Synthesis, molecular modeling studies and selective inhibitory activity against MAO of 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-(1H)-pyrazole derivatives.

A novel series of 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-(1H)-pyrazole derivatives have been synthesized and investigated for the ability to inhibit selectively the activity of the A and B isoforms of monoamine oxidase (MAO). To verify the effects of structural modifications on both inhibition and selectivity toward MAO-A and MAO-B, the substituted 4,5-dihydro-(1H)-pyrazoles 1-10 have been synthesized. In particular, the influence, on the biological behavior, of the introduction of different aromatic rings in the 3 and 5 positions of the dihydro- (1H)-pyrazole nucleus has been investigated. All the synthesized compounds show high activity against both the MAO-A and the MAO-B isoforms with Ki values between 27 and 4 nM and between 50 and 1.5 nM, respectively, except for a few derivatives whose inhibitory activity against MAO-B was in the micromolar range. Knowing that stereochemistry may be an important modulator of biological activity, we performed the semipreparative chromatographic enantioseparation of the most potent, selective, and chiral compounds. The separated enantiomers were then submitted to in vitro biological evaluation. The selectivity of the (-)- (S)-1 enantiomer against MAO-B increases twice and a half, while the selectivity of the (-)- (S)-4 enantiomer against MAO-A triples. Both the MAO-A and MAO-B isoforms respectively of the 1O5W and 1GOS models deposited in the Protein Data Bank were considered in the computational study. The docking study was carried out using several computational approaches with the aim of proposing possible binding modes of the MAO enantioselective compounds 1 and 4.