Design, synthesis and pharmacological evaluation of chalcone derivatives as acetylcholinesterase inhibitors

Bioorg Med Chem. 2014 Nov 1;22(21):6124-33. doi: 10.1016/j.bmc.2014.08.033. Epub 2014 Sep 4.

Abstract

A novel series of chalcone derivatives (4a-8d) were designed, synthesized, and evaluated for the inhibition activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The logP values of the compounds were shown to range from 1.49 to 2.19, which suggested that they were possible to pass blood brain barriers in vivo. The most promising compound 4a (IC50: 4.68 μmol/L) was 2-fold more potent than Rivastigmine against AChE (IC50: 10.54 μmol/L) and showed a high selectivity for AChE over BuChE (ratio: 4.35). Enzyme kinetic study suggested that the inhibition mechanism of compound 4a was a mixed-type inhibition. Meanwhile, the result of molecular docking showed its potent inhibition of AChE and high selectivity for AChE over BuChE.

Keywords: AChE inhibitors; Chalcone derivatives; LogP; Molecular docking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism*
  • Animals
  • Butyrylcholinesterase / chemistry
  • Butyrylcholinesterase / metabolism
  • Chalcone / chemistry*
  • Chalcone / pharmacology*
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / pharmacology*
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Kinetics
  • Molecular Docking Simulation
  • Structure-Activity Relationship
  • Torpedo

Substances

  • Cholinesterase Inhibitors
  • Chalcone
  • Acetylcholinesterase
  • Butyrylcholinesterase