{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T05:36:39Z","timestamp":1777268199342,"version":"3.51.4"},"reference-count":54,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T00:00:00Z","timestamp":1661212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Bari Aldo Moro"},{"name":"Italian Ministry of University and Research (M.U.R.)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a complex multi-factorial neurodegenerative disorder for which only few drugs (including donepezil, DPZ) are available as symptomatic treatments; thus, researchers are focusing on the development of innovative multi-target directed ligands (MTDLs), which could also alter the course of the disease. Among other pathological factors, oxidative stress has emerged as an important factor in AD that could affect several pathways involved in the onset and progression of the pathology. Herein, we propose a new series of hybrid molecules obtained by linking a phenothiazine moiety, known for its antioxidant properties, with N-benzylpiperidine or N-benzylpiperazine fragments, mimicking the core substructure of DPZ. The investigation of the resulting hybrids showed, in addition to their antioxidant properties, their activity against some AD-related targets, such as the inhibition of cholinesterases (both AChE and BChE) and in vitro A\u03b21-40 aggregation, as well as the inhibition of the innovative target fatty acid amide hydrolase (FAAH). Furthermore, the drug-likeness properties of these compounds were assessed using cheminformatic tools. Compounds 11d and 12d showed the most interesting multi-target profiles, with all the assayed activities in the low micromolar range. In silico docking calculations supported the obtained results. Compound 13, on the other hand, while inactive in the DPPH assay, showed the best results in the in vitro antioxidant cell assays conducted on both HepG2 and SHSY-5Y cell lines. These results, paired with the low or absent cytotoxicity of these compounds at tested concentrations, allow us to aim our future research at the study of novel and effective drugs and pro-drugs with similar structural characteristics.<\/jats:p>","DOI":"10.3390\/antiox11091631","type":"journal-article","created":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T21:05:12Z","timestamp":1661288712000},"page":"1631","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Novel Phenothiazine\/Donepezil-like Hybrids Endowed with Antioxidant Activity for a Multi-Target Approach to the Therapy of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2248-9292","authenticated-orcid":false,"given":"Alessia","family":"Carocci","sequence":"first","affiliation":[{"name":"Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy"}]},{"given":"Alexia","family":"Barbarossa","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5229-988X","authenticated-orcid":false,"given":"Rosalba","family":"Leuci","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7725-6667","authenticated-orcid":false,"given":"Antonio","family":"Carrieri","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7787-6639","authenticated-orcid":false,"given":"Leonardo","family":"Brunetti","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6221-6155","authenticated-orcid":false,"given":"Antonio","family":"Laghezza","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8411-304X","authenticated-orcid":false,"given":"Marco","family":"Catto","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy"}]},{"given":"Francesco","family":"Limongelli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy"}]},{"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\/0000-0003-1358-7376","authenticated-orcid":false,"given":"Paolo","family":"Tortorella","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5016-5805","authenticated-orcid":false,"given":"Cosimo Damiano","family":"Altomare","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4069-9368","authenticated-orcid":false,"given":"Maria 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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3384-574X","authenticated-orcid":false,"given":"Fulvio","family":"Loiodice","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Pharmaceutical 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\u2014Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2606","DOI":"10.4103\/1673-5374.336138","article-title":"From cradle to grave: Neurogenesis, neuroregeneration and neurodegeneration in Alzheimer\u2019s and Parkinson\u2019s diseases","volume":"17","author":"Wakhloo","year":"2022","journal-title":"Neural Regen. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1203\/PDR.0b013e3181a9eafb","article-title":"Oxygen Toxicity and Reactive Oxygen Species: The Devil Is in the Details","volume":"66","author":"Auten","year":"2009","journal-title":"Pediatr. 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