Dihydrobenz[e][1,4]oxazepin-2(3H)-ones, a new anthelmintic chemotype immobilising whipworm and reducing infectivity in vivo.
Dihydrobenz[e][1,4]oxazepin-2(3H)-ones, a new anthelmintic chemotype immobilising whipworm and reducing infectivity in vivo.
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DOI：
10.1371/journal.pntd.0005359
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发表时间：
2017-02
影响因子：
3.8
通讯作者：
Sattelle DB
中科院分区：
文献类型：
--
作者：
Partridge FA;Murphy EA;Willis NJ;Bataille CJ;Forman R;Heyer-Chauhan N;Marinič B;Sowood DJ;Wynne GM;Else KJ;Russell AJ;Sattelle DB
鞭虫是一种人类寄生鞭虫，感染全球约5亿人，损害感染者的身体发育和学习成绩。目前的药物治疗选择有限，而且缺乏对抗这种蠕虫的疗效，从而阻碍了根除计划。因此，开发新的治疗鞭毛虫病的方法非常重要。利用已建立的毛滴虫模型，我们筛选了480个新的类药物小分子文库，以寻找导致体外成虫瘫痪的化合物。我们鉴定了一类具有驱虫活性的二氢苯并[1，4]恶氮卓-2(~H)-酮类化合物。进一步筛选结构相关的化合物和重新合成最有效的分子导致了20个活性二氢苯并恶杂环酮类化合物的鉴定，这类分子以前没有涉及线虫控制。最活跃的固定化成虫的EC50值约为25-50μM，与现有的驱虫药左旋咪唑相当。这种化学类型的最好的化合物对小鼠肠道上皮细胞表现出低的细胞毒性，表现出对寄生虫的选择性。为一种被忽视的疾病开发一种新的口服药物治疗并通过大规模给药来部署它是具有挑战性的。有趣的是，二氢苯并恶氮卓酮OX02983降低了小鼠胚胎虫卵在小鼠体内建立感染的能力。这补充了二氢苯并恶氮酮作为口服驱虫剂的潜在开发，这支持了一种替代战略，即开发一种在环境中发挥作用的治疗药物，可能通过喷雾来中断寄生虫的生命周期。这些结果表明，二氢苯并恶氮酮类化合物是一类新的驱虫剂，对鞭毛虫的卵期和成虫期都有活性。它们展示了令人鼓舞的对寄生虫的选择性，重要的是显示了进一步优化的相当大的空间，以提高效力和药代动力学特性，目的是开发临床制剂。鞭虫是一种人类寄生性鞭虫，全球约有5亿人感染，对感染者的身体发育和教育表现有重大影响。目前的药物治疗选择有限，对这种蠕虫缺乏疗效。最重要的是，他们缺乏有效的方案来根除这种寄生虫。因此，开发新的治疗鞭毛虫病的方法非常重要。我们筛选了可以使一种近缘关系密切的小鼠寄生虫的成虫瘫痪的分子，并鉴定了一类化合物，即二氢苯并恶杂环酮类化合物，以前没有被认为是驱虫剂。重要的是，我们的化合物对寄生虫有活性，但对小鼠细胞只有低毒，显示出对寄生虫的选择性。二氢苯并恶杂环酮类化合物可作为治疗鞭毛虫病的潜在药物。由于通过大规模给药来开发和部署被忽视疾病的新药是具有挑战性的，我们还探索了这些化合物是否有可能通过作用于虫卵来中断鞭虫的生命周期。我们的二氢苯并恶氮酮化合物降低了毛滴虫卵在其小鼠宿主中建立感染的能力。这支持了一种环境喷雾战略，以控制旋毛虫在环境热点地区(如厕所)的虫卵。
Trichuris trichiura is a human parasitic whipworm infecting around 500 million people globally, damaging the physical growth and educational performance of those infected. Current drug treatment options are limited and lack efficacy against the worm, preventing an eradication programme. It is therefore important to develop new treatments for trichuriasis. Using Trichuris muris, an established model for T. trichiura, we screened a library of 480 novel drug-like small molecules for compounds causing paralysis of the ex vivo adult parasite. We identified a class of dihydrobenz[e][1,4]oxazepin-2(3H)-one compounds with anthelmintic activity against T. muris. Further screening of structurally related compounds and resynthesis of the most potent molecules led to the identification of 20 active dihydrobenzoxazepinones, a class of molecule not previously implicated in nematode control. The most active immobilise adult T. muris with EC50 values around 25–50μM, comparable to the existing anthelmintic levamisole. The best compounds from this chemotype show low cytotoxicity against murine gut epithelial cells, demonstrating selectivity for the parasite. Developing a novel oral pharmaceutical treatment for a neglected disease and deploying it via mass drug administration is challenging. Interestingly, the dihydrobenzoxazepinone OX02983 reduces the ability of embryonated T. muris eggs to establish infection in the mouse host in vivo. Complementing the potential development of dihydrobenzoxazepinones as an oral anthelmintic, this supports an alternative strategy of developing a therapeutic that acts in the environment, perhaps via a spray, to interrupt the parasite lifecycle. Together these results show that the dihydrobenzoxazepinones are a new class of anthelmintic, active against both egg and adult stages of Trichuris parasites. They demonstrate encouraging selectivity for the parasite, and importantly show considerable scope for further optimisation to improve potency and pharmacokinetic properties with the aim of developing a clinical agent. Trichuris trichiura is a human parasitic whipworm infecting around 500 million people globally and having major consequences on the physical growth and educational performance of those infected. Current drug treatment options are limited and lack efficacy against the worm. Critically, they lack the effectiveness that would allow for a practical program for eradication of this parasite. It is therefore important to develop new treatments for trichuriasis. We screened for molecules that could paralyse the adult of a closely related mouse parasite, and identified a class of compounds, the dihydrobenzoxazepinones, not previously implicated as anthelmintics. Importantly, our compounds are active against the parasite but show only low toxicity against mouse cells, demonstrating selectivity for the parasite. Dihydrobenzoxazepinones could be developed as potential pharmaceutical treatments for trichuriasis. Since developing and deploying new drugs for neglected diseases by mass administration is challenging, we also explored whether the compounds could potentially be used to interrupt the Trichuris lifecycle by acting on eggs. Our dihydrobenzoxazepinone compounds reduced the ability of T. muris eggs to establish infection in their mouse host. This supports an environmental spray strategy for the control of Trichuris targeting their eggs in environmental hotspots such as latrines.