Synthesis and selective inhibitory activity against MAO of 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives.

A novel series of 1-acetyl-3-(4-hydroxy- and 2,4-dihydroxyphenyl)-5-phenyl-4,5-dihydro-(1H)- pyrazole derivatives have been synthesized and investigated for the ability to selectively inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). The new synthesized compounds proved to be more reversible, potent, and selective inhibitors of MAO-A than of MAO-B. 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 while increasing their inhibitory activity and A selectivity. The (-)-6 enantiomer shows Ki(MAO-A) = 2 nM and SI = 165 000, (+)-6 shows Ki(MAO-A) = 6 nM and SI = 166 666, (-)-11 shows Ki(MAO-A) = 4 nM and SI = 80 000, and (+)-11 shows Ki(MAO-A) = 7 nM and SI = 38 571. The biological results agree with our preliminary hypothesis of a correlation between the presence of polar group/s and high anti-MAO-A activity. These findings will be taken into account when planning novel, selective MAO-A and MAO-B inhibitors, structurally related to the synthesized compounds 1-12, with the aim of developing a SAR model by a rational design in order to explore in depth the nature of the interactions with the active site.