1,5-Diphenylpenta-2,4-dien-1-ones as potent and selective monoamine oxidase-B inhibitors.

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Desideri N, Fioravanti R, Proietti Monaco L, Biava M, Yanez M, Ortuso F, Alcaro S

1,5-Diphenylpenta-2,4-dien-1-ones as potent and selective monoamine oxidase-B inhibitors.

Eur J Med Chem. 2013 Jan;59:91-100. doi: 10.1016/j.ejmech.2012.11.006. Epub 2012 Nov 15.

PubMed ID
23207410 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
ClorgilineAmine oxidase [flavin-containing] AIC 50 (nM)4.5N/AN/ADetails
IproniazidAmine oxidase [flavin-containing] BIC 50 (nM)7540N/AN/ADetails
IsatinAmine oxidase [flavin-containing] BIC 50 (nM)21070N/AN/ADetails
MoclobemideAmine oxidase [flavin-containing] AIC 50 (nM)361380N/AN/ADetails
SelegilineAmine oxidase [flavin-containing] AIC 50 (nM)67250N/AN/ADetails
SelegilineAmine oxidase [flavin-containing] BIC 50 (nM)20N/AN/ADetails