Synthesis and evaluation of 4-substituted coumarins as novel acetylcholinesterase inhibitors

Eur J Med Chem. 2013 Jun:64:252-9. doi: 10.1016/j.ejmech.2013.03.021. Epub 2013 Mar 18.

Abstract

A series of 4-hydroxycoumarin derivatives were designed and synthesized as new acetylcholinesterase (AChE) inhibitors which could be considered for Alzheimer's disease therapeutics. Among the 19 coumarin-derived compounds tested toward Electrophorus electricus acetylcholinesterase (eelAChE) and horse serum butyrylcholinesterase (eqBChE), N-(1-benzylpiperidin-4-yl)acetamide derivative 4m displayed highest AChE inhibitory activity (IC50 = 1.2 μM) and good selectivity (37 times). The docking study of the most potent compound 4m, indicated that Phe330 is responsible for ligand recognition and trafficking by forming π-cation interaction with benzylpiperidine moiety. Furthermore, the formation of an additional π-π interaction between coumarin moiety and Trp279 of peripheral anionic site could stabilize the ligand in the active site resulting in more potent inhibition of the enzyme.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Animals
  • Butyrylcholinesterase / metabolism*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Coumarins / chemical synthesis
  • Coumarins / chemistry
  • Coumarins / pharmacology*
  • Dose-Response Relationship, Drug
  • Electrophorus
  • Horses
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Cholinesterase Inhibitors
  • Coumarins
  • Acetylcholinesterase
  • Butyrylcholinesterase