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

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 IC50 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.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A series of 1,5-diphenylpenta-2,4-dien-1-ones were synthesized. ► The compounds were evaluated in vitro as inhibitors of the two human MAO isoforms. ► Most of the analogs showed a potent and selective MAO-B inhibitory activity. ► Compounds 3g and 3h act as reversible inhibitors of MAO-B.