title: Design, synthesis and biological evaluation of N-methyl-N-[(1,2,3-triazol-4-yl)alkyl]propargylamines as novel monoamine oxidase B inhibitors.
abstract: Different azides and alkynes have been coupled via Cu-catalyzed 1,3-dipolar Huisgen cycloaddition to afford a novel family of N1- and C5-substituted 1,2,3-triazole derivatives that feature the propargylamine group typical of irreversible MAO-B inhibitors at the C4-side chain of the triazole ring. All the synthesized compounds were evaluated against human MAO-A and MAO-B. Structure-activity relationships and molecular modeling were utilized to gain insight into the structural and chemical features that enhance the binding affinity and selectivity between the two enzyme isoforms. Several lead compounds, in terms of potency (submicromolar to low micromolar range), MAO-B selective recognition, and brain permeability, were identified. One of these leads (MAO-B IC50of 3.54μM, selectivity MAO-A/MAO-B index of 27.7) was further subjected to reversibility and time-dependence inhibition studies, which disclosed a slow and irreversible inhibition of human MAO-B. Overall, the results support the suitability of the 4-triazolylalkyl propargylamine scaffold for exploring the design of multipotent anti-Alzheimer compounds endowed with irreversible MAO-B inhibitory activity.
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
authors.forename: Ornella
authors.initials: O
authors.lastname: Di Pietro
authors.affiliation: Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona, Av. Prat de la Riba 171, E-08921 Santa Coloma de Gramenet, Spain.
authors.forename: Nelson
authors.initials: N
authors.lastname: Alencar
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Medicina and Institut de Neurociències, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.
authors.forename: Gerard
authors.initials: G
authors.lastname: Esteban
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Viayna
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Szałaj
authors.affiliation: Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona, Av. Prat de la Riba 171, E-08921 Santa Coloma de Gramenet, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Vázquez
authors.affiliation: Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona, Av. Prat de la Riba 171, E-08921 Santa Coloma de Gramenet, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Juárez-Jiménez
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Sola
authors.affiliation: Departament de Farmacologia, Terapéutica i Toxicologia, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Pérez
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Medicina and Institut de Neurociències, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.
authors.forename: Montse
authors.initials: M
authors.lastname: Solé
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Medicina and Institut de Neurociències, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Unzeta
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain. Electronic address: dmunoztorrero@ub.edu.
authors.forename: Diego
authors.initials: D
authors.lastname: Muñoz-Torrero
authors.affiliation: Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona, Av. Prat de la Riba 171, E-08921 Santa Coloma de Gramenet, Spain. Electronic address: fjluque@ub.edu.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010293:Pargyline / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D008996:Monoamine Oxidase Inhibitors; D010293:Pargyline; D008995:Monoamine Oxidase
keywords: Alzheimer’s disease; Click-chemistry; Irreversible inhibition; Monoamine oxidase B