title: Discovery of New Chemical Entities for Old Targets: Insights on the Lead Optimization of Chromone-Based Monoamine Oxidase B (MAO-B) Inhibitors.
abstract: The discovery of new chemical entities endowed with potent, selective, and reversible monoamine oxidase B inhibitory activity is a clinically relevant subject. Therefore, a small library of chromone derivatives was synthesized and screened toward human monoamine oxidase isoforms (hMAO-A and hMAO-B). The structure-activity relationships studies strengthen the importance of the amide spacer and the direct linkage of carbonyl group to the γ-pyrone ring, along with the presence of meta and para substituents in the exocyclic ring. The most potent MAO-B inhibitors were N-(3'-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (20) (IC50 = 403 pM) and N-(3',4'-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (27) (IC50 = 669 pM), acting as competitive and noncompetitive reversible inhibitors, respectively. Computational docking studies provided insights into enzyme-inhibitor interactions and a rationale for the observed selectivity and potency. Compound 27 stands out due to its favorable toxicological profile and physicochemical properties, which pointed toward blood-brain barrier permeability, thus being a valid candidate for subsequent animal studies.
authors.affiliation: CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto , 4169-007, Porto, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Reis
authors.affiliation: CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto , 4169-007, Porto, Portugal.
authors.forename: Fernando
authors.initials: F
authors.lastname: Cagide
authors.affiliation: CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto , 4169-007, Porto, Portugal.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chavarria
authors.affiliation: CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto , 4169-007, Porto, Portugal.
authors.forename: Tiago
authors.initials: T
authors.lastname: Silva
authors.affiliation: CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto , 4169-007, Porto, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandes
authors.affiliation: CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto , 4169-007, Porto, Portugal.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gaspar
authors.affiliation: Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela , 15782 Santiago de Compostela, Spain.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Uriarte
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto , 4050-313, Porto, Portugal.
authors.forename: Fernando
authors.initials: F
authors.lastname: Remião
authors.affiliation: Department of "Scienze della Vita", University "Magna Græcia" of Catanzaro , 88100 Catanzaro, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.affiliation: Department of "Scienze della Vita", University "Magna Græcia" of Catanzaro , 88100 Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.affiliation: CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto , 4169-007, Porto, Portugal.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D002867:Chromones; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase