Synthesis and evaluation of 6-methyl-3-phenylcoumarins as potent and selective MAO-B inhibitors

A series of 6-methyl-3-phenylcoumarins 3-6 were synthesized and evaluated as monoamine oxidase A and B (MAO-A and MAO-B) inhibitors. A comparative study between the three possible mono methoxy 3-phenyl derivatives and the p-hydroxy analogue is reported. The synthesis of these new resveratrol-coumarin hybrids was carried out by a Perkin reaction between the 5-methylsalicylaldehyde and the corresponding phenylacetic acids. The p-methoxy substituted compound 3 was hydrolyzed to 6 by a traditional reaction with hydriodic acid. The prepared compounds show high selectivity to the MAO-B isoenzyme, some of them with IC(50) values in the low nanomolar range. Compound 4, with the methoxy group in meta position, is the most active of this series, with an IC(50) against MAO-B of 0.80 nM, and is several times more potent and MAO-B selective than the R-(-)-deprenyl (reference compound). (C) 2009 Elsevier Ltd. All rights reserved.