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In vitro bioactivity assays indicated that some compounds have very good antioxidant (radical-scavenging) activity. The compounds also displayed good inhibitory activity against cholinesterases, though the bigger-sized hybrids showed higher inhibitory ability for butyrylcholinesterase (BChE) than for acetylcholinesterase (AChE), due to the larger active site cavity of BChE. All the hybrids exhibited an inhibition capacity for self-induced amyloid-\u03b2 (A\u03b21\u201342) aggregation. Furthermore, cell assays demonstrated that some compounds showed capacity for rescuing neuroblastoma cells from toxicity induced by reactive oxygen species (ROS). Among these RIV hybrids, the best in vitro multifunctional capacity was found for the caffeic acid derivatives enclosing catechol moieties (4AY5, 4AY6), though the Trolox derivatives (4AY2, 4BY2) presented the best cell neuroprotective activity against oxidative damage. Molecular-docking studies provided structural insights into the binding modes of RIV-based hybrids to the cholinesterases, revealing key interaction patterns despite some lack of correlation with inhibitory potency. Overall, the balanced multifunctional profiles of these hybrids render them potentially promising candidates for treating AD, thus deserving further investigation.<\/jats:p>","DOI":"10.3390\/antiox14080921","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T14:50:03Z","timestamp":1753714203000},"page":"921","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Rivastigmine Templates with Antioxidant Motifs\u2014A Medicinal Chemist\u2019s Toolbox Towards New Multipotent AD Drugs"],"prefix":"10.3390","volume":"14","author":[{"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"}]},{"given":"Marl\u00e8ne","family":"Emmanuel","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"}]},{"given":"Paul","family":"Vogt","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"}]},{"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, Universidade de Coimbra, 3004-504 Coimbra, Portugal"}]},{"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, Universidade de Coimbra, 3004-504 Coimbra, Portugal"}]},{"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, Universidade de Coimbra, 3004-504 Coimbra, Portugal"},{"name":"FMUC, Faculdade de Medicina, Universidade de Coimbra, 3004-504 Coimbra, Portugal"}]},{"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, 1649-003 Lisboa, Portugal"}]},{"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"}]},{"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"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e12465","DOI":"10.1002\/trc2.12465","article-title":"Alzheimer\u2019s disease drug development pipeline: 2024","volume":"10","author":"Cummings","year":"2024","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_2","unstructured":"Bhatt, J., Commas-Herrera, A., D\u2019Amico, F., Farina, N., Wong, J., Orange, J., Gaber, S., Knapp, M., Salcher-Konrad, M., and Stevens, M. (2019). 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