Synthesis and in Vitro and in Vivo Pharmacological Evaluation of New 4-Aminoquinoline-Based Compounds

作者：Matshawandile Tukulula, Mathew Njoroge, Efrem Abay, Grace Mugumbate, Lubbe Wiesner, Dale Taylor, Liezl Gibhard, Jennifer Norman, K.J Swart, Jiří Gut, Philip J. Rosenthal, Samuel Barteau, Judith Streckfuss, Jacques Kameni-Tcheudji, Kelly Chibale · 发表于：ACS Medicinal Chemistry Letters · 年份：2013 · DOI：10.1021/ml400311r · 被引用次数：21 · 研究领域：Malaria Research and Control、Computational Drug Discovery Methods、Cancer therapeutics and mechanisms

A new class of 4-aminoquinolines was synthesized and evaluated in vitro for antiplasmodial activity against both the chloroquine-sensitive (3D7) and -resistant (K1 and W2) strains. The most active compounds 3c-3e had acceptable cytotoxicity but showed strong inhibition toward a panel of cytochrome P450 enzymes in vitro. Pharmacokinetic studies on 3d and 3e in mice showed that they had moderate half-life (4-6 h) and low oral bioavailability. The front runner compound 3d exhibited moderate inhibition of the malaria parasite on P. berghei infected mice following oral administration (5 mg/kg), achieving reduction of parasitemia population by 47% on day 7.