title: 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.
authors: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, M5S 3M2, Canada.
authors: Ian E
authors: IE
authors: Crandall
authors: Ewa
authors: E
authors: Wasilewski
authors: Angelica M
authors: AM
authors: Bello
authors: Asif
authors: A
authors: Mohmmed
authors: Pawan
authors: P
authors: Malhotra
authors: Emil F
authors: EF
authors: Pai
authors: Kevin C
authors: KC
authors: Kain
authors: Lakshmi P
authors: LP
authors: Kotra
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004347:Drug Interactions; D004351:Drug Resistance / Q000187:drug effects; D005260:Female; D051379:Mice; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000037:antagonists & inhibitors; D010962:Plasmodium berghei / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D011355:Prodrugs / Q000378:metabolism*; D014529:Uridine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C581210:6-iodouridine; D000962:Antimalarials; D011355:Prodrugs; D009964:Orotidine-5'-Phosphate Decarboxylase; D014529:Uridine