Expedient Discovery for Novel Antifungal Leads Targeting Succinate Dehydrogenase: Pyrazole-4-formylhydrazide Derivatives Bearing a Diphenyl Ether Fragment
Expedient Discovery for Novel Antifungal Leads Targeting Succinate Dehydrogenase: Pyrazole-4-formylhydrazide Derivatives Bearing a Diphenyl Ether Fragment
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快速发现针对琥珀酸脱氢酶的新型抗真菌先导化合物：带有二苯醚片段的吡唑-4-甲酰肼衍生物
DOI：
10.1021/acs.jafc.0c03736
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发表时间：
2020-12-09
影响因子：
6.1
通讯作者：
Xue, Wei
中科院分区：
文献类型：
--
作者：
Wang, Xiaobin;Wang, An;Xue, Wei
含有柔性酰胺链的吡唑-4-甲酰胺支架已成为针对琥珀酸脱氢酶（SDH）的高效农业杀菌剂的分子骨架。基于琥珀酸脱氢酶抑制剂（SDHI）的上述重要结构特征，在生物活性分子与SDH虚拟对接比较的指导下，合理构想出三类带有二苯醚部分的新型吡唑-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)-1H-吡唑-4-碳酰肼支架。引人注目的是，N'-(4-苯氧基苯基)-1H-吡唑-4-碳酰肼衍生物11o对立枯丝核菌、11m对禾谷镰刀菌、11g对灰葡萄孢均表现出优异的抗真菌效果，相应的EC50值为0.14、0.27和0.52 μg/mL，明显优于 多菌灵对立枯病菌（0.34μg/mL）和禾谷镰刀菌（0.57μg/mL）以及吡噻菌胺对灰霉病菌（0.83μg/mL）。进一步探讨了针对茄病菌的体内生物测定、针对SDH的生物活性评价以及分子对接的相关研究，以确定化合物11o作为潜在的针对SDH的杀菌剂的实用价值。目前的工作为针对 SDH 的抗真菌先导化合物的结构优化提供了不可忽视的补充。
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 mu g/mL, which were obviously better than carbendazim against R. solani (0.34 mu g/mL) and F. graminearum (0.57 mu g/mL) as well as penthiopyrad against B. cinerea (0.83 mu g/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.