Norcantharidin analogues with nematocidal activity in Haemonchus contortus
Norcantharidin analogues with nematocidal activity in Haemonchus contortus
复制标题
DOI：
10.1016/j.bmcl.2011.04.031
复制
发表时间：
2011-06-01
影响因子：
2.7
通讯作者：
Gasser, Robin B.
中科院分区：
文献类型：
--
作者：
Campbell, Bronwyn E.;Tarleton, Mark;Gasser, Robin B.
由于家畜寄生线虫对驱虫药物的抗药性问题突出，迫切需要开发新型杀线虫剂。在本研究中，我们采用有针对性的方法设计了一系列去甲斑蝥素类似物（n = 54），用于在幼虫发育试验（LDA）中针对小反刍动物的捻转血矛线虫（Haemonchus contortus）进行活性测试，并对九种不同的人类细胞系进行毒性测试。尽管合成的 54 种类似物中没有一种对这些细胞系有毒，但其中三种（N-辛基-7-氧杂双环（2.2.1）庚烷-2,3-二甲酰亚胺（B2）、N-癸基-7-氧杂双环（2.2.1）庚烷-2,3-二甲酰亚胺（B3）和4-[(4-甲基)-3-乙基-2-甲基-5-苯基呋喃-10-oxa-4-氮杂三环[5.2.1]癸烷-3,5-二酮 (B21) 在 LDA 中可重复地显示出对 H. contortus 的 99-100% 致死率，LD(50) 为 25-40 mu M。高“命中率”(5.6%) 表明所采取的方法与传统的药物筛选方法相比，去甲斑蝥素类似物的一个主要优点是，它们可以通过一到两个步骤以低成本和高纯度进行大量生产，并且不需要任何额外的步骤来分离活性异构体，这使其非常适合商业开发。 (C) 2011 Elsevier Ltd. 保留所有权利。
With the major problems with resistance in parasitic nematodes of livestock to anthelmintic drugs, there is an urgent need to develop new nematocides. In the present study, we employed a targeted approach for the design of a series of norcantharidin analogues (n = 54) for activity testing against the barber's pole worm (Haemonchus contortus) of small ruminants in a larval development assay (LDA) and also for toxicity testing on nine distinct human cell lines. Although none of the 54 analogues synthesized were toxic to any of these cell lines, three of them (N-octyl-7-oxabicyclo(2.2.1)heptane-2,3-dicarboximide (B2), N-decyl-7-oxabicyclo(2.2.1)heptane-2,3-dicarboximide (B3) and 4-[(4-methyl)-3-ethyl-2-methyl-5-phenylfuran-10-oxa-4-azatricyclo[5.2.1]decane-3,5-dione (B21) reproducibly displayed 99-100% lethality to H. contortus in LDA, with LD(50)s of 25-40 mu M. The high 'hit rate' (5.6%) indicates that the approach taken here has advantages over conventional drug screening methods. A major advantage of norcantharidin analogues over some other currently available anthelmintics is that they can be produced in one to two steps in large amounts at low cost and high purity, and do not require any additional steps for the isolation of the active isomer. This positions them well for commercial development. (C) 2011 Elsevier Ltd. All rights reserved.