title: Homoisoflavonoids: natural scaffolds with potent and selective monoamine oxidase-B inhibition properties.
abstract: A series of homoisoflavonoids [(E)-3-benzylidenechroman-4-ones 1a-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 1a-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.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Università La Sapienza 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: Adriana
authors.initials: A
authors.lastname: Bolasco
authors.forename: Rossella
authors.initials: R
authors.lastname: Fioravanti
authors.forename: Luca Proietti
authors.initials: LP
authors.lastname: Monaco
authors.forename: Francisco
authors.initials: F
authors.lastname: Orallo
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: D055808:Drug Discovery; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D005419:Flavonoids; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase