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European Journal of Medicinal Chemistry 2020-Aug

Simple Analogues of Natural Product Chelerythrine: Discovery of a Novel Anticholinesterase 2-phenylisoquinolin-2-ium Scaffold With Excellent Potency Against Acetylcholinesterase

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Bohang Zhou
Hui Li
Zhiming Cui
Ding Li
Huiling Geng
Jinming Gao
Le Zhou

Keywords

Abstract

As simple analogues of the natural compound chelerythrine, a novel anti-cholinesterase 2-phenylisoquinolin-2-ium scaffold was designed by structure imitation. The activity evaluation led to the discovery of seven compounds with potent anti-acetylcholinesterase activity with IC50 values of ≤0.72 μM, superior to chelerythrine and standard drugs galantamine. Particularly, compound 8y showed the excellent dual acetylcholinesterase-butyrylcholinesterase inhibition activity, superior to rivastigmine, a dual cholinesterase inhibitor drug. Furthermore, the compounds displayed a competitive anti-acetylcholinesterase mechanism with the substrate and low cytotoxicity. Molecular docking showed that the isoquinoline moiety is embedded in a cavity surrounded by four aromatic residues of acetylcholinesterase by the π-π action. Structure-activity relationship showed that the p-substituents on the C-ring can dramatically improve the anti-acetylcholinesterase activity, while 8-OMe can increase the activity against the two cholinesterases simultaneously. Thus, the title compounds emerged as promising lead compounds for the development of novel cholinesterase inhibitor agents.

Keywords: Acetylcholinesterase; Benzo[c]phenanthridine; Butyrylcholinesterase; Isoquinoline; Molecular docking; Structure-activity relationship.

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