Abstract

An aminomethylthiazole pyrazole carboxamide lead 3 with good in vitro antiplasmodial activity [IC₅₀: 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 mousemodel 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 exhibitedmoderate potential to inhibitCYP1A2 (IC₅₀=1.5μM) and 2D6 (IC₅₀=0.4 μM) as well as having a potential hERG liability (IC₅₀ = 3.7 μM).

Read the full article on the ACS Publications website [2].