Benzofuran-derived benzylpyridinium bromides as potent acetylcholinesterase inhibitors

•Bezofuran-based compounds 5a–o were synthesized as AChE inhibitors.•All compound had potent anti-AChE activity comparable or superior than donepezil.•Compound 5e with IC50 value of 4.1 nM was the most active compound.•Compound 5e was 7-fold more potent than donepezil against AChE.

A series of benzofuran-based N-benzylpyridinium derivatives 5a–o were designed and synthesized as novel AChE inhibitors. The synthetic pathway of the compounds involved the preparation of 4-(benzofuran-2-yl)pyridine intermediates via the reaction of different salicylaldehyde derivatives and 4-(bromomethyl)pyridine, followed by intramolecular cyclization. Subsequently, the 4-(benzofuran-2-yl)pyridines were N-benzylated by using appropriate benzyl bromide to afford the final product 5a–o. The results of in vitro AChE activity evaluation of synthesized compounds revealed that all compound had potent anti-AChE activity comparable or more potent than standard drug donepezil. The N-(3,5-dimethylbenzyl) derivative 5e with IC50 value of 4.1 nM was the most active compound, being 7-fold more potent than donepezil.

Graphical abstractA series of N-benzyl-4-(benzofuran-2-yl)pyridinium bromides 5a–o were synthesized as novel AChE inhibitors. The N-(3,5-dimethylbenzyl) derivative 5e was the most active compound (IC50 = 4.1 nM), being 7-fold more potent than donepezil.Figure optionsDownload full-size imageDownload as PowerPoint slide