3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential

摘要: A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening a commercially available SoftFocus kinase library. The compounds were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) NF54 (chloroquine-susceptible as well cytotoxicity. Synthesis structure–activity studies number promising with selective activity. One these frontrunner compounds, 15, was equipotent across the two strains (K1 = 25.0 nM, 28.0 nM) superior to chloroquine strain IC50 194.0 nM). Compound 15 completely cured Plasmodium berghei-infected mice single oral dose 30 mg/kg. Dose–response generated ED50 ED90 values 0.83 1.74 mg/kg standard four-dose Peters test. Pharmacokinetic rat indicated that this compound good bioavailab...