Novel coumarin-3-carboxamides bearing N-benzylpiperidine moiety as potent acetylcholinesterase inhibitors

Some novel coumarin-3-carboxamide derivatives linked to N-benzylpiperidine scaffold were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. The screening results showed that most of compounds exhibited potent anti-AChE activity in the range of nM concentrations. Among them, compound 10c bearing an N-ethylcarboxamide linker and a 6-nitro substituent showed the most potent activity (IC50 = 0.3 nM) and the highest selectivity (SI = 26,300). Compound 10c was 46-fold more potent than standard drug donepezil against AChE. The kinetic study revealed that compound 10c exhibited mixed-type inhibition against AChE. Protein-ligand docking study demonstrated that the target compounds have dual binding site interaction mode and these results are in agreement with kinetic study. [Display omitted] Novel coumarin-3-carboxamides linked to N-benzylpiperidine scaffold were synthesized and evaluated as AChE and BuChE inhibitors. Compound 10c showed the most potent activity and the highest selectivity against AChE. •N-Benzylpiperidine-linked coumarins were designed as AChE inhibitors.•Compound 10c was the most potent derivative against AChE (IC50 = 0.3 nM).•Compound 10c showed the highest selectivity for AChE (SI = 26,300).•Docking study showed the dual binding site ability of 10c to inhibit AChE.