Design, synthesis and cholinesterase inhibitory evaluation study of fluorescent N-benzylpiperidine-4-one derivatives

Some N-benzylpiperidine-4-one derivatives were synthesized via one-pot three-component protocols in excellent yields, and were evaluated for their potential cholinesterase inhibition. The mono-substituted derivatives except 4b showed butyrylcholinesterase selective, while unsubstituted and di-substituted derivatives showed acetylcholinesterase selective inhibitions. It is interesting to note that all the mono-substituted derivatives showing butyrylcholinesterase inhibitory activity were more potent than galanthamine. Compound 4c bearing ortho-methoxy group showed the most potent, mixed-mode inhibitory activity on both acetylcholinesterase and butyrylcholinesterase with IC50 5.67 and 0.87 mu M, respectively. Molecular docking revealed that compound 4c had hydrophobic interactions and hydrogen bonding at the catalytic triad and choline binding sites of the enzymes. In conclusion, this simple and cheaper synthesis method yielded derivatives with good cholinesterase inhibition and favorable photophysical properties.