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