Design and Synthesis of New Non-Antibiotic Doxycyclin Derivatives Against alpha-Synuclein Aggregation with Anti-Inflammatory Properties

Doxycycline is a tetracycline commonly used for its antibiotic properties and capacity to treat acne- and rosacea-like skin lesions. It has also recently demonstrated interesting effects against Parkinson's disease pathomechanisms. Notably, doxycycline was reported to limit amyloid-type aggregation of α-synuclein and curtail neurodegeneration-related inflammatory processes. However, the potential therapeutic interest of doxycycline is limited due to its antibiotic activity. The design of novel doxycycline derivatives was undertaken to generate non-antimicrobial doxycycline derivatives with still neuroprotective properties. Specifically, the dimethyl-amino at C4 group was reduced to significantly diminish the antibiotic activity, and several coupling reactions were performed at position C9 of the D ring. Among 18 novel tetracyclines, seven derivatives with reduced antibiotic activity were more efficient than their parent compound in reducing α-synuclein aggregation. Among those, two derivatives exerted better anti-inflammatory effects than doxycycline, at concentrations that are not cytotoxic. Thus, compounds 1 and 6 seem to have a better neuroprotective potential than doxycycline, making them excellent candidates for further pre-clinical investigations.