C9-Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α-Synuclein Aggregation and Neuroinflammation in Parkinson's Disease Degeneration.

Autor: Rose C; BioCIS, CNRS, Université Paris-Saclay, 91400, Orsay, France., Tomas-Grau RH; IMMCA, CONICET-UNT-SIPROSA, Tucumán, 4000, Argentina., Zabala B; Paris Brain Institute-ICM, Inserm, Sorbonne Université, CNRS, Hôpital Pitié Salpêtrière, 75013, Paris, France., Michel PP; Paris Brain Institute-ICM, Inserm, Sorbonne Université, CNRS, Hôpital Pitié Salpêtrière, 75013, Paris, France., Brunel JM; UMR_MD1 Membranes et Cibles Thérapeutiques, U1261 INSERM, Aix-Marseille Université, 13385, Marseille, France., Chehín R; IMMCA, CONICET-UNT-SIPROSA, Tucumán, 4000, Argentina., Raisman-Vozari R; Paris Brain Institute-ICM, Inserm, Sorbonne Université, CNRS, Hôpital Pitié Salpêtrière, 75013, Paris, France., Ferrié L; BioCIS, CNRS, Université Paris-Saclay, 91400, Orsay, France., Figadère B; BioCIS, CNRS, Université Paris-Saclay, 91400, Orsay, France.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2024 Jun 17; Vol. 19 (12), pp. e202300597. Date of Electronic Publication: 2024 Apr 22.
DOI: 10.1002/cmdc.202300597
Abstrakt: Doxycycline, a semi-synthetic tetracycline, is a widely used antibiotic for treating mild-to-moderate infections, including skin problems. However, its anti-inflammatory and antioxidant properties, combined with its ability to interfere with α-synuclein aggregation, make it an attractive candidate for repositioning in Parkinson's disease. Nevertheless, the antibiotic activity of doxycycline restricts its potential use for long-term treatment of Parkinsonian patients. In the search for non-antibiotic tetracyclines that could operate against Parkinson's disease pathomechanisms, eighteen novel doxycycline derivatives were designed. Specifically, the dimethyl-amino group at C 4 was reduced, resulting in limited antimicrobial activity, and several coupling reactions were performed at position C 9 of the aromatic D ring, this position being one of the most reactive for introducing substituents. Using the Thioflavin-T assay, we found seven compounds were more effective than doxycycline in inhibiting α-synuclein aggregation. Furthermore, two of these derivatives exhibited better anti-inflammatory effects than doxycycline in a culture system of microglial cells used to model Parkinson's disease neuroinflammatory processes. Overall, through structure-activity relationship studies, we identified two newly designed tetracyclines as promising drug candidates for Parkinson's disease treatment.
(© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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