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

详细信息    查看全文

• 作者：Nicoletta Desideri^a ; ^{nicoletta.desideri@uniroma1.it} ; Rossella Fioravanti^a ; Luca Proietti Monaco^a ; Mariangela Biava^a ; Matilde Yá ; ñ ; ez^b ; Francesco Ortuso^c ; Stefano Alcaro^c
• 关键词：1 ; 5-Diphenylpenta-2 ; 4-dien-1-ones ; Monoamine oxidase ; hMAO-B inhibitors ; Structure&ndash ; activity relationship ; Docking
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：January, 2013
• 年：2013
• 卷：59
• 期：Complete
• 页码：91-100
• 全文大小：669 K

文摘

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.