Background: Benzimidazole is an interesting pharmacophore which has been extensively
studied in medicinal chemistry due to its high affinity towards various enzymes and receptors. Its derivatives
have been previously shown to possess a wide range of biological activities including anthelmintic,
antihypertensive, antiulcer, as well as anticholinesterase activity.
Objective: The objective of this study is to search for more potent benzimidazole-based cholinesterase
inhibitors, through the modification of the 1- and 2-positions of the benzimidazole core.
Methods: Synthesis of compounds were carried out via a 4-step reaction scheme following a previously
reported protocol. Structure-activity relationship of the compounds are established through in
vitro cholinesterase assays and in silico docking studies. Furthermore, cytotoxicity and blood brain
barrier (BBB) permeability of the compounds were also investigated.
Results: Among the synthesised compounds, three of them (5IIa, 5IIb, and 5IIc) exhibited potent
selective butyrylcholinesterase inhibition at 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.
Conclusion: In total 10 benzimidazole derivatives were synthesized and screened for their AChE and
BuChE inhibitory activities. Lead compound 5Iic, represents a valuable compound for further development
as potential AD therapeutics.