Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus.
Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus.
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DOI：
10.1186/s13071-017-2191-8
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发表时间：
2017-05-31
影响因子：
3.2
通讯作者：
Gasser RB
中科院分区：
文献类型：
--
作者：
Jiao Y;Preston S;Song H;Jabbar A;Liu Y;Baell J;Hofmann A;Hutchinson D;Wang T;Koehler AV;Fisher GM;Andrews KT;Laleu B;Palmer MJ;Burrows JN;Wells TNC;Wang Q;Gasser RB
在这项研究中，我们测试了五个系列的吡唑-5-甲酰胺类化合物(n = 55)对反刍动物最具致病性的寄生虫之一--缠绕线虫(Haemonchus Torortus)寄生阶段的活性。在一种优化的全生物筛选试验中，使用外鞘第三期(XL3)和第四期(L4)幼虫，测定了对螺旋藻幼虫活动和发育的抑制。在55个化合物中，我们鉴定了两个化合物(命名为a-15和a-17)，它们可以重复地抑制XL3运动以及L4运动和发育，IC50值在~3.4到55.6gμM之间。我们通过测量耗氧量来研究这两个化合物对线粒体功能的影响。这项评估表明，与未处理的xL3s相比，暴露在这些化合物中的xL3s消耗的氧气和线粒体活性显著减少，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。本研究结果为今后的工作提供了良好的基础，旨在确定化合物a-15和a-17的目标，并确定这些化学物质在螺旋藻中的作用模式。本文的在线版本(doi：10.1186/s13071-017-2191-8)包含补充材料，授权用户可以使用。
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 IC50 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. The online version of this article (doi:10.1186/s13071-017-2191-8) contains supplementary material, which is available to authorized users.