{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T08:30:32Z","timestamp":1786696232460,"version":"build-2736575974"},"reference-count":43,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009888","name":"Tuscany Region","doi-asserted-by":"publisher","award":["DEM-AGING"],"award-info":[{"award-number":["DEM-AGING"]}],"id":[{"id":"10.13039\/501100009888","id-type":"DOI","asserted-by":"publisher"}]},{"award":["DEM-AGING"],"award-info":[{"award-number":["DEM-AGING"]}],"id":[{"id":"https:\/\/ror.org\/02r6c6d62","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Tuscany Health Ecosystem (THE)\u2014Spoke n. 02 \u201cPreventive and Predictive Medicine\u201d","award":["PNRR ECS00000017 CUP I53C22000780001"],"award-info":[{"award-number":["PNRR ECS00000017 CUP I53C22000780001"]}]},{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","award":["67562227"],"award-info":[{"award-number":["67562227"]}],"id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a multifactorial neurodegenerative disorder involving metabolic impairment, neuroinflammation, synaptic failure, and comorbidities. Hence, therapeutic development for AD is rapidly shifting from a single-target approach, centred on amyloid-beta (A\u03b2) reduction, to multi-target strategies. In this study, we investigated the neuroprotective profile of two acetanilide derivatives, SG-22 and SG-23, originated from the halogen-free thyronamine-like lead compound SG-2. Their efficacy was evaluated through an integrated approach combining in vitro cellular models, in vivo phenotypic screening in a Caenorhabditis elegans AD model, and comprehensive ADME-Tox profiling. In U87MG cells, both SG-22 and SG-23 effectively prevented A\u03b225\u201335-induced cytotoxicity and restored autophagy-related gene expression, including LC3, SIRT1, and SIRT6, while reducing mTOR and SIRT5 levels. Furthermore, all compounds exhibited anti-inflammatory effects in activated HMC3 microglial cells, reducing IL-6 and increasing IL-10 levels, with evidence suggesting partial involvement of TAAR1 signalling. ADME-Tox analyses revealed improved safety and metabolic profiles for the tested compounds, particularly SG-22, which showed reduced hERG liability and enhanced cytochrome P450 stability. However, in vivo studies demonstrated that only SG-2 and SG-23 improved motility and fitness in the C. elegans AD model, consistent with their ability to activate autophagy, whereas SG-22 was ineffective due to limited organismal uptake. Ultimately, the monoacetylated analogue SG-23 emerges as a promising candidate, balancing neuroprotective efficacy and drug-like properties, and supporting thyronamine-like analogues as multi-target agents for AD.<\/jats:p>","DOI":"10.3390\/molecules31162833","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T08:08:29Z","timestamp":1786694909000},"page":"2833","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Insights into the Pleiotropic Neuroprotective Action of Synthetic Halogen Free Thyronamine-like Analogues"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3608-2031","authenticated-orcid":false,"given":"Massimiliano","family":"Runfola","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2664-6091","authenticated-orcid":false,"given":"Beatrice","family":"Polini","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, Molecular Pathology and Critical Care, University of Pisa, Via Savi 10, 56100 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Mazzierli","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, Molecular Pathology and Critical Care, University of Pisa, Via Savi 10, 56100 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2728-0987","authenticated-orcid":false,"given":"Lorenzo","family":"Raffellini","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2161-6717","authenticated-orcid":false,"given":"Fabio","family":"Di Ricco","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Italo","family":"Cirone","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1592-7522","authenticated-orcid":false,"given":"Simona","family":"Sagona","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2543-1643","authenticated-orcid":false,"given":"Sheraz","family":"Gul","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0090-7070","authenticated-orcid":false,"given":"Marco","family":"Lessi","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Industrial Chemistry, University of Pisa, Via Giuseppe Moruzzi 13, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela Rosa","family":"Cuzzola","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Industrial Chemistry, University of Pisa, Via Giuseppe Moruzzi 13, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5408-9416","authenticated-orcid":false,"given":"Rosarita","family":"D\u2019Orsi","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Industrial Chemistry, University of Pisa, Via Giuseppe Moruzzi 13, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4939-7008","authenticated-orcid":false,"given":"Fabio","family":"Bellina","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Industrial Chemistry, University of Pisa, Via Giuseppe Moruzzi 13, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clementina","family":"Manera","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"},{"name":"Center for Instrument Sharing, University of Pisa (CISUP), Lungarno Pacinotti 43, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6703-5820","authenticated-orcid":false,"given":"Grazia","family":"Chiellini","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, Molecular Pathology and Critical Care, University of Pisa, Via Savi 10, 56100 Pisa, Italy"},{"name":"Center for Instrument Sharing, University of Pisa (CISUP), Lungarno Pacinotti 43, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0146-6358","authenticated-orcid":false,"given":"Simona","family":"Rapposelli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"},{"name":"Center for Instrument Sharing, University of Pisa (CISUP), Lungarno Pacinotti 43, 56126 Pisa, 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