Department of Chemistry, College of Science, China Agricultural University, Beijing, China.
Pest Manag Sci. 2023 Aug;79(8):2920-2933. doi: 10.1002/ps.7470. Epub 2023 Apr 6.
Succinate dehydrogenase inhibitors (SDHIs) are the fastest growing agricultural fungicides at present, but their rapidly growing resistance is a serious problem for their application. Previously, we screened out a fungicidal lead compound CBUA-TPP (1) through triphenylphosphonium (TPP)-driven mitochondrial-targeting strategy. The targeting led to the rapid accumulation of 1 in mitochondria and the saturation inhibition of complex II in a short time, resulting in electron leakage and the explosion of reactive oxygen species (ROS). However, the contribution of biphenyl-2-amines to the activity of these compounds and their structure-activity relationship are still unknown.
Two series of CBUA-TPP (1) analogues (series 2 and 3) were designed and synthesized. The bioassay results indicated that series 2 compounds generally showed much higher fungicidal activities than series 3, suggesting the crucial contribution of the biarylamine module in these targeted molecules and the pyridinyl substitution of phenyl is unfavorable to their activities. Interestingly, these two series of compounds displayed almost opposite substituent effects. Several compounds showed excellent fungicidal activities in vitro, among which compound 2-1 exhibited excellent field control efficacy on potato late blight.
By optimizing the lead compound, the contribution of biarylamine in CBUA-TPP (1) analogs to the fungicidal activity is clarified. Several compounds, represented by 2-1, have great potential as fungicide candidates. They exhibit high and broad-spectrum fungicidal activities and are highly effective against common pathogenic fungi infecting vegetables and fruits both in vitro and field control. It not only provided a new choice for controlling these diseases, but its low resistance tendency also provided a better scheme for resistance management. © 2023 Society of Chemical Industry.
琥珀酸脱氢酶抑制剂（SDHIs）是目前增长最快的农用杀菌剂，但它们的抗药性迅速增长是其应用的一个严重问题。此前，我们通过三苯基膦（TPP）驱动的线粒体靶向策略筛选出一种杀菌先导化合物 CBUA-TPP（1）。靶向作用导致 1 在短时间内快速积累在线粒体中，并使复合物 II 饱和抑制，导致电子泄漏和活性氧物种（ROS）爆炸。然而，联苯-2-胺对这些化合物活性的贡献及其结构-活性关系仍不清楚。
设计并合成了两个系列的 CBUA-TPP（1）类似物（系列 2 和 3）。生物测定结果表明，系列 2 化合物通常表现出比系列 3 更高的杀菌活性，这表明联苯胺模块在这些靶向分子中的关键贡献，以及苯基上吡啶基取代不利于其活性。有趣的是，这两个系列的化合物表现出几乎相反的取代基效应。几种化合物在体外表现出优异的杀菌活性，其中化合物 2-1 对马铃薯晚疫病具有优异的田间控制效果。
通过优化先导化合物，阐明了联苯-2-胺在 CBUA-TPP（1）类似物中对杀菌活性的贡献。以 2-1 为代表的几种化合物具有作为杀菌剂候选物的巨大潜力。它们在体外和田间控制中对常见的感染蔬菜和水果的病原菌具有高和广谱的杀菌活性，且高效。它不仅为控制这些疾病提供了新的选择，而且其低抗性倾向也为抗性管理提供了更好的方案。© 2023 化学工业协会。
