Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 21, Pages 8860-8871Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm401278d
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Funding
- Medicines for Malaria Venture [MMV09/0002]
- South African Technology Innovation Agency (TIA)
- University of Cape Town
- South African Medical Research Council
- South African Research Chairs initiative of the Department of Science and Technology
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Replacement of the pyridine core of antimalarial 3,5-diaryl-2-aminopyridines led to the identification of a novel series of pyrazine analogues with potent oral antimalarial activity. However, other changes to the pyridine core and replacement or substitution of the 2-amino group led to loss of antimalarial activity. The 3,5-diaryl-2-arninopyrazine series showed impressive in vitro antiplasmodial activity against the K1 (multidrug resistant) and NF54 (sensitive) strains of Plasmodium falciparum in the nanomolar IC50 range of 6-94 nM while also demonstrating good in vitro metabolic stability in human liver microsomes. In the Plasmodium berghei mouse model, this series generally exhibited good efficacy at low oral doses. One of the frontrunner compounds, 4, displayed potent in vitro antiplasmodial activity with IC50 values of 8.4 and 10 nM against the K1 and NF54 strains, respectively. When evaluated in P. berghei-infected mice, compound 4 was completely curative at an oral dose of 4 x 10 mg/kg.
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