Abstract：
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.
摘要：
在啶酰菌胺的疏水尾部进行脱芳构化，以构建一系列包含肟醚片段的新型吡唑-4-甲酰胺衍生物。通过杀菌剂相似性分析和虚拟筛选，设计并合成了24个对真菌琥珀酸脱氢酶（SDH）具有理论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可以选择性地抑制R.solani的体外生长，EC50值为1.1μg/mL，优于农用杀菌剂啶酰菌胺（2.2μg/mL）。通过扫描电子显微镜（SEM）和透射电子显微镜（TEM）的观察表明，E1可以降低菌丝体密度，并显着增加菌丝体细胞质中的线粒体数量。这类似于啶酰菌胺治疗的现象。酶活性测定表明，E1对solani的SDH有明显的抑制作用，IC50值为3.3μM，优于剖腹产（7.9μM）。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。本研究利用苯环的去芳构化策略构建含肟醚片段的吡唑-4-甲酰胺类药物，为设计靶向SDH的新型抗真菌药物提供了独特的思路。
