Discovery of potent and reversible MAO-B inhibitors as furanochalcones

Int J Biol Macromol. 2018 Mar:108:660-664. doi: 10.1016/j.ijbiomac.2017.11.159. Epub 2017 Nov 28.

Abstract

A series of twelve furanochalcones (F1-F12) was synthesized and investigated for their human monoamine oxidase inhibitory activities. Among the series, compound (2E, 4E)-1-(furan-2-yl)-5-phenylpenta-2, 4-dien-1-one (F1), which was analyzed by single-crystal X-ray diffraction, showed potent and selective MAO-B inhibitory activity with an inhibition constant (Ki) value of 0.0041 μM and selectivity index of (SI) 172.4, and exhibited competitive inhibition. Introduction of a cinnamyl group to the furanochalcone significantly increased the inhibitory activity. In the dilution-recovery experiments, the residual activities of MAO-A and MAO-B by F1 under the diluted condition fully recovered as compared with the undiluted condition, indicating F1 is a reversible inhibitor. The Ki value of F1 is the lowest among the values of chalcone derivatives and furthermore lower than that (0.0079 μM) of the reversible MAO-B inhibitor, lazabemide, a marketed drug. Molecular docking study against hMAO-B provided the binding site interactions of the lead compound, including strong π-π stacking between the phenyl system and FAD nucleus.

Keywords: Furanochalcone; MAO-B; Molecular docking; Potent; Reversible and competitive inhibitor.

MeSH terms

  • Binding Sites
  • Chalcones / chemistry*
  • Chalcones / pharmacology*
  • Drug Discovery*
  • Humans
  • Kinetics
  • Molecular Conformation
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Monoamine Oxidase / chemistry
  • Monoamine Oxidase Inhibitors / chemistry*
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Chalcones
  • Monoamine Oxidase Inhibitors
  • Monoamine Oxidase