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J Med Chem. 2011 Nov 10;54(21):7713-9. doi: 10.1021/jm201108k. Epub 2011 Oct 11.

Novel orally active antimalarial thiazoles.

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  • 1Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.


An aminomethylthiazole pyrazole carboxamide lead 3 with good in vitro antiplasmodial activity [IC(50): 0.08 μM (K1, chloroquine and multidrug resistant strain) and 0.07 μM (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 × 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 μM) and 2D6 (IC(50) = 0.4 μM) as well as having a potential hERG liability (IC(50) = 3.7 μM).

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