具有新颖碳硫双手性鱼尼丁受体抑制剂作用的绿色生态杀虫剂的设计、合成及构效关系研究

Significant progress has been made in the development of green ecological insecticides targeting at the insect ryanodine receptor (RyR). Representative RyR-targeting insecticides like Flubendiamide and Chloranthraniliprole are commercially available on the world market. They exhibit highly potent activating effects on insect RyRs, cause uncontrolled release of calcium, and this will eveventually leads to muscle paralysis and fatality. Based on our previous study of chiral diamides with excellent bioactivities, new chemicals with dual chiral centers (carbon and sulfur) will be designed and synthesized by applying such approaches as computer simulation technology, bioisosterism and partition coefficient comparison etc. Their insecticidal activity will be evaluated against Lepidoptera, to establish the relationship between chiral structures and insecticidal ativity. It will be interesting to systemically investigate the chiral synergetic effect of carbon and sulfur impact on bioactivity, so that we could find potential novel chiral candidate insecticides with high activity, low toxicity and favorable safety profile. In addition, to study the insecticidal mechanism of new chiral compounds, electrophysiological techniques will be applied to investigate the influence on intracellular calcium ion concentration, as well as the cause of death at cellular and molecular level. This study will be helpful to the development of novel RyR regulators in future.

以鱼尼丁受体为靶标的绿色生态杀虫剂对环境生态十分安全，目前已取得突破性的进展。代表性商品有氟虫酰胺和氯虫酰胺，其新一代作用机制不是直接杀死害虫，而是作用于其体内鱼尼丁受体，激活钙离子通道致使Ca2+不断释放，导致昆虫运动肌肉抽搐麻痹不能取食而死亡。.基于我们前期手性双酰胺类杀虫剂的研究基础，本申请利用计算机模拟技术、生物电子等排、调整油水分配比等药物分子设计理念，合理设计含有碳硫双手性中心的新型鱼尼丁受体抑制剂，进行生物活性评价，系统研究碳硫手性因素对生物活性的影响，总结构效关系规律，以期发现高效、低毒、对环境生态友好、具有新颖作用机制的手性杀虫剂。此外利用电生理技术研究手性化合物的作用机制，通过测定昆虫细胞内Ca2+浓度的动力学变化，在细胞水平和分子水平上探索药物和昆虫细胞的相互作用原理以及昆虫死亡原因，将为创制具有我国自主知识产权的超高活性鱼尼丁受体抑制剂提供了一定的理论指导意义。

本项目开展基于已知的高活性的母体结构，运用计算机模拟技术、电子生物等排体等原理进行药物分子设计，并结合对此类化合物已建立设计合成经验以及生物活性的筛选结果，设计合成了9个系列239个双酰胺类化合物，并探索其生物活性的研究，总结构效关系规律，深入开展电生理研究工作等。结果表明个别化合物对东方粘虫和小菜蛾具有优异的杀虫活性，可作为先导结构进一步优化。同时，在农药分子的设计探索过程中，我们也发现了新的关于硫的方法学以及亚磺酰亚胺向Sulfinylimine的转化。开创新的方法学，拓展了亚磺酰亚胺的实用价值，为创制新型鱼尼丁受体杀虫剂提供更为有效的手段，也为农药创制提供了新的机遇。