Inhibition of monoamine oxidases by functionalized coumarin derivatives: Biological activities, QSARs, and 3D-QSARs

A large series of coumarin derivatives (71 compounds) were tested for their monoamine oxidase A and B (MAO-A and MAO-B) inhibitory activity. Most of t he compounds acted preferentially on MAO-B with IC50 values in the micromol ar to low-nanomolar range; high inhibitory activities toward MAO-A were als o measured for sulfonic acid esters. The most active compound was 7-[(3,4-d ifluorobenzyl)oxy]-3,4-dimethylcoumarin, with an IC50 value toward MAO-B of 1.14 nM. A QSAR study of 7-X-benzyloxy meta-substituted 3,4-dimethylcoumar in derivatives acting on MAO-B yielded good statistical results (q(2) = 0.7 2, r(2) = 0.86), revealing the importance of lipophilic interactions in mod ulating the inhibition and excluding any dependence on electronic propertie s. CoMFA was performed on two data sets of MAO-A and MAO-B inhibitors. The GOLPE procedure, with variable selection criteria, was applied to improve t he predictivity of the models and to facilitate the graphical interpretatio n of results.