Ha_2021_Curr.Alzheimer.Res__

Benzimidazole is an interesting pharmacophore, and its derivatives have been previously shown to possess cholinesterase inhibitory activity. In this study, benzimidazole derivatives were synthesized via a 4-step reaction scheme and screened for their acetylcholinesterase and butyrylcholinesterase inhibitory activities. Among the synthesised compounds, three of them (5IIa, 5IIb, and 5IIc) exhibited potent, selective butyrylcholinesterase inhibition at a low micromolar level. The compounds did not show any significant cytotoxicity when tested against a panel of human cell lines. Moreover, the most active compound, 5IIc, was highly permeable across the blood-brain barrier. The structure-activity relationship and molecular interactions of the synthesized benzimidazole derivatives were also analysed and discussed.