Novel Orally Active Antimalarial Thiazoles


An aminomethylthiazole pyrazole carboxamide lead with good in vitro antiplasmodial activity [IC<sub>50</sub>: 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. The compound 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<sub>1/2</sub> 3 h), and high volume of distribution with moderately high plasma and blood clearance after IV administration. With regard to toxicity profiling, the compound exhibited moderate potential to inhibit CYP1A2 (IC<sub>50</sub> = 1.5 µM) and 2D6 (IC<sub>50</sub> = 0.4 µM) as well as having a potential hERG liability (IC<sub>50</sub> = 3.7 µM).


González Cabrera, D.; Douelle, F.; Feng, T.S.; Nchinda, A.T.; Younis, Y.; White, K.L.; Wu, Q.; Ryan, E.; Burrows, J.N.; Waterson, D.; Witty, M.J.; Wittlin, S.; Charman, S.A.; Chibale, K. Novel Orally Active Antimalarial Thiazoles. Journal of Medicinal Chemistry (2011) 54 (21) 7713-7719. [DOI: 10.1021/jm201108k]

Novel Orally Active Antimalarial Thiazoles

Published 1 January 2011