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Since its aetiology is diverse, recent research on anti-AD drugs has been focused on multi-target compounds. In this work, seven novel hybrids (RIV\u2013BIM) conjugating the active moiety of the drug rivastigmine (RIV) with 2 isomeric hydroxyphenylbenzimidazole (BIM) units were developed and studied. While RIV assures the inhibition of cholinesterases, BIM provides further appropriate properties, such as inhibition of amyloid \u03b2-peptide (A\u03b2) aggregation, antioxidation and metal chelation. The evaluated biological properties of these hybrids included antioxidant activity; inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and A\u03b242 aggregation; as well as promotion of cell viability and neuroprotection. All the compounds are better inhibitors of AChE than rivastigmine (IC50 = 32.1 \u00b5M), but compounds of series 5 are better inhibitors of BChE (IC50 = 0.9\u22121.7 \u00b5M) than those of series 4. Series 5 also showed good capacity to inhibit self- (42.1\u221258.7%) and Cu(II)-induced (40.3\u221260.8%) A\u03b2 aggregation and also to narrow (22.4\u221242.6%) amyloid fibrils, the relevant compounds being 5b and 5d. Some of these compounds can also prevent the toxicity induced in SH-SY5Y cells by A\u03b242 and oxidative stress. Therefore, RIV\u2013BIM hybrids seem to be potential drug candidates for AD with multi-target abilities.<\/jats:p>","DOI":"10.3390\/biomedicines10071510","type":"journal-article","created":{"date-parts":[[2022,6,26]],"date-time":"2022-06-26T09:00:13Z","timestamp":1656234013000},"page":"1510","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Novel Rivastigmine Derivatives as Promising Multi-Target Compounds for Potential Treatment of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8946-2858","authenticated-orcid":false,"given":"David","family":"Vicente-Zurdo","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"},{"name":"Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, Avenida Complutense s\/n, 28040 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7984-8340","authenticated-orcid":false,"given":"Noelia","family":"Rosales-Conrado","sequence":"additional","affiliation":[{"name":"Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, Avenida Complutense s\/n, 28040 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2498-0085","authenticated-orcid":false,"given":"M. Eugenia","family":"Le\u00f3n-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, Avenida Complutense s\/n, 28040 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7787-6639","authenticated-orcid":false,"given":"Leonardo","family":"Brunetti","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"},{"name":"Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7980-5818","authenticated-orcid":false,"given":"Luca","family":"Piemontese","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1595-3360","authenticated-orcid":false,"given":"A. Raquel","family":"Pereira-Santos","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3000-370 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2199-0555","authenticated-orcid":false,"given":"Sandra M.","family":"Cardoso","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3000-370 Coimbra, Portugal"},{"name":"FMUC-Faculty of Medicine, University of Coimbra, 3000-370 Coimbra, Portugal"}]},{"given":"Yolanda","family":"Madrid","sequence":"additional","affiliation":[{"name":"Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, Avenida Complutense s\/n, 28040 Madrid, Spain"}]},{"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":[[2022,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.4103\/1673-5374.303007","article-title":"Regulation of neuronal bioenergetics as a therapeutic strategy in neurodegenerative diseases","volume":"16","author":"Onyango","year":"2021","journal-title":"Neural Regen. Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2021). 2021 Alzheimer\u2019s disease facts and figures. 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