Jiao Yaqing, Preston Sarah, Song Hongjian, Jabbar Abdul, Liu Yuxiu, Baell Jonathan, Hofmann Andreas, Hutchinson Dana, Wang Tao, Koehler Anson V, Fisher Gillian M, Andrews Katherine T, Laleu Benoît, Palmer Michael J, Burrows Jeremy N, Wells Timothy N C, Wang Qingmin, Gasser Robin B
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.
Faculty of Science and Technology, Federation University, Ballarat, VIC, 3350, Australia.
Parasit Vectors. 2017 May 31;10(1):272. doi: 10.1186/s13071-017-2191-8.
In this study, we tested five series of pyrazole-5-carboxamide compounds (n = 55) for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm), one of the most pathogenic parasites of ruminants.
In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility and development of H. contortus.
Amongst the 55 compounds, we identified two compounds (designated a-15 and a-17) that reproducibly inhibit xL3 motility as well as L4 motility and development, with IC values ranging between ~3.4 and 55.6 μM. We studied the effect of these two 'hit' compounds on mitochondrial function by measuring oxygen consumption. This assessment showed that xL3s exposed to each of these compounds consumed significantly less oxygen and had less mitochondrial activity than untreated xL3s, which was consistent with specific inhibition of complex I of the respiratory electron transport chain in arthropods.
The present findings provide a sound basis for future work, aimed at identifying the targets of compounds a-15 and a-17 and establishing the modes of action of these chemicals in H. contortus.
在本研究中，我们测试了五组吡唑 - 5 - 甲酰胺化合物（n = 55）对捻转血矛线虫（捻转胃虫）寄生阶段的活性，捻转血矛线虫是反刍动物最具致病性的寄生虫之一。
在优化的全生物体筛选试验中，使用脱鞘第三期（xL3）和第四期（L4）幼虫，我们测量了捻转血矛线虫幼虫运动和发育的抑制情况。
在这55种化合物中，我们鉴定出两种化合物（命名为a - 15和a - 17），它们可重复性地抑制xL3运动以及L4运动和发育，IC值在约3.4至55.6 μM之间。我们通过测量氧气消耗来研究这两种“命中”化合物对线粒体功能的影响。该评估表明，与未处理的xL3相比，暴露于每种化合物的xL3消耗的氧气显著减少，线粒体活性也较低，这与节肢动物呼吸电子传递链复合体I的特异性抑制一致。
本研究结果为未来的工作提供了坚实的基础，旨在确定化合物a - 15和a - 17的靶点，并确定这些化学物质在捻转血矛线虫中的作用模式。
