Synthesis of a series of unsaturated ketone derivatives as selective and reversible monoamine oxidase inhibitors

Bioorg Med Chem. 2015 Oct 1;23(19):6486-96. doi: 10.1016/j.bmc.2015.08.012. Epub 2015 Aug 19.

Abstract

We have synthesized three categories of α,β-unsaturated carbonyl derivatives and evaluated their MAO-A and MAO-B inhibitory activities. Among them, compound 10b including α,β-unsaturated ketone group showed the most potent and selective MAO-B inhibitory activity (IC₅₀ human MAO-B 16 nM, >6000-fold selective vs MAO-A) and compound 10b exhibited good reversibility compared with selegiline, a well-known irreversible MAO-B inhibitor. However, both α,β-unsaturated amide and ester derivatives exhibited weaker MAO-B inhibition potencies. The docking studies provided insights into the possible binding modes and the key interaction sites of the synthesized MAO-B inhibitors.

Keywords: Chalcone; MAO-B inhibitor; Monoamine oxidase; Reversible inhibitor; α,β-Unsaturated carbonyl derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Free Radical Scavengers / chemical synthesis
  • Free Radical Scavengers / chemistry
  • Humans
  • Hydrogen Peroxide / chemistry
  • Ketones / chemical synthesis
  • Ketones / chemistry*
  • Ketones / metabolism
  • Kinetics
  • Molecular Docking Simulation
  • Monoamine Oxidase / chemistry*
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / chemical synthesis*
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Structure-Activity Relationship

Substances

  • Free Radical Scavengers
  • Ketones
  • Monoamine Oxidase Inhibitors
  • Hydrogen Peroxide
  • Monoamine Oxidase