Experimental Chemotherapy Laboratory, Mail Code RD-33, VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA.
Exp Parasitol. 2011 Feb;127(2):545-51. doi: 10.1016/j.exppara.2010.10.016. Epub 2010 Oct 30.
Our prior work on tricyclic acridones combined with a desire to minimize the tricyclic system led to an interest in antimalarial quinolones and a reexamination of endochin, an experimental antimalarial from the 1940's. In the present article, we show that endochin is unstable in the presence of murine, rat, and human microsomes which may explain its relatively poor antimalarial activity in mammalian systems. We also profile the structure-activity relationships of ≈ 30 endochin-like quinolone (ELQ) analogs and highlight features that are associated with enhanced metabolic stability, potent antiplasmodial activity against multidrug resistant strains of Plasmodium falciparum, and equal activity against an atovaquone-resistant clinical isolate. Our work also features an ELQ construct containing a polyethylene glycol carbonate pro-moiety that is highly efficacious by oral administration in a murine malaria model. These findings provide compelling evidence that development of ELQ therapeutics is feasible.
我们之前的三环吖啶酮研究工作以及将三环系统最小化的愿望促使我们对抗疟喹啉产生了兴趣，并重新研究了来自 20 世纪 40 年代的实验性抗疟药恩西宁。在本文中，我们表明恩西宁在鼠、大鼠和人微粒体存在下不稳定，这可能解释了它在哺乳动物系统中相对较差的抗疟活性。我们还对约 30 种恩西宁样喹啉（ELQ）类似物的结构-活性关系进行了分析，并强调了与增强代谢稳定性、对耐多药疟原虫株具有强大抗疟活性以及对阿托伐醌耐药的临床分离株具有同等活性相关的特征。我们的工作还包含一个含有聚乙二醇碳酸酯前药的 ELQ 构建体，该构建体在小鼠疟疾模型中通过口服给药具有很高的疗效。这些发现提供了令人信服的证据，表明 ELQ 治疗药物的开发是可行的。
