Synthesis and molecular modelling of novel substituted-4,5-dihydro-(1H)-pyrazole derivatives as potent and highly selective monoamine oxidase-A inhibitors.
This report describes novel pyrazoline derivatives investigated for their ability to selectively inhibit the activity of the A and B isoforms of monoamine oxidase. These new synthetic compounds proved to be reversible, potent, and selective inhibitors of monoamine oxidase-A rather than of monoamine oxidase-B, and are promising candidates to further advance drug discovery efforts. The most active compounds show inhibitory activity on monoamine oxidase-A in the 1.0x10(-8)-8.6x10(-9) M range. Moreover, it should be pointed out that for some compounds a high IC50>or=10(-9) M value is associated with a high A-selectivity (Selectivity Index monoamine oxidase-B/monoamine oxidase-A in the 10,000-12,500 range). Further insight to understand enzyme-inhibitor molecular interaction was obtained by docking experiments with the monoamine oxidase-A and monoamine oxidase-B isoforms.
Chimenti
Franco
F
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi di Roma La Sapienza, P.le Aldo Moro 5, 00185 Rome, Italy.
Bolasco
Adriana
A
Manna
Fedele
F
Secci
Daniela
D
Chimenti
Paola
P
Granese
Arianna
A
Befani
Olivia
O
Turini
Paola
P
Alcaro
Stefano
S
Ortuso
Francesco
F
D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D008996:Monoamine Oxidase Inhibitors; D011720:Pyrazoles; D008995:Monoamine Oxidase