Novel orally active antimalarial thiazoles

González Cabrera D., and Douelle, F. and Feng, T. S. and Nchinda, A. T. and Younis, Y. and White, K. L. and Wu, Q. and Ryan, E. and Burrows, J. N. and Waterson, D. and Witty, M. J. and Wittlin, S. and Charman, S. A. and Chibale, K.. (2011) Novel orally active antimalarial thiazoles. Journal of medicinal chemistry, 54 (21). pp. 7713-7719.

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Official URL: http://edoc.unibas.ch/dok/A6002288

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An aminomethylthiazole pyrazole carboxamide lead 3 with good in vitro antiplasmodial activity [IC(50): 0.08 muM (K1, chloroquine and multidrug resistant strain) and 0.07 muM (NF54, chloroquine sensitive strain)] and microsomal metabolic stability was identified from whole cell screening of a SoftFocus kinase library. Compound 3 also exhibited in vivo activity in the P. berghei mouse model at 4 x 50 mg/kg administration via the oral route, showing 99.5% activity and 9 days survival and showed low in vitro cytotoxicity. Pharmacokinetic studies in rats revealed good oral bioavailability (51% at 22 mg/kg) with a moderate rate of absorption, reasonable half-life (t(1/2) 3 h), and high volume of distribution with moderately high plasma and blood clearance after IV administration. Toward toxicity profiling, 3 exhibited moderate potential to inhibit CYP1A2 (IC(50) = 1.5 muM) and 2D6 (IC(50) = 0.4 muM) as well as having a potential hERG liability (IC(50) = 3.7 muM)
Faculties and Departments: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
Publisher:American Chemical Society
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:20 Oct 2017 06:43
Deposited On:08 Nov 2012 16:21

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