3-nitrobenzoic acid as the basic compound. The structure of the novel benzimidazoles was characterized and confirmed by the elemental and mass spectral analyses as well as 1H NMR spectroscopic data. Of the 34 novel synthesized compounds, three benzimidazoles revealed AChE inhibition with IC50 < 10 μM. The highest inhibitory activity (IC50 = 5.12 μM for AChE and IC50 = 8.63 μM for BChE) corresponds to the compound 5IIc (ethyl 1-(3-(1H-imidazol-1-yl)propyl)-2-(4-nitrophenyl)-1H-benzo[d]imidazole-5-carboxylate). The relationship between lipophilicity and the chemical structures as well as their limited structure–activity relationship was discussed.

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