Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.
J Antimicrob Chemother. 2012 Aug;67(8):1979-86. doi: 10.1093/jac/dks141. Epub 2012 May 2.
Compounds characterized by a peroxidic skeleton are an interesting starting point for antischistosomal drug discovery. Previously a series of 3-alkoxy-1,2-dioxolanes, which are chemically stable cyclic peroxides, demonstrated significant in vitro activity against Plasmodium falciparum. We aimed to evaluate the potential of these compounds against Schistosoma mansoni and elucidate the roles of iron and peroxidic groups in activity.
Drugs were tested against juvenile and adult stages of S. mansoni in vitro and in vivo. Selected structures were assessed in vitro against schistosomes in the presence of additional iron sources. In addition, drugs were tested in vitro and in vivo against Echinostoma caproni, a non-blood-feeding intestinal fluke. Finally, the activity of non-peroxidic analogues was evaluated.
Three dioxolanes displayed IC₅₀s ≤ 20.1 μM against adult schistosomes and values as low as 4.2 μM against newly transformed schistosomula. Nonetheless, only moderate, non-significant worm burden reductions were observed after treatment of mice harbouring adult infections. Drugs lacked activity against juvenile schistosomes in vivo. Two selected dioxolanes showed in vitro activity against E. caproni down to concentrations of 5 mg/L, but none of the compounds revealed in vivo activity. All tested non-peroxidic analogues lacked activity in vitro against both parasites.
Selected dioxolanes presented interesting in vitro activity, but low in vivo activities have to be overcome to identify a lead candidate. Although the inactivity of non-peroxidic analogues underlines the necessity of a peroxide functional group, incubation of adult schistosomes with additional iron sources did not alter activity, supporting an iron-independent mode of activation.
具有过氧骨架的化合物是抗血吸虫药物发现的一个有趣起点。此前，一系列化学稳定的环状过氧化物 3-烷氧基-1,2-二恶烷对恶性疟原虫表现出显著的体外活性。我们旨在评估这些化合物对曼氏血吸虫的潜在作用，并阐明铁和过氧基团在活性中的作用。
在体外和体内评估药物对曼氏血吸虫的幼体和成虫阶段的作用。评估选定结构在存在其他铁源的情况下对血吸虫的体外活性。此外，还在体外和体内测试药物对非吸血肠道吸虫棘口科东毕吸虫的活性。最后，评估非过氧化物类似物的活性。
三种二恶烷对成年血吸虫的 IC₅₀值≤20.1 μM，对新转化的尾蚴的 IC₅₀值低至 4.2 μM。尽管如此，在治疗携带成年感染的小鼠后，仅观察到中度、非显著的蠕虫负担减少。药物在体内对幼体血吸虫无活性。两种选定的二恶烷对棘口科东毕吸虫的体外活性低至 5 mg/L，但没有一种化合物具有体内活性。所有测试的非过氧化物类似物在体外对两种寄生虫均无活性。
选定的二恶烷表现出有趣的体外活性，但必须克服低体内活性，以确定候选药物。尽管非过氧化物类似物的无活性突出了过氧功能基团的必要性，但用额外的铁源孵育成虫并没有改变其活性，支持一种铁独立的激活模式。
