Antimalarial Activities of 6‑Iodouridine and Its Prodrugs and Potential for Combination Therapy

Resistance by <i>Plasmodium falciparum</i> to almost all clinically used antimalarial drugs requires the development of new classes of antimalarials. 6-Iodouridine (<b>15</b>), a novel and potent inhibitor of orotidine 5′-monophosphate decarboxylase (ODCase), exhibited efficacy in a mouse model infected by <i>P. chabaudi chabaudi</i>. Compound <b>15</b> exhibited promising antimalarial activity against <i>P. falciparum</i>, including drug-resistant isolates, and no rapid drug-resistant populations of the parasite were observed when challenged with <b>15</b>. Uridine provided options to overcome any toxicity in the host but still suppressing the parasite load when treated with <b>15</b>. In drug combination studies, compound <b>15</b> showed good efficacy in vivo with artemisinin and azithromycin. The propionyl ester of <b>15</b> exhibited superior antimalarial efficacy. Antimalarial activities of <b>15</b> and its prodrugs and potential for combination therapy are discussed in the context of novel strategies