Synthesis and Antifungal Activity of Nicotinamide Derivatives as Succinate Dehydrogenase Inhibitors
Synthesis and Antifungal Activity of Nicotinamide Derivatives as Succinate Dehydrogenase Inhibitors
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DOI：
10.1021/jf405437k
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发表时间：
2014-05-07
影响因子：
6.1
通讯作者：
Zhu, Hai-Liang
中科院分区：
文献类型：
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作者：
Ye, Yong-Hao;Ma, Liang;Zhu, Hai-Liang
设计并合成了38个烟酰胺衍生物作为潜在的琥珀酸脱氢酶抑制剂（SDHI），并通过H-1 NMR，ESI-MS和元素分析进行了精确表征。采用离体菌丝生长抑制试验，评价了化合物对两种植物病原真菌立枯丝核菌（Rhizoctonia solani）和核盘菌（Sclerotinia sclerotiorum）的抑制作用。大部分化合物表现出中等活性，其中3a-17对红曲霉菌的活性最强。solani和S.的IC 50值分别为15.8和20.3 μ M，与常用的杀菌剂啶酰菌胺和多菌灵相当。构效关系表明，苯胺的间位是烟酰胺类化合物抗真菌活性的关键位置。对两种真菌的抑菌活性进行了测试，并获得了相同的趋势，从体外抗真菌试验获得的数据。值得注意的是，3a-17被证明成功地抑制了S.科尔体内感染菌核病。在分子对接模拟中，3a-17的硫和氯分别与SDH同源模型的PHE 291和PRO 150结合，这可以解释抑制蛋白与靶蛋白之间可能的作用机制。
Thirty-eight nicotinamide derivatives were designed and synthesized as potential succinate dehydrogenase inhibitors (SDHI) and precisely characterized by H-1 NMR, ESI-MS, and elemental analysis. The compounds were evaluated against two phytopathogenic fungi, Rhizoctonia solani and Sclerotinia sclerotiorum, by mycelia growth inhibition assay in vitro. Most of the compounds displayed moderate activity, in which, 3a-17 exhibited the most potent antifungal activity against R. solani and S. sclerotiorum with IC50 values of 15.8 and 20.3 mu M, respectively, comparable to those of the commonly used fungicides boscalid and carbendazim. The structure-activity relationship (SAR) of nicotinamide derivatives demonstrated that the meta-position of aniline was a key position contributing to the antifungal activity. Inhibition activities against two fungal SDHs were tested and achieved the same tendency with the data acquired from in vitro antifungal assay. Significantly, 3a-17 was demonstrated to successfully suppress disease development in S. sclerotiorum infected cole in vivo. In the molecular docking simulation, sulfur and chlorine of 3a-17 were bound with PHE291 and PRO150 of the SDH homology model, respectively, which could explain the probable mechanism of action between the inhibitory and target protein.