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

05 Mar 2012

Yassir Younis, Frederic Douelle, Tzu-Shean Feng, Diego González Cabrera, Claire Le Manach, Aloysius T. Nchinda, Sandra Duffy, Karen L. White, David M. Shackleford, Julia Morizzi, Janne Mannila, Kasiram Katneni, Ravi Bhamidipati, K. Mohammed Zabiulla, Jayan T. Joseph, Sridevi Bashyam, David Waterson, Michael J. Witty, David Hardick, Sergio Wittlin, Vicky Avery, Susan A. Charman, and Kelly Chibale

Journal of Medicinal Chemistry
DOI: 10.1021/jm3001373


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 IC50 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 ED50 and ED90 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 (t1/2~7–8 h).

The full article can be viewed on the ACS Publications website.