Abstract：
Pyrazole carboxamides are a class of traditional succinate dehydrogenase inhibitors (SDHIs) that have developed into a variety of commercialized fungicides. In the present work, a series of novel 1,5-disubstituted-1H-pyrazole-4-carboxamide derivatives were designed and synthesized based on the active backbone of 5-trifluoromethyl-1H-4-pyrazole carboxamide. Bioassay results indicated that some target compounds exhibited excellent in vitro antifungal activities against six phytopathogenic fungi. Notably, the EC50 values of Y47 against Gibberella zeae, Nigrospora oryzae, Thanatephorus cucumeris, and Verticillium dahliae were 5.2, 9.2, 12.8, and 17.6 mg/L, respectively. The in vivo protective and curative activities of Y47 at 100 mg/L against G. zeae on maize were 50.7 and 44.2%, respectively. Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis revealed that the large steric hindrance and electronegative groups on the 5-position of the pyrazole ring were important for the activity. The IC50 value of Y47 against succinate dehydrogenase (SDH) was 7.7 mg/L, superior to fluopyram (24.7 mg/L), which was consistent with the docking results. Morphological studies with fluorescence microscopy (FM) and scanning electron microscopy (SEM) found that Y47 could affect the membrane integrity of mycelium by inducing endogenous reactive oxygen species (ROS) production and causing peroxidation of cellular lipids, which was further verified by the malondialdehyde (MDA) content. Antifungal mechanism analysis demonstrated that the target compound Y47 not only had significant SDH inhibition activity but could also affect the membrane integrity of mycelium, exhibiting obvious dual action modes. This research provides a novel approach to the development of traditional SDHIs and their derivatives.
摘要：
吡唑甲酰胺是一类传统的琥珀酸脱氢酶抑制剂(SDHI),其已发展成为多种商业化的杀真菌剂。在目前的工作中,基于5-三氟甲基-1H-4-吡唑甲酰胺的活性骨架，设计并合成了一系列新型1,5-二取代-1H-吡唑-4-甲酰胺衍生物。生物测定结果表明，某些目标化合物对6种植物病原真菌具有良好的体外抗真菌活性。值得注意的是,Y47对玉米赤霉素的EC50值，米黑质孢子菌,黄瓜，黄萎病菌分别为5.2、9.2、12.8和17.6mg/L，分别。100mg/L的Y47对玉米G的体内保护和治疗活性分别为50.7和44.2％，分别。三维定量结构-活性关系（3D-QSAR）分析显示，吡唑环5位的大空间位阻和电负性基团对活性很重要。Y47对琥珀酸脱氢酶(SDH)的IC50值为7.7mg/L,优于氟吡仑（24.7mg/L），这与对接结果一致。荧光显微镜（FM）和扫描电子显微镜（SEM）的形态学研究发现，Y47可以通过诱导内源性活性氧（ROS）的产生和引起细胞脂质的过氧化作用来影响菌丝体的膜完整性。丙二醛(MDA)含量进一步验证。抗真菌机理分析表明,目标化合物Y47不仅具有显著的SDH抑制活性,而且能影响菌丝体的膜完整性,表现出明显的双重作用模式。本研究为传统SDHIs及其衍生物的开发提供了一种新方法。
