Potent and selective MAO-B inhibitory activity: amino- versus nitro-3-arylcoumarin derivatives

Bioorg Med Chem Lett. 2015 Feb 1;25(3):642-8. doi: 10.1016/j.bmcl.2014.12.001. Epub 2014 Dec 8.

Abstract

In this study we synthesized and evaluated a new series of amino and nitro 3-arylcoumarins as hMAO-A and hMAO-B inhibitors. Compounds 2, 3, 5 and 6 presented a better activity and selectivity profile against the hMAO-B isoform (IC50 values between 2 and 6nM) than selegiline. In general, the amino derivatives (4-6) proved to be more selective against MAO-B than the nitro derivatives (1-3). Additionally, a theoretical study of some physicochemical properties, PAMPA and reversibility assays for the most potent derivative, and molecular docking simulations were carried out to further explain the pharmacological results, and to identify the hypothetical binding mode for the compounds inside the hMAO-B.

Keywords: 3-Arylcoumarins; ADME theoretical properties; Docking studies; Monoamine oxidase inhibitors; PAMPA assay; Perkin reaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Coumarins / chemistry*
  • Coumarins / metabolism
  • Humans
  • Molecular Docking Simulation
  • Monoamine Oxidase / chemistry*
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / chemistry*
  • Monoamine Oxidase Inhibitors / metabolism
  • Protein Binding
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • Selegiline / chemistry
  • Selegiline / metabolism
  • Structure-Activity Relationship

Substances

  • Coumarins
  • Monoamine Oxidase Inhibitors
  • Protein Isoforms
  • Selegiline
  • Monoamine Oxidase