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首页> 美国卫生研究院文献>International Journal for Parasitology: Drugs and Drug Resistance >Arylpyrrole and fipronil analogues that inhibit the motility and/or development of Haemonchus contortus in vitro
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Arylpyrrole and fipronil analogues that inhibit the motility and/or development of Haemonchus contortus in vitro

机译：芳吡咯和氟虫腈类似物在体外可抑制扭扭线虫的运动和/或发育

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Due to widespread drug resistance in parasitic nematodes, there is a need to develop new anthelmintics. Given the cost and time involved in developing a new drug, the repurposing of known chemicals can be a promising, alternative approach. In this context, we tested a library (n = 600) of natural product-inspired pesticide analogues against exsheathed third stage-larvae (xL3s) of Haemonchus contortus (barber's pole worm) using a whole-organism, phenotypic screening technique that measures the inhibition of motility and development in treated larvae. In the primary screen, we identified 32 active analogues derived from chemical scaffolds of arylpyrrole or fipronil. The seven most promising compounds, selected based on their anthelmintic activity and/or limited cytotoxicity, are arylpyrroles that reduced the motility of fourth-stage larvae (L4s) with significant potency (IC50 values ranged from 0.04 ± 0.01 μM to 4.25 ± 0.82 μM, and selectivity indices ranged from 10.6 to 412.5). Since the parent structures of the active compounds are uncouplers of oxidative phosphorylation, we tested the effect of selected analogues on oxygen consumption in xL3s using the Seahorse XF24 flux analyser. Larvae treated with the test compounds showed a significant increase in oxygen consumption compared with the untreated control, demonstrating their uncoupling activity. Overall, the results of the present study have identified natural product-derived molecules that are worth considering for chemical optimisation as anthelmintic drug leads.
机译：由于寄生线虫中广泛的耐药性，因此需要开发新的驱虫药。考虑到开发新药的成本和时间，重新利用已知化学物质可能是一种有前途的替代方法。在这种情况下，我们使用可检测抑制作用的全生物表型筛选技术，对自然产物启发的农药类似物库（n = 600）进行了测试，以对抗弯曲的Haemonchus contortus（理发杆虫）的第三阶段幼虫（xL3s）。幼虫的活力和发育在初步筛选中，我们鉴定了32种衍生自芳基吡咯或氟虫腈的化学支架的活性类似物。根据其驱虫活性和/或有限的细胞毒性选择的七种最有前途的化合物是芳基吡咯，可降低第四阶段幼虫（L4s）的活力，并具有显着的效力（IC50值范围从0.04±0.01μM到4.25±0.82 M，选择性指数介于10.6至412.5之间。由于活性化合物的母体结构是氧化磷酸化的解偶联剂，因此我们使用Seahorse XF24通量分析仪测试了所选类似物对xL3中耗氧量的影响。与未处理的对照相比，用受试化合物处理的幼虫显示出耗氧量的显着增加，证明了它们的解偶联活性。总的来说，本研究的结果确定了天然产物衍生的分子，作为驱虫药线索，值得进行化学优化。

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