New coumarin derivatives: design, synthesis and use as inhibitors of hMAO

Bioorg Med Chem. 2014 Jul 15;22(14):3732-8. doi: 10.1016/j.bmc.2014.05.002. Epub 2014 May 14.

Abstract

A series new 2H-chromene-3-carboxamides (4a-4i) and S-2H-chromene-3-carbothioates (5j-5t) were synthesized and evaluated as monoamine oxidase A and B inhibitors. Among them, compound 5k (IC50=0.21μM, IC50 iproniazid=7.65μM) showed the most activity and higher MAO-B selectivity (189.2-fold vs 1-fold) with respect to the MAO-A isoform. The need to clarify at a 3D level some important molecular aspects of discussed SAR, we undertaked a number of docking simulations to better assess. The steric effect was analyzed interms of both posing and scoring by investigating the nature of the binding interactions. The docking results of active compound 5k with hMAO-B complex indicated that conserved residue ILE 199 was important for ligand binding via Sigma-Pi interaction.

Keywords: Coumarin; Design; Inhibitors; Synthesis; hMAO-B.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Coumarins / chemical synthesis
  • Coumarins / chemistry
  • Coumarins / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / chemical synthesis
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Coumarins
  • Monoamine Oxidase Inhibitors
  • coumarin
  • Monoamine Oxidase