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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\u2010amidocoumarins are described that exert neuroprotection in vitro against hydrogen peroxide in rat cortical neurons, as well as antioxidant activity in a 1,1\u2010diphenyl\u20102\u2010picrylhydrazyl (DPPH\u22c5) radical scavenging assay. Selective and reversible inhibitors of the MAO\u2010B isoform were identified. Interestingly, in the case of the 3\u2010benzamidocoumarins, substitution at position\u20054 with a hydroxy group abolishes MAO\u2010B activity, but the compounds remain active in the neuroprotection model. Further evaluation of 3\u2010heteroarylamide 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\u2013brain barrier permeability of this compound class. However, the compounds described herein adhere to Lipinski\u2032s rule of five, suggesting that this novel scaffold has desirable properties for the development of potential drug candidates.<\/jats:p>","DOI":"10.1002\/cmdc.201500408","type":"journal-article","created":{"date-parts":[[2015,10,24]],"date-time":"2015-10-24T07:59:47Z","timestamp":1445673587000},"page":"2071-2079","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["3\u2010Amidocoumarins as Potential Multifunctional Agents against Neurodegenerative Diseases"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3470-8299","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Matos","sequence":"first","affiliation":[{"name":"CIQUP\/Departamento de Qu\u00edmica e Bioqu\u00edmica Faculdade de Ci\u00eancias Universidade do Porto  4169-007 Porto Portugal"}]},{"given":"Fernanda","family":"Rodr\u00edguez\u2010Enr\u00edquez","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, CIMUS Universidad de Santiago de Compostela  15782 Santiago de Compostela Spain"}]},{"given":"Fernanda","family":"Borges","sequence":"additional","affiliation":[{"name":"CIQUP\/Departamento de Qu\u00edmica e Bioqu\u00edmica Faculdade de Ci\u00eancias Universidade do Porto  4169-007 Porto Portugal"}]},{"given":"Lourdes","family":"Santana","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica Facultad de Farmacia Universidad de Santiago de Compostela  15782 Santiago de Compostela Spain"}]},{"given":"Eugenio","family":"Uriarte","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica Facultad de Farmacia Universidad de Santiago de Compostela  15782 Santiago de Compostela Spain"}]},{"given":"Mart\u00edn","family":"Estrada","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica Consejo Superior de Investigaciones Cient\u00edficas (IQM-CSIC)  C\/Juan de la Cierva\u20053 28006 Madrid Spain"}]},{"given":"Mar\u00eda Isabel","family":"Rodr\u00edguez\u2010Franco","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica Consejo Superior de Investigaciones Cient\u00edficas (IQM-CSIC)  C\/Juan de la Cierva\u20053 28006 Madrid Spain"}]},{"given":"Reyes","family":"Laguna","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, CIMUS Universidad de Santiago de Compostela  15782 Santiago de Compostela Spain"}]},{"given":"Dolores","family":"Vi\u00f1a","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, CIMUS Universidad de Santiago de Compostela  15782 Santiago de Compostela Spain"}]}],"member":"311","published-online":{"date-parts":[[2015,10,23]]},"reference":[{"key":"e_1_2_6_1_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.publhealth.23.100901.140525"},{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-7091-0643-3_7"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1532-5415.2012.03956.x"},{"key":"e_1_2_6_4_1","first-page":"005593","volume":"1","author":"Birks J.","year":"2006","journal-title":"Cochrane Database Syst. 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