Nucleoside analogues for the treatment of animal trypanosomiasis

Animal trypanosomiasis (AT) is a parasitic disease with high socio-economic impact. Given the limited therapeutic options and problems of toxicity and drug resistance, this study assessed redirecting our previously identified antitrypanosomal nucleosides for the treatment of AT. Promising hits were identified with excellent in vitro activity across all important animal trypanosome species. Compound 7, an inosine analogue, and our previously described lead compound, 3???-deoxytubercidin (8), showed broad spectrum anti-AT activity, metabolic stability in the target host species and absence of toxicity, but with variable efficacy ranging from limited activity to full cure in mouse models of Trypanosoma congolense and T. vivax infection. Several compounds show promise against T. evansi (surra) and T. equiperdum (dourine). Given the preferred target product profile for a broadspectrum compound against AT, this study emphasizes the need to include T. vivax in the screening cascade given its divergent susceptibility profile and provides a basis for lead optimization towards such broad spectrum anti-AT compound.

Automated summary

Animal trypanosomiasis is a parasitic disease with significant socio-economic impact. This study evaluated the potential use of antitrypanosomal nucleosides as a treatment for animal trypanosomiasis and identified promising compounds with excellent in vitro activity. Compound 7 and compound 8 exhibited broad spectrum anti-animal trypanosomiasis activity in mouse models, but with varying efficacy.