Novel orally active antimalarial thiazoles

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). © 2011 American Chemical Society.