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3,5-Diaryl-2-aminopyridines as a novel class of orally active antimalarials demonstrating single dose cure in mice and clinical candidate potential
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
ID
1634653
Author(s)
Younis, Y.; Douelle, F.; Feng, T. S.; Cabrera, D. G.; Manach, C. L.; Nchinda, A. T.; Duffy, S.; White, K. L.; Shackleford, D. M.; Morizzi, J.; Mannila, J.; Katneni, K.; Bhamidipati, R.; Zabiulla, K. M.; Joseph, J. T.; Bashyam, S.; Waterson, D.; Witty, M. J.; Hardick, D.; Wittlin, S.; Avery, V.; Charman, S. A.; Chibale, K.
3,5-Diaryl-2-aminopyridines as a novel class of orally active antimalarials demonstrating single dose cure in mice and clinical candidate potential
Journal
Journal of medicinal chemistry
Volume
55
Number
7
Pages / Article-Number
3479-3487
Abstract
A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a commercially available SoftFocus kinase library. The compounds were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) and NF54 (chloroquine-susceptible strain) as well as for their cytotoxicity. Synthesis and structure-activity studies identified a number of promising compounds with selective antiplasmodial activity. One of these frontrunner compounds, 15, was equipotent across the two strains (K1 = 25.0 nM, NF54 = 28.0 nM) and superior to chloroquine in the K1 strain (chloroquine IC(50) K1 = 194.0 nM). Compound 15 completely cured Plasmodium berghei-infected mice with a single oral dose of 30 mg/kg. Dose-response studies generated ED(50) and ED(90) values of 0.83 and 1.74 mg/kg for 15 in the standard four-dose Peters test. Pharmacokinetic studies in the rat indicated that this compound has good oral bioavailability (51% at 20 mg/kg) and a reasonable half-life (t(1/2) approximately 7-8 h)
