Synthesis and Evaluation of the First Generation of Glycosylated Nucleoside Analogues as Potential Inhibitors of the Base J Metabolism in Kinetoplastid Parasites

Leishmaniasis and trypanosomiasis are severe parasitic infections with significant impacts on veterinary and public health, particularly affecting the poorest populations. The therapeutic arsenal against these neglected tropical diseases is limited, and the emergence of resistance to available medicines complicates treatment. These kinetoplastid parasites share a unique DNA modification, that is β-d-glucosyl-5-hydroxymethyluracil (base J), which appears to play an essential role in parasite development and survival through an original epigenetic mechanism, allowing adaptation to environmental changes. To date, the regulatory pathway of this unique nucleobase has not been explored as a potential therapeutic target. In this work, we report the synthesis of several families of base J analogues and assess their potential against different kinetoplastid species. Some compounds have shown antiparasitic activity and no toxicity toward human primary fibroblasts, revealing promising new strategies for antiparasitic therapy.