Novel Orally Active Antimalarial Thiazoles

作者：Diego González Cabrera, Frédèric Douelle, Tzu‐Shean Feng, Aloysius T. Nchinda, Yassir Younis, Karen L. White, Quoc K. Wu, Eileen Ryan, Jeremy N. Burrows, David Waterson, Michael J. Witty, Sergio Wittlin, Susan A. Charman, Kelly Chibale · 发表于：Journal of Medicinal Chemistry · 年份：2011 · DOI：10.1021/jm201108k · 被引用次数：81 · 研究领域：Quinazolinone synthesis and applications、Synthesis and biological activity、Cancer therapeutics and mechanisms

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).