Synthesis and evaluation of aplysinopsin analogs as inhibitors of human monoamine oxidase A and B

Bioorg Med Chem Lett. 2012 Aug 1;22(15):4926-9. doi: 10.1016/j.bmcl.2012.06.058. Epub 2012 Jun 23.

Abstract

Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms. Previous studies have shown aplysinopsin analogs to possess a variety of biological activities, including modulation of neurotransmissions. A series of fifty aplysinopsin analogs was synthesized and assayed for monoamine oxidase A and B inhibitory activity. Three compounds displayed significant MAO inhibitory activity and selectivity. The compound (E)-5-[(6-bromo-1H-indol-3-yl)methylene]-2-imino-1,3-dimethylimidazolidin-4-one (3x) possessed an IC(50) of 5.6 nM at MAO-A and had a selectivity index of 80.24. An SAR study revealed that multiple N-methylations, one of which should be at position N-2', and bromination at C-5 or C-6 are important factors for MAO-A potency and selectivity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Monoamine Oxidase / chemistry
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / chemical synthesis*
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / metabolism
  • Protein Binding / drug effects
  • Structure-Activity Relationship
  • Tryptophan / analogs & derivatives*
  • Tryptophan / chemical synthesis
  • Tryptophan / chemistry
  • Tryptophan / metabolism
  • Tryptophan / pharmacology

Substances

  • Enzyme Inhibitors
  • Monoamine Oxidase Inhibitors
  • aplysinopsin
  • Tryptophan
  • Monoamine Oxidase