School of Chemical Engineering, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
Shandong University-Helmholtz Institute of Biotechnology, School of Life Science, Shandong University, Jinan, P. R. China.
Sci Rep. 2019 Feb 14;9(1):2010. doi: 10.1038/s41598-019-38561-3.
Parasite death via ion channel activations is the hallmark of anthelmintic and antiparasitic drugs. Glutamate gated chloride channel (GluCl) is a prominent targets for drug selection and design in parasitology. We report several iodine-fluorine based lead activators of GluCl by computational studies and structure-activity relationship analysis. 5-Fluoro-4-iodo-1H-pyrrolo [2, 3-b] pyridine and 5-iodoindole were bioactive hits that displayed in vitro anthelmintic and insecticidal activities against Bursaphelenchus xylophilus, Meloidogyne incognita, and Tenebrio molitor. Two important findings stood out: (i) 5F4IPP induced parasite death, and interacted proficiently with Gln amino acid of pentameric GluCl in docking analysis, and (ii) 5-iodoindole appeared to act by forming giant vacuoles in nematodes, which led to a form of non-apoptotic death known as methuosis. The study suggests halogenated-indoles and 1H-pyrrolo [2, 3-b] pyridine derivatives be regarded potential biocides for plant-parasitic nematodes and insects, and warrants further research on the mode of actions, and field investigations.
寄生虫通过离子通道激活而死亡是驱虫药和抗寄生虫药物的主要特征。谷氨酸门控氯离子通道（GluCl）是寄生虫学中药物选择和设计的重要靶点。我们通过计算研究和构效关系分析，报告了几种基于碘-氟的 GluCl 先导激活剂。5-氟-4-碘-1H-吡咯并[2,3-b]吡啶和 5-碘吲哚是具有生物活性的化合物，它们对松材线虫、南方根结线虫和黄粉虫表现出体外驱虫和杀虫活性。有两个重要发现：（i）5F4IPP 诱导寄生虫死亡，并在对接分析中与五聚体 GluCl 的 Gln 氨基酸有效地相互作用；（ii）5-碘吲哚似乎通过在线虫中形成巨大空泡而起作用，导致一种非凋亡性死亡形式，称为 methuosis。该研究表明，卤代吲哚和 1H-吡咯并[2,3-b]吡啶衍生物可被视为植物寄生线虫和昆虫的潜在杀菌剂，有必要进一步研究其作用模式和田间调查。
