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Structure-activity-relationship studies around the 2-amino group and pyridine core of antimalarial 3,5-diarylaminopyridines lead to a novel series of pyrazine analogues with oral in vivo activity

Younis, Yassir and Douelle, Frederic and González Cabrera, Diego and Le Manach, Claire and Nchinda, Aloysius T. and Paquet, Tanya and Street, Leslie J. and White, Karen L. and Zabiulla, K. Mohammed and Joseph, Jayan T. and Bashyam, Sridevi and Waterson, David and Witty, Michael J. and Wittlin, Sergio and Charman, Susan A. and Chibale, Kelly. (2013) Structure-activity-relationship studies around the 2-amino group and pyridine core of antimalarial 3,5-diarylaminopyridines lead to a novel series of pyrazine analogues with oral in vivo activity. Journal of medicinal chemistry, 56 (21). pp. 8860-8871.

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Official URL: http://edoc.unibas.ch/dok/A6212241

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Abstract

Replacement of the pyridine core of antimalarial 3,5-diaryl-2-aminopyridines led to the identification of a novel series of pyrazine analogues with potent oral antimalarial activity. However, other changes to the pyridine core and replacement or substitution of the 2-amino group led to loss of antimalarial activity. The 3,5-diaryl-2-aminopyrazine series showed impressive in vitro antiplasmodial activity against the K1 (multidrug resistant) and NF54 (sensitive) strains of Plasmodium falciparum in the nanomolar IC50 range of 6-94 nM while also demonstrating good in vitro metabolic stability in human liver microsomes. In the Plasmodium berghei mouse model, this series generally exhibited good efficacy at low oral doses. One of the frontrunner compounds, 4, displayed potent in vitro antiplasmodial activity with IC50 values of 8.4 and 10 nM against the K1 and NF54 strains, respectively. When evaluated in P. berghei -infected mice, compound 4 was completely curative at an oral dose of 4 × 10 mg/kg.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Chemical Society
ISSN:0022-2623
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:20 Oct 2017 06:37
Deposited On:25 Apr 2014 08:00

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