Design, Synthesis, Antifungal Activity, and Action Mechanism of Pyrazole-4-carboxamide Derivatives Containing Oxime Ether Active Fragment As Succinate Dehydrogenase Inhibitors,Journal of Agricultural and Food Chemistry

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Design, Synthesis, Antifungal Activity, and Action Mechanism of Pyrazole-4-carboxamide Derivatives Containing Oxime Ether Active Fragment As Succinate Dehydrogenase Inhibitors
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2024-05-08 , DOI: 10.1021/acs.jafc.3c07880
Jian-Qi Chai _{1,

2} , Xiao-Bin Wang _{1,

2,

3} , Kai Yue ₁ , Shuai-Tao Hou _{1,

2} , Fei Jin _{1,

2} , Yv Liu _{1,

2} , Lang Tai ₁ , Min Chen _{1,

2} , Chun-Long Yang _{1,

2}

Affiliation

The dearomatization at the hydrophobic tail of the boscalid was carried out to construct a series of novel pyrazole-4-carboxamide derivatives containing an oxime ether fragment. By using fungicide-likeness analyses and virtual screening, 24 target compounds with theoretical strong inhibitory effects against fungal succinate dehydrogenase (SDH) were designed and synthesized. Antifungal bioassays showed that the target compound E1 could selectively inhibit the in vitro growth of R. solani, with the EC₅₀ value of 1.1 μg/mL that was superior to that of the agricultural fungicide boscalid (2.2 μg/mL). The observations by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) demonstrated that E1 could reduce mycelial density and significantly increase the mitochondrial number in mycelia cytoplasm, which was similar to the phenomenon treated with boscalid. Enzyme activity assay showed that the E1 had the significant inhibitory effect against the SDH from R. solani, with the IC₅₀ value of 3.3 μM that was superior to that of boscalid (7.9 μM). The mode of action of the target compound E1 with SDH was further analyzed by molecular docking and molecular dynamics simulation studies. Among them, the number of hydrogen bonds was significantly more in the SDH-E1 complex than that in the SDH-boscalid complex. This research on the dearomatization strategy of the benzene ring for constructing pyrazole-4-carboxamides containing an oxime ether fragment provides a unique thought to design new antifungal drugs targeting SDH.

中文翻译：

含肟醚活性片段的吡唑-4-甲酰胺衍生物琥珀酸脱氢酶抑制剂的设计、合成、抗真菌活性及作用机制

对啶酰菌胺疏水尾部进行脱芳构化，构建了一系列含有肟醚片段的新型吡唑-4-甲酰胺衍生物。通过类杀菌剂分析和虚拟筛选，设计合成了24个理论上对真菌琥珀酸脱氢酶（SDH）具有强抑制作用的目标化合物。抗真菌生物测定表明，目标化合物E1可选择性抑制立枯丝核菌体外生长，EC ₅₀值为1.1 μg/mL，优于农用杀菌剂啶酰菌胺（2.2 μg/mL）。扫描电镜（SEM）和透射电镜（TEM）观察表明， E1可以降低菌丝密度，显着增加菌丝胞质中的线粒体数量，这与啶酰菌胺处理的现象相似。酶活性测定表明， E1对茄病菌SDH有显着的抑制作用，IC ₅₀值为3.3 μM，优于啶酰菌胺（7.9 μM）。通过分子对接和分子动力学模拟研究，进一步分析了目标化合物E1与SDH的作用模式。其中，SDH- E1复合物中的氢键数量明显多于SDH-啶酰菌胺复合物中的氢键数量。该研究通过苯环脱芳构化策略构建含有肟醚片段的吡唑-4-甲酰胺，为设计针对SDH的新型抗真菌药物提供了独特的思路。

更新日期：2024-05-08

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