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However, its anti\u2010inflammatory and antioxidant properties, combined with its ability to interfere with \u03b1\u2010synuclein aggregation, make it an attractive candidate for repositioning in Parkinson's disease. Nevertheless, the antibiotic activity of doxycycline restricts its potential use for long\u2010term treatment of Parkinsonian patients. In the search for non\u2010antibiotic tetracyclines that could operate against Parkinson's disease pathomechanisms, eighteen novel doxycycline derivatives were designed. Specifically, the dimethyl\u2010amino group at C<jats:sub>4<\/jats:sub> was reduced, resulting in limited antimicrobial activity, and several coupling reactions were performed at position C<jats:sub>9<\/jats:sub> of the aromatic D ring, this position being one of the most reactive for introducing substituents. Using the Thioflavin\u2010T assay, we found seven compounds were more effective than doxycycline in inhibiting \u03b1\u2010synuclein aggregation. 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Overall, through structure\u2010activity relationship studies, we identified two newly designed tetracyclines as promising drug candidates for Parkinson's disease treatment.<\/jats:p>","DOI":"10.1002\/cmdc.202300597","type":"journal-article","created":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T08:14:15Z","timestamp":1711354455000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["C9\u2010Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological \u03b1\u2010Synuclein Aggregation and Neuroinflammation in Parkinson's Disease Degeneration"],"prefix":"10.1002","volume":"19","author":[{"given":"Cl\u00e9mence","family":"Rose","sequence":"first","affiliation":[{"name":"BioCIS CNRS, Universit\u00e9 Paris-Saclay  91400 Orsay France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0177-6009","authenticated-orcid":false,"given":"Rodrigo 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