Chromone 3-phenylcarboxamides as potent and selective MAO-B inhibitors

Bioorg Med Chem Lett. 2011 Jan 15;21(2):707-9. doi: 10.1016/j.bmcl.2010.11.128. Epub 2010 Dec 5.

Abstract

Monoamine oxidase (MAO) is an enzyme, present in mammals in two isoforms MAO-A and MAO-B. These isoforms have a crucial role in neurotransmitters metabolism, representing an attractive drug target in the therapy of neurodegenerative diseases (MAO-B) and depression (MAO-A). In this context, our work has been focused on the discovery of new chemical entities (NCEs) for MAO inhibition, based on the development of chromone carboxamides. Chromone derivatives with a carboxamide function located in position 2- and 3- of the benzo-γ-pyrone core, (compounds 2-6 and 8-12) were synthesized, with moderate/good yields, by a one-pot condensation reaction using phosphonium salts as coupling reagents. The synthetic compounds were screened towards human MAO isoforms (hMAO) to evaluate their potency and selectivity. The chromone-3-carboxamides show high selectivity to hMAO-B, with compounds 9 and 12 displaying IC(50) values at nanomolar range.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Chromones / chemistry*
  • Chromones / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / chemistry*
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Neurodegenerative Diseases / drug therapy
  • Neurodegenerative Diseases / enzymology
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Structure-Activity Relationship

Substances

  • Chromones
  • Monoamine Oxidase Inhibitors
  • Protein Isoforms
  • Monoamine Oxidase