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

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• 作者：Ian E. Crandall ; Ewa Wasilewski ; Angelica M. Bello ; Asif Mohmmed ; Pawan Malhotra ; Emil F. Pai ; Kevin C. Kain ; Lakshmi P. Kotra
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2348-2358
• 全文大小：502K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

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鈥?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.