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The multifactorial nature of these diseases has encouraged the development of new drugs such as multi-target-directed ligands (MTDLs). In this work, an anti-AD drug (rivastigmine, RIV) was fused and conjugated with a series of antioxidant scaffolds to obtain a small library of RIV\u2013antiox hybrids. In addition to inhibitory activity towards both cholinesterases, these hybrids exhibited radical scavenging activity, inhibition of A\u03b2 aggregation, and neuroprotection against cell death induced in AD models. The relevant anti-AD properties already found for these hybrids challenged us to also assess their capacity to modulate and interfere with ROS-associated harmful dysfunctions, namely in the dysregulation of biometal ions (Fe3+, Cu2+, and Zn2+) and upregulation of monoamine oxidases (MAOs). In particular, the capacity of the hybrids for metal chelation and inhibition of Cu-induced A\u03b2 aggregation and MAO isoforms was evaluated, as well as their neuroprotection capacity in cell models of PD. Overall, some of these RIV hybrids appear as lead compounds for the development of novel multifunctional agents against NDs.<\/jats:p>","DOI":"10.3390\/ijms27083637","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T08:24:23Z","timestamp":1776673463000},"page":"3637","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Emerging Roles of Rivastigmine Derivatives Bearing Antioxidant Motifs as Multi-Target Agents for the Management of Neurodegenerative Diseases"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6930-4175","authenticated-orcid":false,"given":"In\u00eas","family":"Dias","sequence":"first","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Departamento de Engenharia Qu\u00edmica, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9007-1280","authenticated-orcid":false,"given":"Catarina","family":"Guerreiro-Oliveira","sequence":"additional","affiliation":[{"name":"CNC-UC, Center for Neuroscience and Cell Biology, Universidade de Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Centre for Innovative Biomedicine and Biotechnology, University de Coimbra, 3004-504 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2128-296X","authenticated-orcid":false,"given":"In\u00eas","family":"Melo-Marques","sequence":"additional","affiliation":[{"name":"CNC-UC, Center for Neuroscience and Cell Biology, Universidade de Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Centre for Innovative Biomedicine and Biotechnology, University de Coimbra, 3004-504 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2199-0555","authenticated-orcid":false,"given":"Sandra M.","family":"Cardoso","sequence":"additional","affiliation":[{"name":"CNC-UC, Center for Neuroscience and Cell Biology, Universidade de Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Centre for Innovative Biomedicine and Biotechnology, University de Coimbra, 3004-504 Coimbra, Portugal"},{"name":"FMUC, Faculdade de Medicina, Universidade de Coimbra, 3004-504 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5790-9181","authenticated-orcid":false,"given":"Rita C.","family":"Guedes","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3718-3264","authenticated-orcid":false,"given":"Ismael","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4014-2109","authenticated-orcid":false,"given":"Teresa","family":"Rocha","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Biomedicine, Pharmacology and Therapeutics Unit, Faculty of Medicine, University of Porto, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7010-9808","authenticated-orcid":false,"given":"Daniel","family":"Chavarria","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Biomedicine, Pharmacology and Therapeutics Unit, Faculty of Medicine, University of Porto, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8554-4992","authenticated-orcid":false,"given":"S\u00edlvia","family":"Chaves","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Departamento de Engenharia Qu\u00edmica, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4069-9368","authenticated-orcid":false,"given":"M. Am\u00e9lia","family":"Santos","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Departamento de Engenharia Qu\u00edmica, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,19]]},"reference":[{"key":"ref_1","unstructured":"Alzheimer\u2019s Association Report (2025). 2025 Alzheimer\u2019s disease facts and figures. 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