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首页> 外文期刊>Veterinary Parasitology >Screening of a drug repurposing library with a nematode motility assay identifies promising anthelmintic hits against Cooperia oncophora and other ruminant parasites
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Screening of a drug repurposing library with a nematode motility assay identifies promising anthelmintic hits against Cooperia oncophora and other ruminant parasites

机译：筛选用线虫动力测定的药物修复文库鉴定有前途的Anthelmintic命中对抗Coperia Oncophora和其他反刍动物寄生虫

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摘要

Parasitic nematodes continue to cause significant economic losses in livestock globally. Given the limited number of anthelmintic drugs on the market and the currently increasing drug resistance, there is an urgent need for novel anthelmintics. Most motility assays of anthelmintic activity for parasitic nematodes are laborious and low throughput, and therefore not suitable for screening large compound libraries. Cooperia oncophora accounts for a large proportion of reports on the drug-resistance development of parasites globally. Therefore, using a WMicroTracker instrument, we established a practical, automated and low-cost whole-organism motility assay against exsheathed L3 stages (xL3s) of the ruminant parasite Cooperia oncophora, and screened a repurposing library comprising 2745 molecules. Fourteen known anthelmintics contained in this library were picked up in this blind screen, as well as four novel hits: thonzonium bromide, NH125, physostigmine sulfate, and EVP4593. The four hits were also active against xL3s of Ostertagia ostertagi, Haemonchus contortus and Teladorsagia circumcincta using the same assay. Cytotoxicity testing showed that thonzonium bromide and NH125 (1-Benzyl-3-cetyl-2-methylimidazolium iodide) have significant cytotoxicity. EVP4593 (N(4)-(2-(4-phenoxyphenyl)ethyl)-4,6-quinazolinediamine) demonstrated a potent and broad anthelmintic activity, and a high selectivity index. Moreover, given its novel and unexplored chemical scaffold for anthelmintic activity, EVP4593 is an interesting anthelmintic hit for further optimization.
机译：寄生线虫继续在全球畜牧业中造成重大的经济损失。鉴于市场上有限数量的市场和目前增加的耐药性，迫切需要新颖的Anthelmintics。对于寄生线虫的大多数动力测定是寄生线虫的慢性活性，因此吞吐量低，因此不适合筛选大型复合文库。 Coperia Oncophora占全球寄生虫耐药性发育的大部分报告。因此，使用WMICROTRACKER仪器，我们建立了反对反刍动物寄生合作社onCophora的exSheached的L3阶段（XL3s）的实用，自动化和低成本的全生物动力测定，并筛选了包含2745分子的重新施加文库。在这种盲屏中拾取了本文库中包含的14名已知的，并且四种新的命中：溴化萘鎓，NH125，水溶硫酸钠和EVP4593。使用相同的测定，四次命中对Ostertagia Ostertagi，Haemonchus intertorus和Teladoragia circulcincta的XL3也是活跃的。细胞毒性测试显示溴化吡啶和NH125（1-苄基-3-十六烷基-2-甲基咪唑鎓碘化物）具有显着的细胞毒性。 EVP4593（N（4） - （2-（4-苯氧基苯基）乙基）-4,6-喹唑二胺）证明了有效且宽的植物活性，以及​​高选择性指数。此外，鉴于其用于弓形活动的新型和未开发的化学支架，EVP4593是进一步优化的有趣的触发性。

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