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

FERRIÉ, LAURENT; FIGADÈRE, BRUNO; ROSE, CLÉMENCE; TOMAS-GRAU, RODRIGO HERNÁN; CHEHÍN, ROSANA; ZABALA, BRENDA; MICHEL, PATRICK PIERRE; RAISMAN-VOZARI, RITA; BRUNEL, JEAN-MICHEL

CHEMMEDCHEM

WILEY-V C H VERLAG GMBH

Año: 2024

1860-7179

Doxycycline, a semi-synthetic tetracycline, is a widely usedantibiotic for treating mild-to-moderate infections, including skinproblems. 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'sdisease. Nevertheless, the antibiotic activity of doxycycline restrictsits potential use for long-term treatment of Parkinsonian patients. Inthe search for non-antibiotic tetracyclines that could operate againstParkinson’s disease pathomechanisms, eighteen novel doxycyclinederivatives were designed. Specifically, the dimethyl-amino group atC4 was reduced, resulting in limited antimicrobial activity, and severalcoupling reactions were performed at position C9 of the aromatic Dring, this position being one of the most reactive for introducingsubstituents. Using the Thioflavin-T assay, we found sevencompounds were more effective than doxycycline in inhibiting α-synuclein aggregation. Furthermore, two of these derivativesexhibited better anti-inflammatory effects than doxycycline in a culturesystem of microglial cells used to model Parkinson’s diseaseneuroinflammatory processes. Overall, through structure-activityrelationship studies, we identified two newly designed tetracyclines aspromising drug candidates for Parkinson’s disease treatment.