新型针对琥珀酸脱氢酶的抗真菌药物的权宜之计：带有二苯醚片段的吡唑-4-甲酰肼衍生物,Journal of Agricultural and Food Chemistry

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新型针对琥珀酸脱氢酶的抗真菌药物的权宜之计：带有二苯醚片段的吡唑-4-甲酰肼衍生物
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2020-11-20 , DOI: 10.1021/acs.jafc.0c03736
Xiaobin Wang _{1,

2,

3} , An Wang ₁ , Lingling Qiu ₁ , Min Chen _{1,

2} , Aimin Lu _{1,

2} , Guohua Li _{1,

2} , Chunlong Yang _{1,

2} , Wei Xue ₃

Affiliation

含有柔性酰胺链的吡唑-4-羧酰胺支架已经成为靶向琥珀酸脱氢酶（SDH）的高效农业杀菌剂的分子骨架。基于上述琥珀酸脱氢酶抑制剂（SDHI）的重要结构特征，在生物活性分子与SDH之间的虚拟对接比较的指导下，合理构思了三种新型的带有联苯醚部分的吡唑-4-甲酰肼衍生物。与分子对接比较的虚拟验证结果一致，体外抗真菌生物测定表明，标题化合物的骨架结构应优化为N '-（4-苯氧基苯基）-1 H-吡唑-4-碳酰肼支架。惊人地N '-（4-苯氧基苯基）-1 H-吡唑-4-碳酰肼衍生物对solani solani的影响11o，对禾谷镰刀菌（Fusarium graminearum）的11m和对灰葡萄孢的11g表现出优异的抗真菌作用，相应的EC ₅₀值为0.14、0.27和0.52 μg/ mL，明显优于多菌灵（针对多菌灵（0.34μg / mL）和禾本科镰刀菌（0.57μg/ mL））和戊硫吡拉（对灰霉病）（0.83μg / mL）。solani solani体内生物测定的相关研究，针对SDH的生物活性评估以及分子对接的研究进一步确定了化合物11o作为靶向SDH的潜在杀菌剂的实用价值。目前的工作为针对SDH的抗真菌引线的结构优化提供了不可忽略的补充。

"点击查看英文标题和摘要"

Expedient Discovery for Novel Antifungal Leads Targeting Succinate Dehydrogenase: Pyrazole-4-formylhydrazide Derivatives Bearing a Diphenyl Ether Fragment

The pyrazole-4-carboxamide scaffold containing a flexible amide chain has emerged as the molecular skeleton of highly efficient agricultural fungicides targeting succinate dehydrogenase (SDH). Based on the above vital structural features of succinate dehydrogenase inhibitors (SDHI), three types of novel pyrazole-4-formylhydrazine derivatives bearing a diphenyl ether moiety were rationally conceived under the guidance of a virtual docking comparison between bioactive molecules and SDH. Consistent with the virtual verification results of a molecular docking comparison, the in vitro antifungal bioassays indicated that the skeleton structure of title compounds should be optimized as an N′-(4-phenoxyphenyl)-1H-pyrazole-4-carbohydrazide scaffold. Strikingly, N′-(4-phenoxyphenyl)-1H-pyrazole-4-carbohydrazide derivatives 11o against Rhizoctonia solani, 11m against Fusarium graminearum, and 11g against Botrytis cinerea exhibited excellent antifungal effects, with corresponding EC₅₀ values of 0.14, 0.27, and 0.52 μg/mL, which were obviously better than carbendazim against R. solani (0.34 μg/mL) and F. graminearum (0.57 μg/mL) as well as penthiopyrad against B. cinerea (0.83 μg/mL). The relative studies on an in vivo bioassay against R. solani, bioactive evaluation against SDH, and molecular docking were further explored to ascertain the practical value of compound 11o as a potential fungicide targeting SDH. The present work provided a non-negligible complement for the structural optimization of antifungal leads targeting SDH.

更新日期：2020-12-09

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