College of Sciences, China Agricultural University, Beijing 100193, China.
College of Biological Science, China Agricultural University, Beijing 100193, China.
J Agric Food Chem. 2023 Feb 15;71(6):2842-2852. doi: 10.1021/acs.jafc.2c07902. Epub 2023 Feb 1.
Pyrimorph is a carboxylic acid amide (CAA) fungicide, which shows excellent activity against oomycetes such as pepper , , 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 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. 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.
啶虫脒是一种羧酸酰胺（CAA）类杀菌剂，对辣椒疫霉、番茄晚疫病菌和黄瓜霜霉病菌等卵菌具有优异的防治效果。其主要通过抑制卵菌细胞壁的生物合成发挥作用。然而，啶虫脒也表现出较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 类杀菌剂。为了提高啶虫脒对线粒体的作用效果，并开发可能具有新型作用机制的杀菌剂，本文通过拆分啶虫脒并将其片段与线粒体靶向递药系统（三苯基膦）偶联，设计并合成了 3 个系列的啶虫脒线粒体靶向类似物。结果表明，吡啶基 1,1-二芳基是啶虫脒抑制线粒体功能的核心模块。在这些缀合物中，具有短连接子的化合物 表现出最高和广谱的杀菌活性、较强的呼吸抑制活性和腺苷 5'-三磷酸合成抑制活性，表明其具有作为杀菌剂候选物的潜力。该化合物对线粒体的作用明显增强，如破坏病原菌的线粒体功能，导致线粒体肿胀，削弱其对细胞壁形态的影响等。更重要的是，该研究为增强对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。
