title: 1,5-Diphenylpenta-2,4-dien-1-ones as potent and selective monoamine oxidase-B inhibitors.
abstract: A series of (2E,4E)-1-(2-hydroxyphenyl)-5-phenylpenta-2,4-dien-1-ones (3a-r) and (2Z,4E)-3-hydroxy-1-(2-hydroxyphenyl)-5-phenylpenta-2,4-dien-1-ones (6a-l) were synthesized and evaluated in vitro as inhibitors of the two human Monoamine oxidase (hMAO) isoforms, MAO-A and MAO-B. Most of the compounds showed a selective MAO-B inhibitory activity in the nanomolar or low micromolar range. (2E,4E)-5-(4-Chlorophenyl)-1-(2-hydroxy-4-methoxyphenyl)penta-2,4-dien-1-one (3g) and (2E,4E)-5-(4-chlorophenyl)-1-(2,4-dihydroxyphenyl)penta-2,4-dien-1-one (3h) were the most potent hMAO-B inhibitors exhibiting IC(50) of 4.51 nM and 11.35 nM, respectively, coupled with high selectivity. Moreover, partial recovery of MAO-B activity was observed after repeated washing in the presence of isatin (reversible inhibitor) and compounds 3g and 3h suggesting a reversible inhibition of the enzyme. Molecular mechanics and quantum chemistry methods were used to elucidate the MAO recognition of the most active inhibitors 3g and 3h.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza - Università di Roma, P.le Aldo Moro 5, 00185 Rome, Italy. nicoletta.desideri@uniroma1.it
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Desideri
authors.forename: Rossella
authors.initials: R
authors.lastname: Fioravanti
authors.forename: Luca
authors.initials: L
authors.lastname: Proietti Monaco
authors.forename: Mariangela
authors.initials: M
authors.lastname: Biava
authors.forename: Matilde
authors.initials: M
authors.lastname: Yáñez
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
mesh_terms: D002478:Cells, Cultured; D003474:Curcumin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011789:Quantum Theory; D013329:Structure-Activity Relationship
chemical_list: C583878:(2E,4E)-5-(4-chlorophenyl)-1-(2,4-dihydroxyphenyl)penta-2,4-dien-1-one; C583877:(2E,4E)-5-(4-chlorophenyl)-1-(2-hydroxy-4-methoxyphenyl)penta-2,4-dien-1-one; D008996:Monoamine Oxidase Inhibitors; D003474:Curcumin