In the present study, the anthelmintic activity of a human tyrosine kinase inhibitor, AG-1295, and 14 related tetrahydroquinoxaline analogues against Haemonchus contortus was explored. These compounds were screened against parasitic larvae - exsheathed third-stage (xL3) and fourth-stage (L4) - using a whole-organism screening assay. All compounds were shown to have inhibitory effects on larval motility, development and growth, and induced evisceration through the excretory pore in xL3s. The estimated IC50 values ranged from 3.5 to 52.0 μM for inhibition of larval motility or development. Cytotoxicity IC50 against human MCF10A cells was generally higher than 50 μM. Microscopic studies revealed that this eviscerated (Evi) phenotype occurs rapidly (<20 min) and relates to a protrusion of internal tissues and organs (evisceration) through the excretory pore in xL3s; severe pathological damage in L4s as well as a suppression of larval growth in both stages were also observed. Using a relatively low concentration (12.5 μM) of compound m10, it was established that the inhibitor has to be present for a relatively short time (between 30 h and 42 h) during in vitro development from xL3 to L4, to induce the Evi phenotype. Increasing external osmotic pressure prevented evisceration and moulting, and xL3s remained unaffected by the test compound. These results point to a mode of action involving a dysregulation of morphogenetic processes during a critical time-frame, in agreement with the expected behaviour of a tyrosine kinase inhibitor, and suggest potential for development of this compound class as nematocidal drugs.

中文翻译：

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在体外，四氢喹喔啉可在捻转血矛线虫中诱导致命的内脏表型。

在本研究中，探索了人类酪氨酸激酶抑制剂AG-1295和14种相关的四氢喹喔啉类似物对弯曲杆菌的驱虫活性。使用全生物筛选测定法筛选了这些化合物的寄生幼虫-出鞘的第三阶段（xL3）和第四阶段（L4）。所有化合物均显示出对幼虫运动，发育和生长具有抑制作用，并通过xL3s的排泄孔引起内脏清除。用于抑制幼虫运动或发育的估计IC50值范围为3.5至52.0μM。对人MCF10A细胞的细胞毒性IC50通常高于50μM。显微镜研究表明，这种内脏（Evi）表型快速发生（< 20分钟），并涉及内部组织和器官通过xL3s的排泄孔突出（内脏）；还观察到L4s中的严重病理损伤以及两个阶段中幼虫生长的抑制。使用相对较低浓度（12.5μM）的化合物m10，可以确定在从xL3到L4的体外发育过程中，抑制剂必须存在相对较短的时间（30 h至42 h之间），以诱导Evi表型。外部渗透压的增加阻止了内脏的脱落和蜕皮，并且xL3不受测试化合物的影响。这些结果表明了一种作用模式，该过程涉及关键时间段内形态发生过程的失调，与酪氨酸激酶抑制剂的预期行为相一致，