Novel Orally Active Antimalarial Thiazoles

03 Oct 2011

Diego González Cabrera, Frederic Douelle, Tzu-Shean Feng, Aloysius T. Nchinda, Yassir Younis, Karen L. White, Quoc Wu, Eileen Ryan, Jeremy N. Burrows, David Waterson, Michael J. Witty, Sergio Wittlin, Susan A. Charman, and Kelly Chibale

Journal of Medicinal Chemistry
DOI: 10.1021/jm201108k

Photo: Pichit/


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 (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=1.5μM) 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.