Homoisoflavonoids: Natural Scaffolds with Potent and Selective Monoamine Oxidase-B Inhibition Properties

被引:89
作者
Desideri, Nicoletta [1 ]
Bolasco, Adriana [1 ]
Fioravanti, Rossella [1 ]
Monaco, Luca Proietti [1 ]
Orallo, Francisco [2 ,3 ]
Yanez, Matilde [2 ,3 ]
Ortuso, Francesco [4 ]
Acaro, Stefano [4 ]
机构
[1] Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, I-00185 Rome, Italy
[2] Univ Santiago de Compostela, Dept Farmacol, E-15782 Santiago De Compostela, La Coruna, Spain
[3] Univ Santiago de Compostela, Fac Farm, Inst Farm Ind, E-15782 Santiago De Compostela, La Coruna, Spain
[4] Univ Catanzaro Magna Graecia, Dipartimento Sci Farmacobiol, I-88021 Catanzaro, Italy
关键词
ANTIMUTAGENIC HOMOISOFLAVONOIDS; HOFFMANOSSEGGIA-INTRICATA; MAO-INHIBITORS; ANALOGS; DERIVATIVES; CAFFEINE; DISEASE; GENES; BRAIN; MODEL;
D O I
10.1021/jm1013709
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of homoisoflavonoids [(E)-3-benzylidenechroman-4-ones la-w, 3-benzyl-4H-chromen-4-ones 2a-g, and 3-benzylchroman-4-ones 3a-e] have been synthesized and tested in vitro as inhibitors of human monoamine oxidase isoforms A and B (hMAO-A and hMAO-B). Most of the compounds were found to be potent and selective MAO-B inhibitors. In general, the (E)-3-benzylidenechroman-4-ones la-w showed activities in the nano- or micromolar range coupled with high selectivity against hMAO-B. The reduction of the exocyclic double bond results in compounds 3a-e selective against isoform B and active in the micromolar range. In contrast, the endocyclic migration of the double bond (compounds 2a-g) generally produces the loss of the inhibitory activity or a marked reduction in potency. (E)-3-(4-(Dimethylamino)benzylidene)chroman-4-one (1l) and (E)-5,7-dihydroxy-3-(4-hydroxybenzylidene)chroman-4-one (1h) were the most interesting compounds of the entire series of inhibitors, showing hMAO-B affinity better than the selective inhibitor selegiline. Molecular modeling studies have been carried out to explain the selectivity of the most active homoisoflavonoids 1h and 1l.
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页码:2155 / 2164
页数:10
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