title: 8-Substituted 3-arylcoumarins as potent and selective MAO-B inhibitors: synthesis, pharmacological evaluation, and docking studies.
abstract: Neurodegenerative disorders are becoming more prevalent given the increase in the aging population. This has inspired active research in the development of new drugs that could mark an important advance in the treatment of complex diseases such as Alzheimer's and Parkinson's. With the aim of finding new MAO-B-selective inhibitors, we report the synthesis, in vitro evaluation, and docking simulation of a new series of 3-arylcoumarins variously substituted at the 8-position. Most of the studied compounds show high affinity and selectivity for the hMAO-B isoform, with IC₅₀ values in the low micro- to nanomolar range. Some of them have greater hMAO-B inhibitory activity and selectivity than the reference compound, selegiline. Compounds 7 and 8 are the most active of this series, with compound 8 being fivefold more potent against MAO-B and severalfold more selective than selegiline. Docking experiments were carried out with hMAO-B crystal structures, providing new information about the enzyme-inhibitor interaction and the potential therapeutic application of the new 8-substituted 3-arylcoumarins.
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Viña
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Matos
authors.forename: Giulio
authors.initials: G
authors.lastname: Ferino
authors.forename: Enzo
authors.initials: E
authors.lastname: Cadoni
authors.forename: Reyes
authors.initials: R
authors.lastname: Laguna
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
authors.forename: Eugenio
authors.initials: E
authors.lastname: Uriarte
authors.forename: Lourdes
authors.initials: L
authors.lastname: Santana
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D012642:Selegiline / Q000494:pharmacology; D012996:Solutions
chemical_list: D003374:Coumarins; D008996:Monoamine Oxidase Inhibitors; D020033:Protein Isoforms; D012996:Solutions; D012642:Selegiline; D008995:Monoamine Oxidase