{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T01:26:26Z","timestamp":1773451586278,"version":"3.50.1"},"reference-count":56,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,2,22]],"date-time":"2020-02-22T00:00:00Z","timestamp":1582329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine\/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer\u2019s disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and \u03b2\u2013amyloid (A\u03b2) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound 5, containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds 9 and 10 displayed the highest reduction of A\u03b2-induced cell toxicity. In silico calculations of some pharmacokinetic descriptors indicate that all the compounds but the nitro derivatives have good potential oral-bioavailability. Overall, it can be concluded that most of the studied DNP-BIM conjugates showed quite good anti-AD properties, therefore deserving to be considered in further studies with the aim of understanding and treating AD.<\/jats:p>","DOI":"10.3390\/molecules25040985","type":"journal-article","created":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T03:21:16Z","timestamp":1582773676000},"page":"985","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8554-4992","authenticated-orcid":false,"given":"S\u00edlvia","family":"Chaves","sequence":"first","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural and Departamento de Engenharia Qu\u00edmica, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}]},{"given":"Simonetta","family":"Resta","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural and Departamento de Engenharia Qu\u00edmica, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"},{"name":"Dipartimento di Farmacia\u2013Scienze del Farmaco, Universit\u00e0 degli Studi di Bari \u201cAldo Moro\u201d, Via E. Orabona 4, I-70125 Bari, Italy"}]},{"given":"Federica","family":"Rinaldo","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural and Departamento de Engenharia Qu\u00edmica, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"},{"name":"Dipartimento di Farmacia\u2013Scienze del Farmaco, Universit\u00e0 degli Studi di Bari \u201cAldo Moro\u201d, Via E. Orabona 4, I-70125 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8419-7709","authenticated-orcid":false,"given":"Marina","family":"Costa","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural and Departamento de Engenharia Qu\u00edmica, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}]},{"given":"Romane","family":"Josselin","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural and Departamento de Engenharia Qu\u00edmica, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}]},{"given":"Karolina","family":"Gwizdala","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural and Departamento de Engenharia Qu\u00edmica, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7980-5818","authenticated-orcid":false,"given":"Luca","family":"Piemontese","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia\u2013Scienze del Farmaco, Universit\u00e0 degli Studi di Bari \u201cAldo Moro\u201d, Via E. Orabona 4, I-70125 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4883-7128","authenticated-orcid":false,"given":"Vito","family":"Capriati","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia\u2013Scienze del Farmaco, Universit\u00e0 degli Studi di Bari \u201cAldo Moro\u201d, Via E. Orabona 4, I-70125 Bari, Italy"},{"name":"Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125 Bari, Italy"}]},{"given":"A. Raquel","family":"Pereira-Santos","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Institute of Molecular and Cell Biology, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"given":"Sandra M.","family":"Cardoso","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Institute of Molecular and Cell Biology, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, 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 and Departamento de Engenharia Qu\u00edmica, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. 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