Benzofuran-derived benzylpyridinium bromides as potent acetylcholinesterase inhibitors

Eur J Med Chem. 2015 Mar 26:93:196-201. doi: 10.1016/j.ejmech.2015.02.009. Epub 2015 Feb 7.

Abstract

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.

Keywords: Acetylcholinesterase; Alzheimer's disease; Benzofuran; Docking study; Pyridinium.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / enzymology
  • Benzofurans / chemical synthesis*
  • Benzofurans / chemistry
  • Benzofurans / pharmacology
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Drug Design
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Pyridinium Compounds / chemical synthesis*
  • Pyridinium Compounds / chemistry
  • Pyridinium Compounds / pharmacology
  • Structure-Activity Relationship

Substances

  • Benzofurans
  • Cholinesterase Inhibitors
  • Pyridinium Compounds
  • Acetylcholinesterase