1,5-Diphenylpenta-2,4-dien-1-ones as Potent and Selective Monoamine oxidase-B Inhibitors

Eur J Med Chem. 2013 Jan;59:91-100. doi: 10.1016/j.ejmech.2012.11.006. Epub 2012 Nov 15.

Abstract

A series of (2E,4E)-1-(2-hydroxyphenyl)-5-phenylpenta-2,4-dien-1-ones (3a-r) and (2Z,4E)-3-hydroxy-1-(2-hydroxyphenyl)-5-phenylpenta-2,4-dien-1-ones (6a-l) were synthesized and evaluated in vitro as inhibitors of the two human Monoamine oxidase (hMAO) isoforms, MAO-A and MAO-B. Most of the compounds showed a selective MAO-B inhibitory activity in the nanomolar or low micromolar range. (2E,4E)-5-(4-Chlorophenyl)-1-(2-hydroxy-4-methoxyphenyl)penta-2,4-dien-1-one (3g) and (2E,4E)-5-(4-chlorophenyl)-1-(2,4-dihydroxyphenyl)penta-2,4-dien-1-one (3h) were the most potent hMAO-B inhibitors exhibiting IC(50) of 4.51 nM and 11.35 nM, respectively, coupled with high selectivity. Moreover, partial recovery of MAO-B activity was observed after repeated washing in the presence of isatin (reversible inhibitor) and compounds 3g and 3h suggesting a reversible inhibition of the enzyme. Molecular mechanics and quantum chemistry methods were used to elucidate the MAO recognition of the most active inhibitors 3g and 3h.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Curcumin / analogs & derivatives*
  • Curcumin / chemical synthesis
  • Curcumin / chemistry
  • Curcumin / pharmacology
  • Enzyme Activation / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Monoamine Oxidase Inhibitors / chemical synthesis
  • Monoamine Oxidase Inhibitors / chemistry*
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Quantum Theory
  • Structure-Activity Relationship

Substances

  • (2E,4E)-5-(4-chlorophenyl)-1-(2,4-dihydroxyphenyl)penta-2,4-dien-1-one
  • (2E,4E)-5-(4-chlorophenyl)-1-(2-hydroxy-4-methoxyphenyl)penta-2,4-dien-1-one
  • Monoamine Oxidase Inhibitors
  • Curcumin