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 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.
Gnerre
C
C
Institut de Chimie Thérapeutique, Université de Lausanne, BEP, CH-1015 Lausanne, Switzerland.
Catto
M
M
Leonetti
F
F
Weber
P
P
Carrupt
P A
PA
Altomare
C
C
Carotti
A
A
Testa
B
B
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013056:Spectrophotometry, Ultraviolet
D001643:Bridged Bicyclo Compounds; D002867:Chromones; D003374:Coumarins; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase