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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
3,5-diaryl-2-aminopyridines as a novel class of orally active antimalarials demonstrating single dose cure in mice and clinical candidate potential
Journal of Medicinal Chemistry, Volume 55, No. 7, Year 2012
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Description
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). © 2012 American Chemical Society.
Authors & Co-Authors
Younis, Yassir
South Africa, Cape Town
University of Cape Town
Douelle, Frederic
South Africa, Cape Town
University of Cape Town
Feng, Tzu Shean
South Africa, Cape Town
University of Cape Town
Cabrera, Diego González
South Africa, Cape Town
University of Cape Town
Manach, Claire Le
South Africa, Cape Town
University of Cape Town
Nchinda, Aloysius T.
South Africa, Cape Town
University of Cape Town
Duffy, S.
Australia, Brisbane
Griffith University
White, Karen L.
Australia, Melbourne
Monash University, Centre for Drug Candidate Optimisation
Shackleford, David M.
Australia, Melbourne
Monash University, Centre for Drug Candidate Optimisation
Morizzi, Julia
Australia, Melbourne
Monash University, Centre for Drug Candidate Optimisation
Mannila, Janne
Australia, Melbourne
Monash University, Centre for Drug Candidate Optimisation
Katneni, Kasiram
Australia, Melbourne
Monash University, Centre for Drug Candidate Optimisation
Bhamidipati, Ravi
Australia, Melbourne
Monash University, Centre for Drug Candidate Optimisation
Zabiulla, K. Mohammed
India, Bengaluru
Syngene International Ltd
Joseph, Jayan T.
India, Bengaluru
Syngene International Ltd
Bashyam, Sridevi
India, Bengaluru
Syngene International Ltd
Waterson, David
Switzerland, Geneve
Icc
Witty, Michael J.
Switzerland, Geneve
Icc
Hardick, David
United Kingdom, Saffron Walden
Biofocus Dpi Ltd
Wittlin, Sergio
Switzerland, Allschwil
Swiss Tropical and Public Health Institute Swiss Tph
Switzerland, Basel
Universitat Basel
AVERY, Vicky M.
Australia, Brisbane
Griffith University
Charman, Susan A.
Australia, Melbourne
Monash University, Centre for Drug Candidate Optimisation
Chibale, Kelly
South Africa, Cape Town
University of Cape Town
Statistics
Citations: 124
Authors: 23
Affiliations: 8
Identifiers
Doi:
10.1021/jm3001373
ISSN:
00222623
e-ISSN:
15204804
Research Areas
Health System And Policy