Inhibition of monoamine oxidase by 8-[(phenylethyl)sulfanyl]caffeine analogues

Bioorg Med Chem. 2012 Dec 15;20(24):7040-50. doi: 10.1016/j.bmc.2012.10.005. Epub 2012 Oct 16.

Abstract

In a previous study we have investigated the monoamine oxidase (MAO) inhibitory properties of a series of 8-sulfanylcaffeine analogues. Among the compounds studied, 8-[(phenylethyl)sulfanyl]caffeine (IC(50) = 0.223 μM) was found to be a particularly potent inhibitor of the type B MAO isoform. In an attempt to discover potent MAO inhibitors and to further examine the structure-activity relationships (SAR) of MAO inhibition by 8-sulfanylcaffeine analogues, in the present study a series of 8-[(phenylethyl)sulfanyl]caffeine analogues were synthesized and evaluated as inhibitors of human MAO-A and -B. The results document that substitution on C3 and C4 of the phenyl ring with alkyl groups and halogens yields 8-[(phenylethyl)sulfanyl]caffeine analogues which are potent and selective MAO-B inhibitors with IC(50) values ranging from 0.017 to 0.125 μM. The MAO inhibitory properties of a series of 8-sulfinylcaffeine analogues were also examined. The results show that, compared to the corresponding 8-sulfanylcaffeine analogues, the 8-sulfinylcaffeins are weaker MAO-B inhibitors. Both the 8-sulfanylcaffeine and 8-sulfinylcaffeine analogues were found to be weak MAO-A inhibitors. This study also reports the MAO inhibition properties of selected 8-[(phenylpropyl)sulfanyl]caffeine analogues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caffeine / analogs & derivatives*
  • Caffeine / chemistry
  • Caffeine / pharmacology
  • Humans
  • Models, Molecular
  • Monoamine Oxidase / chemistry
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Monoamine Oxidase Inhibitors
  • Caffeine
  • Monoamine Oxidase