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

Gnerre, Carmela
Catto, M.
Leonetti, F.
Weber, P.
Altomare, Cosimo
Carotti, Angelo
Testa, Bernard
Published in Journal of Medicinal Chemistry. 2000, vol. 43, no. 25, p. 4747-4758
Abstract 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 the compounds acted preferentially on MAO-B with IC(50) values in the micromolar to low-nanomolar range; high inhibitory activities toward MAO-A were also measured for sulfonic acid esters. The most active compound was 7-[(3, 4-difluorobenzyl)oxy]-3,4-dimethylcoumarin, with an IC(50) value toward MAO-B of 1.14 nM. A QSAR study of 7-X-benzyloxy meta-substituted 3,4-dimethylcoumarin derivatives acting on MAO-B yielded good statistical results (q(2)() = 0.72, r(2)() = 0.86), revealing the importance of lipophilic interactions in modulating the inhibition and excluding any dependence on electronic properties. 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 the predictivity of the models and to facilitate the graphical interpretation of results.
Keywords AnimalsBicyclo Compounds/*chemical synthesis/chemistry/pharmacologyChromones/*chemical synthesis/chemistry/pharmacologyCoumarins/*chemical synthesis/chemistry/pharmacologyModels, MolecularMonoamine Oxidase/*metabolismMonoamine Oxidase Inhibitors/*chemical synthesis/chemistry/pharmacologyQuantitative Structure-Activity RelationshipRatsSpectrophotometry, Ultraviolet
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PMID: 11123983

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Deposited on : 2010-08-06

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