Membrane-Permeable 5-Fluorodeoxyuridine Triphosphate Derivatives Inhibit the Proliferation of <i>Plasmodium falciparum</i>

Malaria tropica remains a major global health challenge, raising the need for new therapeutic strategies against <i>Plasmodium falciparum</i>. While nucleoside analogues are effective against viruses and cancer, their use against <i>P. falciparum</i> is limited by the lack of nucleoside kinases in this species. To overcome this, we generated and tested cell-permeable derivatives of 5-fluorodeoxyuridine triphosphate (cpFdUTP) for antiparasitic activity in infected human red blood cells. cpFdUTP rapidly and potently inhibited the proliferation of <i>P. falciparum</i>, arresting development at the trophozoite-to-schizont transition by stalling DNA replication, as observed in a <i>P. falciparum</i> nuclear cycle sensor line. Although cpFdUTP also impaired the growth of human cells, supplementation with thymidine or cell-permeable deoxythymidine triphosphate (cpdTTP) selectively rescued human cells while maintaining parasite inhibition. This identifies a potential therapeutic window for cpFdUTP in combination with thymidine, outlining a novel approach for malaria treatment.