Activity of OZ78 analogues against Fasciola hepatica and Echinostoma caproni.
Activity of OZ78 analogues against Fasciola hepatica and Echinostoma caproni.
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DOI：
10.1016/j.actatropica.2011.02.003
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发表时间：
2011-04
期刊：
影响因子：
2.7
通讯作者：
Keiser, Jennifer
中科院分区：
文献类型：
--
作者：
Kirchhofer, Carla;Vargas, Mireille;Braissant, Olivier;Dong, Yuxiang;Wang, Xiaofang;Vennerstrom, Jonathan L.;Keiser, Jennifer
关键词：
三氯苯达唑耐药性在兽医学中的迅速传播是杀法西斯药物发现和开发的重要动机。本研究的目的是表征杀筋膜药物候选物OZ 78（一种1，2，4-三恶茂烷）的1，2，4，5-四恶烷（MT 04和MT 14）和1，2，4-三恶烷（ST 16和ST 28）类似物的杀筋膜特性。针对大鼠肝片形吸虫的幼年和成年以及小鼠山羊棘口吸虫，确定了剂量反应关系。比较了MT 04、MT 14、ST 16和ST 28与OZ 78对F. hepatica进行体外试验。用等温微量热法研究了OZ 78和MT 04处理后的吸虫的热流。最后，在用50 mg/kg MT 04处理大鼠后18、24和48 h，通过扫描电子显微镜（SEM）监测成虫吸虫的表面变化。给药50-100 mg/kg的合成过氧化物导致完全消除成人F。大鼠肝组织SEM照片显示在用MT 04处理后18小时已经出现脱落和起泡。MT 04（100 mg/kg）治愈了幼年F.而MT 14、ST 16和ST 28仅显示低至中度的蠕虫负荷减少。在300 mg/kg时，MT 14是唯一完全消除蠕虫. caproni感染的小鼠。MT 14对F.体外培养肝细胞。MT 04对F.肝在体外，这是证实了热流测量。总之，我们已经确定MT 04作为另一种具有抗F潜力的先导化合物。因此，需要进一步的临床前研究来确定MT 04是否可以被认为是药物开发候选物。
The rapid spread of triclabendazole resistance in veterinary medicine is an important motivation for fasciocidal drug discovery and development. The aim of this study was to characterize the fasciocidal properties of 1,2,4,5-tetraoxane (MT04 and MT14) and 1,2,4-trioxane (ST16 and ST28) analogues of the fasciocidal drug candidate OZ78, an 1,2,4-trioxolane. Dose response relationships were determined against juvenile and adult Fasciola hepatica in rats and Echinostoma caproni in mice. The temporal effects of MT04, MT14, ST16, and ST28 compared to OZ78 on the viability of F. hepatica were tested in vitro. The heat flow of OZ78 and MT04 treated flukes was studied with isothermal microcalorimetry. Finally, surface changes to adult flukes were monitored by scanning electron microscopy (SEM) 18, 24, and 48 h post-treatment of rats with 50 mg/kg MT04. Administration of 50-100 mg/kg of the synthetic peroxides resulted in complete elimination of adult F. hepatica from rats. SEM pictures revealed sloughing and blebbing already 18 h post-treatment with MT04. MT04 (100 mg/kg) cured infections with juvenile F. hepatica, whereas MT14, ST16, and ST28 showed only low to moderate worm burden reductions. At 300 mg/kg, MT14 was the only compound to completely eliminate worms from E. caproni infected mice. MT14 showed the highest activity against juvenile F. hepatica in vitro. MT04 was very active against adult F. hepatica in vitro, which was confirmed by heat flow measurements. In conclusion, we have identified MT04 as another lead compound with potential against F. hepatica, hence further preclinical studies are necessary to determine if MT04 can be considered a drug development candidate.
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