title: Chromone, a privileged scaffold for the development of monoamine oxidase inhibitors.
abstract: Two series of novel chromone derivatives were synthesized and investigated for their ability to inhibit the activity of monoamine oxidase. The SAR data indicate that chromone derivatives with substituents in position 3 of γ-pyrone nucleus act preferably as MAO-B inhibitors, with IC(50) values in the nanomolar to micromolar range. Almost all chromone 3-carboxamides display selectivity toward MAO-B. Identical substitutions on position 2 of γ-pyrone nucleus result in complete loss of activity in both isoforms (chromones 2-12 except 3 and 5). Notably, chromone (19) exhibits an MAO-B IC(50) of 63 nM, greater than 1000-fold selectivity over MAO-A, and behaves as a quasi-reversible inhibitor. Docking experiments onto the MAO binding of the most active compound highlight different interaction patterns among the isoforms A and B. The differential analysis of the solvation effects among the chromone isomers gave additional insight about the superior outline of the 3-substituted chromone derivatives.
authors.affiliation: CIQUP/Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gaspar
authors.forename: Tiago
authors.initials: T
authors.lastname: Silva
authors.forename: Matilde
authors.initials: M
authors.lastname: Yáñez
authors.forename: Dolores
authors.initials: D
authors.lastname: Vina
authors.forename: Franscisco
authors.initials: F
authors.lastname: Orallo
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.forename: Eugenio
authors.initials: E
authors.lastname: Uriarte
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D000577:Amides; D002867:Chromones; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D014867:Water; D008995:Monoamine Oxidase