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Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria
- Source :
- ACS Infectious Diseases. 3:728-735
- Publication Year :
- 2017
- Publisher :
- American Chemical Society (ACS), 2017.
-
Abstract
- 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 multi-dose 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 hours 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.
- Subjects :
- 0301 basic medicine
Plasmodium falciparum
030106 microbiology
Quinolones
Biology
Pharmacology
Article
Antimalarials
Electron Transport Complex III
Mice
03 medical and health sciences
chemistry.chemical_compound
parasitic diseases
medicine
Animals
Prodrugs
Molecular Structure
Drug candidate
Prodrug
medicine.disease
biology.organism_classification
ELQ-300
Malaria
Mitochondria
Regimen
030104 developmental biology
Infectious Diseases
chemistry
Murine malaria
Plasmodium yoelii
Subjects
Details
- ISSN :
- 23738227
- Volume :
- 3
- Database :
- OpenAIRE
- Journal :
- ACS Infectious Diseases
- Accession number :
- edsair.doi.dedup.....249b65dc64b941bff90c86f25bc6788b
- Full Text :
- https://doi.org/10.1021/acsinfecdis.7b00062