3,5-Diaryl-2-aminopyridines as a novel class of orally active antimalarials demonstrating single dose cure in mice and clinical candidate potential

  • J Med Chem. 2012 Apr 12;55(7):3479-87. doi: 10.1021/jm3001373.
Yassir Younis  1 ,  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 ,  Kelly Chibale
Affiliations
  • 1. Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
PMID: 22390538 DOI: 10.1021/jm3001373
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) ∼ 7-8 h).