基于吡啶盐(噻唑盐或咪唑盐)的两亲性分子的合成及其抗植病细菌活性的研究

Exploring high-efficient bioactive compounds is the important premise in pesticide development and innovation. Plant bacterial diseases, one of the most serious threats to the agricultural crops and economic crops, can cause grain reduction and crop economic losses and are extremely difficult to control. It was found in the preliminary study that pyridinium-tailored aromatic amphiphiles and pyridinium-tailored phenyloxadiazol thioether/sulfoxide/sulfone derivatives displayed good inhibition activity towards plant pathogenic bacteria. Herein, we will comparatively systematic design and synthesize this kind of pyridinium-tailored amphiphiles to obtain excellent antibacterial compounds. Meanwhile, through the modification of the pyridinium part, a series of thiazolium (or imidazolium)-tailored amphiphiles will be synthesized to investigate the necessity of pyridinium group. The quantitative structure-activity relationship (QSAR) will be discussed to summarize the structural features for the highly active compounds according to the tested bioactivity, which will provide a direction for the modification of new compounds. Moreover, fluorescent probe and proteomics techniques will be used to explore the action mechanism of highly reactive compounds. Potential targets of active compounds will be explored. This proposal will provide some scientific references for new pesticide innovation and the management of plant bacterial diseases.

寻找和发现高效活性化合物是新农药创制研发的重要环节。植物细菌性病害是造成我国粮食减产和农作物经济损失的重要原因之一，防治非常困难。申请者课题组前期工作发现含芳基取代的吡啶盐类衍生物和基于吡啶盐的苯基噁二唑硫醚、亚砜和砜类衍生物对植病细菌表现出了良好的抑制活性。本申请在此基础上拟进行较为系统的含吡啶盐的两亲性分子的设计合成，期望从中筛选出杀菌活性优异的两亲性分子。同时对吡啶盐部分进行改造，合成含噻唑盐或咪唑盐的两亲性分子，以考察吡啶盐对生物活性是否是必需的。通过生物活性测试结果进行定量构效关系分析，建立QSAR模型，总结高效抗菌活性化合物的结构特征,为两亲性分子的进一步结构优化提供指导。并拟采用荧光分子探针和蛋白组学技术对高活性化合物的作用机制进行初步探索，寻找高活性化合物的潜在靶标，为新农药创制和植物细菌性病害的防治提供一定的科学参考。

按计划开展了各项研究工作，设计合成了多个系列含吡啶盐、噻唑盐或咪唑盐基团的两亲性分子，并采用浊度法筛选了目标化合物抗水稻白叶枯病菌、抗烟草青枯病菌、抗柑橘溃疡病菌和抗猕猴桃溃疡病菌的生物活性，生测结果表明多个目标化合物展现出了优异的抗菌活性，室内活体生测试验进一步验证了高活性化合物具有较好的防治植物细菌性病害的能力，具有进一步研究的潜力。基于结构与活性分析建立了QSAR模型，为目标化合物的下一步结构优化提供了指导。同时利用了蛋白组学技术、扫描电镜技术、透射电镜技术、流式细胞术技术及荧光显微镜技术等探究了高活性化合物的抗菌机制。上述研究结果对新抗菌先导化合物的发现及新抗菌农药的研发和创制打下了重要的科学基础。