Targeting kinetoplastid parasites with ProTide prodrugs: a proof‐of‐concept study

Neglected tropical diseases (NTDs) remain a major global health challenge, particularly in low- and middle-income countries. Kinetoplastid parasites causing Chagas disease, leishmaniasis, and African trypanosomiasis rely on host purine salvage pathways, making nucleoside analogues attractive therapeutic candidates. However, their clinical utility is limited by poor cellular uptake and rapid metabolism. Herein, we report the application of the ProTide prodrug technology, a clinically validated approach that enhances the intracellular delivery of nucleoside monophosphates for the treatment of kinetoplastids infections. As a proof of concept, a focused library of zidovudine (AZT) and cordycepin ProTide prodrugs was designed, synthesized, and evaluated for antiparasitic activity against T. b. rhodesiense, T. cruzi, and L. donovani, as well as for cytotoxicity in L6 rat myoblasts. Out of these, compound 16 exhibited substantial serum stability and potent activity (IC50 = 5 nM; selectivity index, SI = 2,560) against T. b. rhodesiense with robust activity also observed against T. cruzi and L. donovani. These findings establish the ProTide prodrug technology as a promising strategy for optimizing nucleoside analogues against kinetoplastid parasites and provide a framework for the development of new therapeutics for NTDs.