Faculty of Pharmaceutical Sciences, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Department of Biology, Animal Physiology and Neurobiology Section, KU Leuven, Naamsestraat 59, Box 2465, 3000 Leuven, Belgium.
Faculty of Pharmaceutical Sciences, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
Int J Parasitol. 2018 Sep;48(11):833-844. doi: 10.1016/j.ijpara.2017.11.009. Epub 2018 Jul 18.
Parasitic helminths continue to pose problems in human and veterinary medicine, as well as in agriculture. Resistance to current anthelmintics has prompted the search for new drugs. Anthelmintic metabolites from medicinal plants could be good anthelmintic drug candidates. However, the compounds active against nematodes have not been identified in most medicinal plants with anthelmintic activity. In this study, we aimed to identify the active compounds against helminths in Warburgia ugandensis Sprague subspecies ugandensis (Canellaceae) and study the underlying mechanism of action. A bioassay-guided isolation of anthelmintic compounds from the plant was performed using a Caenorhabditis elegans (C. elegans) test model with a WMicrotracker instrument to monitor motility. Three active compounds were purified and identified by nuclear magnetic resonance and high resolution MS: warburganal (IC: 28.2 ± 8.6 μM), polygodial (IC: 13.1 ± 5.3 μM) and alpha-linolenic acid (ALA, IC: 70.1 ± 17.5 μM). A checkerboard assay for warburganal and ALA as well as polygodial and ALA showed a fractional inhibitory concentration index of 0.41 and 0.37, respectively, suggesting that polygodial and ALA, as well as warburganal and ALA, have a synergistic effect against nematodes. A preliminary structure-activity relationship study for polygodial showed that the α,β-unsaturated 1,4-dialdehyde structural motif is essential for the potent activity. None of a panel of C. elegans mutant strains, resistant against major anthelmintic drug classes, showed significant resistance to polygodial, implying that polygodial may block C. elegans motility through a mechanism which differs from that of currently marketed drugs. Further measurements showed that polygodial inhibits mitochondrial ATP synthesis of C. elegans in a dose-dependent manner (IC: 1.8 ± 1.0 μM). Therefore, we believe that the underlying mechanism of action of polygodial is probably inhibition of mitochondrial ATP synthesis. In conclusion, polygodial could be a promising anthelmintic drug candidate worth considering for further development.
寄生虫蠕虫继续给人类医学、兽医医学和农业带来问题。对现有驱虫药物的耐药性促使人们寻找新的药物。药用植物的驱虫代谢物可能是很好的驱虫药物候选物。然而，在大多数具有驱虫活性的药用植物中，尚未发现对抗线虫有效的化合物。在这项研究中，我们旨在从 Warburgia ugandensis Sprague 亚种 ugandensis（樟科）中鉴定对抗蠕虫的活性化合物，并研究其潜在的作用机制。使用 Caenorhabditis elegans（秀丽隐杆线虫）测试模型和 WMicrotracker 仪器进行驱虫化合物的生物测定导向分离，以监测运动性。通过核磁共振和高分辨率 MS 纯化并鉴定了三种活性化合物：warburganal（IC：28.2±8.6μM）、聚甲酚（IC：13.1±5.3μM）和α-亚麻酸（ALA，IC：70.1±17.5μM）。Warburganal 和 ALA 以及聚甲酚和 ALA 的棋盘试验显示，部分抑制浓度指数分别为 0.41 和 0.37，表明聚甲酚和 ALA 以及 warburganal 和 ALA 对线虫具有协同作用。聚甲酚的初步构效关系研究表明，α,β-不饱和 1,4-二醛结构基序对于强效活性是必需的。对主要驱虫药物类别具有抗性的一组 C. elegans 突变株均未对聚甲酚表现出显著抗性，这表明聚甲酚可能通过与市售药物不同的机制阻止 C. elegans 的运动。进一步的测量表明，聚甲酚以剂量依赖的方式抑制 C. elegans 的线粒体 ATP 合成（IC：1.8±1.0μM）。因此，我们认为聚甲酚的作用机制可能是抑制线粒体 ATP 合成。总之，聚甲酚可能是一种很有前途的驱虫药物候选物，值得进一步开发。
