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

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 alpha-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 C4 was reduced, resulting in limited antimicrobial activity, and several coupling reactions were performed at position C9 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 alpha-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. Modified doxycycline derivatives were synthesized to treat Parkinson's disease. Improvement was reached with some C9-substitution and removal of dimethyl amino-group, leading to improved inhibition of alpha-synuclein aggregation and anti-inflammatory effect and reduced antibiotic activity. These findings pave the way to promising in-vivo studies.+ image