Design, synthesis, biological evaluation and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5212-6. doi: 10.1016/j.bmcl.2015.09.063. Epub 2015 Sep 28.

Abstract

A series of novel 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors have been designed and synthesized. The screening results showed that most of the compounds exhibited potent anti-AChE activity in the range of nM concentrations. The 1-(4-fluorobenzyl) substituted derivative 9d exhibited the most potent anti-AChE activity with IC50 value of 8.9 nM and high AChE/BuChE selectivity (SI>230). Kinetic and molecular modeling studies suggested that compound 9d was mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. Besides, the preliminary structure-activity relationships were discussed.

Keywords: 4-Isochromanone; Acetylcholinesterase; Alzheimer’s disease; Dual binding site; Hybrids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Benzopyrans / chemical synthesis
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology*
  • Binding Sites
  • Butyrylcholinesterase / chemistry
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Molecular Docking Simulation
  • Pyridinium Compounds / chemical synthesis
  • Pyridinium Compounds / chemistry
  • Pyridinium Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • (Z)-4-((7,8-dimethoxy-4-oxoisochroman-3-ylidene)methyl)-1-(4-fluorobenzyl)pyridin-1-ium bromide
  • Benzopyrans
  • Cholinesterase Inhibitors
  • Pyridinium Compounds
  • Acetylcholinesterase
  • Butyrylcholinesterase