新型吡唑联噻吩甲酰胺类衍生物的设计、合成及其抑菌活性研究  

Design,Synthesis and Antifungal Activity of Novel Pyrazole-Thiophene Carboxamide Derivatives

作　　者：李安邦 李中珊 赵洋[1] 姚停停[1] 程敬丽[1] 赵金浩[1] Li Anbang;Li Zhongshan;Zhao Yang;Yao Tingting;Cheng Jingli;Zhao Jinhao(Institute of Pesticide and Environmental Toxicology,Zhejiang University,Hangzhou 310058)

机构地区：[1]浙江大学农药与环境毒理研究所,杭州310058

出　　处：《有机化学》2020年第9期2836-2844,共9页Chinese Journal of Organic Chemistry

基　　金：浙江省自然科学基金(No.LY19C140006);国家重点研发计划(No.2017YFD0200505);国家自然科学基金(No.31872022)资助项目。

摘　　要：琥珀酸脱氢酶抑制剂(SDHI)是一类低毒、高效的杀菌剂,为开发结构新颖、广谱的SDHI杀菌剂,将噻吩环引入吡唑酰胺类杀菌剂的骨架中,设计并合成了24个吡唑联噻吩甲酰胺类衍生物.结构经过1H NMR、13C NMR和HRMS鉴定,其中N-(4-甲氧基苯基)-4-(1-甲基-1H-吡唑-4-基)噻吩-2-甲酰胺(7i)经过X射线衍射确定其空间结构.通过对6种植物病原真菌离体抑制活性测试,发现在50μg/mL的浓度下,部分化合物对水稻纹枯病菌、小麦赤霉病菌和草莓灰霉病菌有较高的抑制活性.其中化合物N-(4-氟苯乙基)-4-(1-甲基-1H-吡唑-4-基)噻吩-2-甲酰胺(7c)对水稻纹枯病菌的EC50为11.6μmol/L,化合物N-(2-氟苯基)-4-(1-甲基-1H-吡唑-4-基)噻吩-2-甲酰胺(7j)对小麦赤霉病菌的EC50为28.9μmol/L,化合物N-(4-氯苯基)-4-(1-甲基-1H-吡唑-4-基)噻吩-2-甲酰胺(7h)对草莓灰霉病菌的EC50为21.3μmol/L.分子对接结果表明,活性较高的目标化合物与琥珀酸脱氢酶关键氨基酸残基形成较强的相互作用.Succinate dehydrogenase inhibitor is a low-toxic and high active fungicide.In order to develop novel and broad-spectrum succinate dehydrogenase inhibitor(SDHI)fungicides,thiophene was introduced into the structure of pyrazole carboxamide fungicides.Twenty four pyrazole-thiophene carboxamides were designed,synthesized and characterized by 1 H NMR,13C NMR and HRMS.The crystal structure of N-(4-methoxyphenyl)-4-(1-methyl-lH-pyrazol-4-yl)thiophene-2-carboxamide(7 i)was determined by X-ray diffraction.The antifungal activity of all the synthesized compounds was determined against six plant pathogenic fungi,and preliminary bioassays suggested that some compounds exhibited good antifungal activity against Rhizoctonia solani,Fusarium graminearum and Botrytis cinerea.Among them,N-(4-fluorophenethyl)-4-(1-methyl-1 H-pyrazol-4-yl)thiophene-2-carboxamide(7 c)exhibited the best antifungal activities against R.solani in vitro with EC50 value of 11.6μmol/L,and N-(2-fluorophenyl)-4-(1-methyl-1 H-pyrazol-4-yl)thiophene-2-carboxamide(7 j)against F.graminearum with EC50 value of 28.9μmol/L.And N-(4-chlorophenyl)-4-(1-methyl-1 H-pyrazol-4-yl)thiophene-2-carboxamide(7 h)showed similar inhibition abilities with thifluzamide against B.cinerea with EC50 value of21.3μmol/L.The molecular docking results showed that the high antifungal activitie compounds form stronger interactions with important amino acid residues of succinate dehydrogenase.

关 键 词：琥珀酸脱氢酶抑制剂 吡唑联噻吩甲酰胺类 杀菌活性 分子对接 

分 类 号：TQ455.4[化学工程—农药化工]