Novel orally active antimalarial thiazoles

An aminomethylthiazole pyrazole carboxamide lead 3 with good in vitro antiplasmodial activity [IC50: 0.08 I?M (K1, chloroquine and multidrug resistant strain) and 0.07 I?M (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 mousemodel 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 (t1/2 3 h), and high volume of distribution with moderately high plasma and blood clearance after IV administration. Toward toxicity profiling, 3 exhibitedmoderate potential to inhibitCYP1A2 (IC50=1.5I?M) and 2D6 (IC50=0.4 I?M) as well as having a potential hERG liability (IC50 = 3.7 I?M).