Triphenylphosphonium-Driven Targeting of Pyrimorph Fragment Derivatives Greatly Improved Its Action on Phytopathogen Mitochondria,Journal of Agricultural and Food Chemistry

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Triphenylphosphonium-Driven Targeting of Pyrimorph Fragment Derivatives Greatly Improved Its Action on Phytopathogen Mitochondria
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2023-02-01 , DOI: 10.1021/acs.jafc.2c07902
Fahong Yin ₁ , Xuelian Liu ₁ , Yong Xu ₂ , Bin Fu ₁ , Xueqin Zhang ₂ , Yumei Xiao ₁ , Jiaqi Li ₁ , Zhaohai Qin ₁

Affiliation

Pyrimorph is a carboxylic acid amide (CAA) fungicide, which shows excellent activity against oomycetes such as pepper phytophthora blight, tomato late blight, and downy mildew of cucumber. It works mainly by inhibiting the biosynthesis of cell wall of oomycetes. However, pyrimorph also shows weak activity of inhibiting mitochondrial complex III, which is the first CAA fungicide found to act on mitochondria. To improve this effect on mitochondria and develop fungicides that may have a novel mechanism of action, in this paper, by disassembling pyrimorph and conjugating the fragments with the mitochondrial-targeted delivery system (triphenylphosphonium), three series of mitochondrial-targeting analogues of pyrimorph were designed and synthesized. The results show that the pyridine-containing 1,1-diaryl is the core module of inhibition mitochondrial function of pyrimorph. Among these conjugates, compound 3b with a short linker showed the highest and broad-spectrum fungicidal activity, strong respiratory inhibition activity, and adenosine 5′-triphosphate synthesis inhibition activity, suggesting its potential as a fungicide candidate. 3b exhibited greatly improved action on mitochondria, such as by destroying the mitochondrial function of pathogens, causing mitochondrial swelling, weakening its influence on cell wall morphology, and so on. More importantly, this study provides a method to strengthen the drugs or pesticides with weak mitochondrial action, which is of special significance for developing mitochondrial bioactive molecules with the novel action mechanism.

中文翻译：

Pyrimorph 片段衍生物的三苯基膦驱动靶向大大提高了其对植物病原体线粒体的作用

Pyrimorph 是一种羧酸酰胺 (CAA) 杀菌剂，对辣椒疫霉病、番茄晚疫病等卵菌表现出优异的活性和黄瓜霜霉病。主要通过抑制卵菌细胞壁的生物合成而起作用。然而，pyrimorph 也显示出弱的抑制线粒体复合物 III 的活性，这是第一个被发现作用于线粒体的 CAA 杀菌剂。为了改善这种对线粒体的作用并开发可能具有新作用机制的杀菌剂，本文通过拆解pyrimorph并将其片段与线粒体靶向递送系统（三苯基膦）缀合，得到了三个系列的pyrimorph线粒体靶向类似物设计和合成。结果表明，含吡啶的1,1-二芳基是嘧啶吗啉抑制线粒体功能的核心模块。在这些缀合物中，化合物3b具有短接头的化合物表现出最高和广谱的杀菌活性、强烈的呼吸抑制活性和5'-三磷酸腺苷合成抑制活性，表明其作为候选杀菌剂的潜力。3b对线粒体的作用大大改善，例如通过破坏病原体的线粒体功能，引起线粒体肿胀，减弱其对细胞壁形态的影响等。更重要的是，该研究为增强线粒体作用较弱的药物或农药提供了一种方法，对于开发具有新型作用机制的线粒体生物活性分子具有特殊意义。

更新日期：2023-02-01

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