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

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 (IC50 = 0.223 mu M) 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 IC50 values ranging from 0.017 to 0.125 mu M. 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. (C) 2012 Elsevier Ltd. All rights reserved.