Journal
ACS INFECTIOUS DISEASES
Volume 3, Issue 10, Pages 728-735Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.7b00062
Keywords
malaria; cytochrome bc1; Plasmodium falciparum; prodrug
Categories
Funding
- United States National Institutes of Health [AI100569, AI028398]
- Veterans Affairs Merit Review Program [i01 BX003312]
- US Department of Defense Peer Reviewed Medical Research Program [PR130649, W81XWH-14-1-0447]
- Military Infectious Disease Research Program
- CDMRP [PR130649, 672537] Funding Source: Federal RePORTER
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ELQ-300 is a preclinical antimalarial drug candidate that is active against liver, blood, and transmission stages of Plasmodium falciparum. While ELQ-300 is highly effective when administered in a low multidose regimen, poor aqueous solubility and high crystallinity have hindered its clinical development. To overcome its challenging physiochemical properties, a number of bioreversible alkoxycarbonate ester prodrugs of ELQ-300 were synthesized. These bioreversible prodrugs are converted to ELQ-300 by host and parasite esterase action in the liver and bloodstream of the host. One such alkoxycarbonate prodrug, ELQ-331, is curative against Plasmodium yoelii with a single low dose of 3 mg/kg in a murine model of patent malaria infection. ELQ-331 is at least as fully protective as ELQ-300 in a murine malaria prophylaxis model when delivered 24 h before sporozoite inoculation at an oral dose of 1 mg/kg. Here, we show that ELQ-331 is a promising prodrug of ELQ-300 with improved physiochemical and metabolic properties and excellent potential for clinical formulation.
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