Design,synthesis and biological evaluation of N-methyl-N-[(1,2,3-triazol-4-yl)alkyl]propargylamines as novel monoamine oxidase B inhibitors |
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| Institution: | 1. 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;2. 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;3. Departament de Bioquímica i Biologia Molecular, Facultat de Medicina and Institut de Neurociències, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain;4. Departament de Farmacologia, Terapéutica i Toxicologia, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain;1. Aix-Marseille Univ, Institut de Chimie Radicalaire, Laboratoire de Pharmacochimie Radicalaire, UMR 7273 CNRS, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 05, France;2. KU Leuven-University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium;3. Department of Drug Chemistry and Technologies, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Roma, Italy;4. Centro Nazionale per il Controllo e la Valutazione dei Farmaci, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Roma, Italy;1. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China;2. Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou 450001, PR China;3. Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou 450001, PR China;4. Henan Qunbo Pharmaceutical Research Institute Co. LTD, Zhengzhou 450001, PR China;1. Université de Lorraine, Laboratoire de Synthèse et Réactivité des Systèmes Moléculaires Complexes UMR-SRSMC 7565, Equipe Hécrin, 1 boulevard Arago, 57070 Metz Technopôle, France;2. Laboratoire de toxicologie, Université Libre de Bruxelles, Brussels, Belgium |
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| 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 IC50 of 3.54 μM, 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. |
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| Keywords: | Click-chemistry Monoamine oxidase B Alzheimer’s disease Irreversible inhibition |
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