Synthesis and selective inhibitory activity of 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives against monoamine oxidase.
A novel series of 1-acetyl-3-(4-hydroxy- and 2,4-dihydroxyphenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole derivatives 1-12 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 1-12 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, 6 and 11. The separated enantiomers were then submitted to in vitro biological evaluation while increasing their inhibitory activity and A selectivity. The (-)-6 enantiomer shows K(i(MAO-A)) = 2 nM and SI = 165 000, (+)-6 shows K(i(MAO-A)) = 6 nM and SI = 166 666, (-)-11 shows K(i(MAO-A)) = 4 nM and SI = 80 000, and (+)-11 shows K(i(MAO-A)) = 7 nM and SI = 38 571.
Chimenti
Franco
F
Dipartimento di Studi di Chimica e Tossicologia delle Sostanze Biologicamente Attive, Università degli Studi di Roma La Sapienza, Piazzale A. Moro 5, 00185 Rome, Italy.
Bolasco
Adriana
A
Manna
Fedele
F
Secci
Daniela
D
Chimenti
Paola
P
Befani
Olivia
O
Turini
Paola
P
Giovannini
Valentina
V
Mondovì
Bruno
B
Cirilli
Roberto
R
La Torre
Francesco
F
D000818:Animals; D001921:Brain / Q000201:enzymology / Q000648:ultrastructure; D002417:Cattle; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D011720:Pyrazoles; D008995:Monoamine Oxidase