Institut für Pharmazie and Lebensmittelchemie, Universität Wuerzburg, Am Hubland, 97074 Würzburg, Germany.
J Med Chem. 2012 Mar 22;55(6):2538-48. doi: 10.1021/jm101439s. Epub 2012 Mar 12.
Human African trypanosomiasis (HAT) or sleeping sickness is caused by two subspecies of Trypanosoma brucei , Trypanosoma brucei gambiense , and Trypanosoma brucei rhodesiense and is one of Africa's old plagues. It causes a huge number of infections and cases of death per year because, apart from limited access to health services, only inefficient chemotherapy is available. Since it was reported that quinolones such as ciprofloxacin show antitrypanosomal activity, a novel quinolone-type library was synthesized and tested. The biological evaluation illustrated that 4-quinolones with a benzylamide function in position 3 and cyclic or acyclic amines in position 7 exhibit high antitrypanosomal activity. Structure-activity relationships (SAR) are established to identify essential structural elements. This analysis led to lead structure 29, which exhibits promising in vitro activity against T. b. brucei (IC(50) = 47 nM) and T. b. rhodesiense (IC(50) = 9 nM) combined with low cytotoxicity against macrophages J774.1. Screening for morphological changes of trypanosomes treated with compounds 19 and 29 suggested differences in the morphology of mitochondria of treated cells compared to those of untreated cells. Segregation of the kinetoplast is hampered in trypanosomes treated with these compounds; however, topoisomerase II is probably not the main drug target.
人类非洲锥虫病（HAT）或昏睡病是由两种布氏锥虫亚种引起的，即布氏锥虫冈比亚亚种和布氏锥虫罗得西亚亚种，是非洲的古老瘟疫之一。它每年导致大量的感染和死亡病例，因为除了有限的获得医疗服务的机会外，仅有的治疗方法是低效的化疗。由于报道称喹诺酮类药物如环丙沙星具有抗锥虫活性，因此合成并测试了一种新型的喹诺酮类化合物库。生物评估表明，在 3 位具有苄酰胺功能和在 7 位具有环状或非环状胺的 4-喹诺酮具有很高的抗锥虫活性。建立了构效关系（SAR）来确定必需的结构要素。该分析导致了先导化合物 29 的出现，它对 T. b. brucei（IC（50）= 47 nM）和 T. b. rhodesiense（IC（50）= 9 nM）具有有前途的体外活性，同时对巨噬细胞 J774.1 的细胞毒性较低。用化合物 19 和 29 处理的锥虫的形态变化筛选表明，与未处理的细胞相比，处理过的细胞中线粒体的形态存在差异。用这些化合物处理的锥虫的动基体分离受到阻碍；然而，拓扑异构酶 II 可能不是主要的药物靶点。
