Zhao Shuyan, Lin Guishan, Duan Wengui, Zhang Qianan, Huang Yinglan, Lei Fuhou
School of Chemistry and Chemical Engineering, Guangxi University, No. 100, Daxue Dong Road, Nanning, Guangxi 530004, P. R. China.
Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, Guangxi Collaborative Innovation Center for Chemistry and Engineering of Forest Products, Guangxi University for Nationalities, No. 188, Daxue Dong Road, Nanning, Guangxi 530006, China.
ACS Omega. 2021 Mar 24;6(13):9104-9111. doi: 10.1021/acsomega.1c00217. eCollection 2021 Apr 6.
Succinate dehydrogenase (SDH) present in the inner mitochondrial membrane is an important target enzyme for the design of SDH inhibitor-type fungicides. Using SDH as the target enzyme, 22 novel longifolene-derived diacylhydrazine compounds were designed and synthesized using the renewable natural product longifolene as the starting material. Their structures were confirmed by IR, H NMR, C NMR, electrospray mass spectrometry, and elemental analysis. In vitro antifungal activity of the target compounds was preliminarily evaluated. As a result, some of them showed better or comparable antifungal activity than that of the commercial fungicide chlorothalonil, in which compound had inhibitory rates of 97.5, 80.5, 72.1, and 67.1% against , , and , respectively, presenting excellent and broad-spectrum activity that deserved further study. Besides, a reasonable and effective three-dimensional structure-activity quantitative relationship model has been established. There was a significant positive correlation between the antifungal activity and the docking-based binding energy analyzed using Spearman's rank correlation algorithm. Also, the simulative binding pattern of the target compounds with SDH was investigated by molecular docking study. Furthermore, the diacylhydrazine and phenol groups of the target compounds were proposed to be the potential pharmacophores by frontier molecular orbital analysis.
存在于线粒体内膜中的琥珀酸脱氢酶（SDH）是设计SDH抑制剂型杀菌剂的重要靶标酶。以SDH为靶标酶，以可再生天然产物长叶烯为起始原料，设计并合成了22种新型长叶烯衍生的二酰肼化合物。通过红外光谱、氢核磁共振、碳核磁共振、电喷雾质谱和元素分析确定了它们的结构。对目标化合物的体外抗真菌活性进行了初步评价。结果表明，其中一些化合物的抗真菌活性优于或与市售杀菌剂百菌清相当，其中化合物对、、和的抑制率分别为97.5%、80.5%、72.1%和67.1%，表现出优异的广谱活性，值得进一步研究。此外，还建立了合理有效的三维构效定量关系模型。使用Spearman秩相关算法分析，抗真菌活性与基于对接的结合能之间存在显著正相关。同时，通过分子对接研究考察了目标化合物与SDH的模拟结合模式。此外，通过前沿分子轨道分析，提出目标化合物的二酰肼和酚基团为潜在药效团。
