{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T12:36:39Z","timestamp":1770726999384,"version":"3.49.0"},"reference-count":63,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T00:00:00Z","timestamp":1614038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Foundation for Science and Technology (FCT) and FEDER\/COMPETE","award":["UIDB\/00081\/2020, PTDC\/MED-QUI\/29164\/2017, POCI-01-0145-FEDER-29164, PTDC\/BIA-MOL\/28607\/2017, POCI-01-0145-FEDER-028607"],"award-info":[{"award-number":["UIDB\/00081\/2020, PTDC\/MED-QUI\/29164\/2017, POCI-01-0145-FEDER-29164, PTDC\/BIA-MOL\/28607\/2017, POCI-01-0145-FEDER-028607"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Neurotransmitter depletion and mitochondrial dysfunction are among the multiple pathological events that lead to neurodegeneration. Following our previous studies related with the development of multitarget mitochondriotropic antioxidants, this study aims to evaluate whether the \u03c0-system extension on the chemical scaffolds of AntiOXCIN2 and AntiOXCIN3 affects their bioactivity and safety profiles. After the synthesis of four triphenylphosphonium (TPP+) conjugates (compounds 2\u20135), we evaluated their antioxidant properties and their effect on neurotransmitter-metabolizing enzymes. All compounds were potent equine butyrylcholinesterase (eqBChE) and moderate electric eel acetylcholinesterase (eeAChE) inhibitors, with catechols 4 and 5 presenting lower IC50 values than AntiOXCIN2 and AntiOXCIN3, respectively. However, differences in the inhibition potency and selectivity of compounds 2\u20135 towards non-human and human cholinesterases (ChEs) were observed. Co-crystallization studies with compounds 2\u20135 in complex with human ChEs (hChEs) showed that these compounds exhibit different binging modes to hAChE and hBChE. Unlike AntiOXCINs, compounds 2\u20135 displayed moderate human monoamine oxidase (hMAO) inhibitory activity. Moreover, compounds 4 and 5 presented higher ORAC-FL indexes and lower oxidation potential values than the corresponding AntiOXCINs. Catechols 4 and 5 exhibited broader safety windows in differentiated neuroblastoma cells than benzodioxole derivatives 2 and 3. Compound 4 is highlighted as a safe mitochondria-targeted antioxidant with dual ChE\/MAO inhibitory activity. Overall, this work is a contribution for the development of dual therapeutic agents addressing both mitochondrial oxidative stress and neurotransmitter depletion.<\/jats:p>","DOI":"10.3390\/antiox10020329","type":"journal-article","created":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T12:40:16Z","timestamp":1614084016000},"page":"329","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7010-9808","authenticated-orcid":false,"given":"Daniel","family":"Chavarria","sequence":"first","affiliation":[{"name":"CIQUP\/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7461-7028","authenticated-orcid":false,"given":"Ophelie","family":"Da Silva","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Toxicologie et Risques Chimiques, Institut de Recherche Biom\u00e9dicale des Arm\u00e9es, 91223 Br\u00e9tigny-sur-Orge, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9645-8152","authenticated-orcid":false,"given":"Sofia","family":"Benfeito","sequence":"additional","affiliation":[{"name":"CIQUP\/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1317-665X","authenticated-orcid":false,"given":"Sandra","family":"Barreiro","sequence":"additional","affiliation":[{"name":"UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8981-231X","authenticated-orcid":false,"given":"Jorge","family":"Garrido","sequence":"additional","affiliation":[{"name":"CIQUP\/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal"},{"name":"CIQUP\/Department of Chemical Engineering, School of Engineering (ISEP), Polytechnic of Porto, 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9410-6874","authenticated-orcid":false,"given":"Fernando","family":"Cagide","sequence":"additional","affiliation":[{"name":"CIQUP\/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal"}]},{"given":"Pedro","family":"Soares","sequence":"additional","affiliation":[{"name":"CIQUP\/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1382-5119","authenticated-orcid":false,"given":"Fernando","family":"Remi\u00e3o","sequence":"additional","affiliation":[{"name":"UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9219-1032","authenticated-orcid":false,"given":"Xavier","family":"Brazzolotto","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Toxicologie et Risques Chimiques, Institut de Recherche Biom\u00e9dicale des Arm\u00e9es, 91223 Br\u00e9tigny-sur-Orge, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0293-2429","authenticated-orcid":false,"given":"Florian","family":"Nachon","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Toxicologie et Risques Chimiques, Institut de Recherche Biom\u00e9dicale des Arm\u00e9es, 91223 Br\u00e9tigny-sur-Orge, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5201-9948","authenticated-orcid":false,"given":"Paulo J.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech, Biocant Park, 3060-197 Cantanhede, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7625-0618","authenticated-orcid":false,"given":"Jos\u00e9","family":"Dias","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Toxicologie et Risques Chimiques, Institut de Recherche Biom\u00e9dicale des Arm\u00e9es, 91223 Br\u00e9tigny-sur-Orge, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1050-2402","authenticated-orcid":false,"given":"Fernanda","family":"Borges","sequence":"additional","affiliation":[{"name":"CIQUP\/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fnins.2016.00375","article-title":"Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration","volume":"10","author":"Ramsay","year":"2016","journal-title":"Front. 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