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

Abstract

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

NMR-based conformational analysis of 2′,6-disubstituted uridines and antiviral evaluation of new phosphoramidate prodrugs

“…[8][9][10] A well-known concept in the development of new biologically active nucleoside derivatives is the importance of their conformational preference in view of their possible interaction with target enzymes. The introduction of a substituent at the 6-position of a pyrimidine base is described in the literature as giving rise to syn-conformationally constrained ribonucleosides, some of which have shown interesting anti-plasmodial [11][12][13] and anti-cancer 14 activities. Their scope as antivirals has largely remained uninvestigated and it is deemed important to provide information on the tolerability of the syn-type conformation of a pyrimidine base at the level of viral kinases and polymerases.…”