Discovery, biological evaluation, and crystal structure of a novel nanomolar selective butyrylcholinesterase inhibitor

J Med Chem. 2014 Oct 9;57(19):8167-79. doi: 10.1021/jm501195e. Epub 2014 Sep 29.


Butyrylcholinesterase (BChE) is regarded as a promising drug target as its levels and activity significantly increase in the late stages of Alzheimer's disease. To discover novel BChE inhibitors, we used a hierarchical virtual screening protocol followed by biochemical evaluation of 40 highest scoring hit compounds. Three of the compounds identified showed significant inhibitory activities against BChE. The most potent, compound 1 (IC50 = 21.3 nM), was resynthesized and resolved into its pure enantiomers. A high degree of stereoselective activity was revealed, and a dissociation constant of 2.7 nM was determined for the most potent stereoisomer (+)-1. The crystal structure of human BChE in complex with compound (+)-1 was solved, revealing the binding mode and providing clues for potential optimization. Additionally, compound 1 inhibited amyloid β(1-42) peptide self-induced aggregation into fibrils (by 61.7% at 10 μM) and protected cultured SH-SY5Y cells against amyloid-β-induced toxicity. These data suggest that compound 1 represents a promising candidate for hit-to-lead follow-up in the drug-discovery process against Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / chemistry
  • Animals
  • Butyrylcholinesterase / chemistry*
  • Cell Line, Tumor
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Chromatography, High Pressure Liquid
  • Crystallization
  • Drug Discovery
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Peptide Fragments / chemistry
  • Protein Aggregates
  • Stereoisomerism


  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Peptide Fragments
  • Protein Aggregates
  • amyloid beta-protein (1-42)
  • Butyrylcholinesterase