{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T22:44:19Z","timestamp":1761864259643,"version":"build-2065373602"},"reference-count":41,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T00:00:00Z","timestamp":1615852800000},"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>Alzheimer\u2019s disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-\u03b2 (A\u03b2) aggregation. Some of these hybrids also prevented A\u03b2-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC50 1.6 \u03bcM); A\u03b2 aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides.<\/jats:p>","DOI":"10.3390\/molecules26061658","type":"journal-article","created":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T21:42:41Z","timestamp":1615930961000},"page":"1658","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Novel Donepezil\u2013Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"26","author":[{"given":"Fausto","family":"Queda","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":"Sonia","family":"Cal\u00f2","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":"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\/0000-0003-4890-4167","authenticated-orcid":false,"given":"Jo\u00e3o D.","family":"Magalh\u00e3es","sequence":"additional","affiliation":[{"name":"CNC\u2013Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Sandra M.","family":"Cardoso","sequence":"additional","affiliation":[{"name":"CNC\u2013Center 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\/0000-0002-8554-4992","authenticated-orcid":false,"given":"S\u00edlvia","family":"Chaves","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"},{"name":"National Research Council (CNR)\u2013ISPA, via Amendola 122\/O, 70126 Bari, Italy"}]},{"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. Rovisco Pais, 1049-001 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.trci.2019.05.008","article-title":"Alzheimer\u2019s disease drug development pipeline","volume":"5","author":"Cummings","year":"2019","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_2","first-page":"759","article-title":"Outcomes of Alzheimer\u2019s disease therapy with acetylcholinesterase inhibitors and memantine","volume":"13","author":"Zemek","year":"2014","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"615","DOI":"10.3233\/JAD-132690","article-title":"Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer\u2019s disease: A systematic review and meta-analysis","volume":"41","author":"Tan","year":"2014","journal-title":"J. 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