INHIBITION OF MONOAMINE OXIDASE-B BY 5H-INDENO[1,2-C]PYRIDAZINES - BIOLOGICAL-ACTIVITIES, QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS (QSARS) AND 3D-QSARS

A large series (66 compounds) of indeno[1,2-c]pyridazin-5-ones (IPs) w ere synthesized and tested on their monoamine oxidase-A (MAO-A) and MA O-B inhibitory activity. All of the tested compounds acted preferentia lly on MAO-B displaying weak (nonmeasurable IC50 values) to high (subm icromolar IC50 values) activities. The most active compound was p-CF3- 3-phenyl-IP (IC50 = 90 nM). Multiple linear regression analysis of the substituted 3-phenyl-IPs yielded good statistical results (q(2) = 0.7 4; r(2) = 0.86) and showed the importance of lipophilic, electronic, a nd steric properties of the substituents in determining inhibitory pot ency. Various comparative molecular field analysis studies were perfor med with different alignments and including the molecular lipophilicit y potential. This led to a model including the steric, electrostatic a nd lipophilicity fields and having a good predictive value (q(2) = 0.7 5; r(2) = 0.93).