Design, synthesis and biological evaluation of novel human monoamine oxidase B inhibitors based on a fragment in an X-ray crystal structure

Bioorg Med Chem Lett. 2019 Apr 15;29(8):1012-1018. doi: 10.1016/j.bmcl.2019.02.008. Epub 2019 Feb 8.

Abstract

Herein we report our efforts of developing reversible selective hMAO-B inhibitors based on isatin, a fragment in an X-ray crystal structure. Five different scaffolds were designed and many compounds were synthesized. Among them, compound A3 demonstrated very high potency and isoform selectivity against hMAO-B, 11 and 13 times more potent (IC50 = 3 nM) and 23.64 and 6.8 times more selective than the marked drugs, selegiline and safinamide. However, the endeavors to modify the polar 3-one group of isatin, that is in a hydrophobic environment in the binding site of hMAO-B, to small nonpolar hydrophobic groups did not bring about improved hMAO-B inhibitors, which may challenge our understanding of molecular interactions and molecular recognition in biological systems.

Keywords: Fragment-based drug design; Isatin; Isoform selectivity; Structure activity relationship; hMAO-B.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Design*
  • Humans
  • Isatin / chemistry
  • Isatin / metabolism
  • Molecular Dynamics Simulation
  • Monoamine Oxidase / chemistry
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / chemical synthesis*
  • Monoamine Oxidase Inhibitors / metabolism
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Structure-Activity Relationship

Substances

  • Monoamine Oxidase Inhibitors
  • Protein Isoforms
  • Isatin
  • Monoamine Oxidase