3‐Amidocoumarins as Potential Multifunctional Agents against Neurodegenerative Diseases |
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| Authors: | Dr. Maria João Matos Fernanda Rodríguez‐Enríquez Prof. Fernanda Borges Prof. Lourdes Santana Prof. Eugenio Uriarte Dr. Martín Estrada Prof. María Isabel Rodríguez‐Franco Prof. Reyes Laguna Prof. Dolores Viña |
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| Affiliation: | 1. CIQUP/Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Porto, Portugal;2. Departamento de Farmacología, CIMUS, Universidad de Santiago de Compostela, Santiago de Compostela, Spain;3. Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, Santiago de Compostela, Spain;4. Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), Madrid, Spain |
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| Abstract: | Monoamine oxidase (MAO) generates reactive oxygen species (ROS), which cause neuronal cell death, causing neurodegeneration. Agents that are able to concurrently inhibit MAO and scavenge free radicals represent promising multifunctional neuroprotective agents that could be used to delay or slow the progression of neurodegenerative diseases. In this work, variously substituted 3‐amidocoumarins are described that exert neuroprotection in vitro against hydrogen peroxide in rat cortical neurons, as well as antioxidant activity in a 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH?) radical scavenging assay. Selective and reversible inhibitors of the MAO‐B isoform were identified. Interestingly, in the case of the 3‐benzamidocoumarins, substitution at position 4 with a hydroxy group abolishes MAO‐B activity, but the compounds remain active in the neuroprotection model. Further evaluation of 3‐heteroarylamide derivatives indicates that it is the nature of the heterocycle that determines the neuroprotective effects. Evaluation in a parallel artificial membrane permeability assay (PAMPA) highlighted the need to further improve the blood–brain barrier permeability of this compound class. However, the compounds described herein adhere to Lipinski′s rule of five, suggesting that this novel scaffold has desirable properties for the development of potential drug candidates. |
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| Keywords: | coumarin inhibitors monoamine oxidase neuroprotection Parkinson′ s disease |
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