新型吡唑乙酰胺类琥珀酸脱氢酶抑制剂的设计、合成及抑菌活性  

Design,Synthesis and Antifungal Activities of Novel Succinate Dehydrogenase Inhibitors Bearing a Pyrazolyl Acetamide Scaffold

作　　者：王晓斌 董雪 王瑞颖 张娟 王濛琪 张宗群 杨婷玉 许梦寒 WANG Xiaobin;DONG Xue;WANG Ruiying;ZHANG Juan;WANG Mengqi;ZHANG Zongqun;YANG Tingyu;XU Menghan(Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening,College of Pharmacy,School of Ocean Engineering,Jiangsu Ocean University,Lianyungang 222005,China;Research Center of Ocean Engineering Technology,School of Ocean Engineering,Jiangsu Ocean University,Lianyungang 222005,China;Jiangsu Key Laboratory of Pesticide Science,College of Sciences,Nanjing Agricultural University,Nanjing 210095,China)

机构地区：[1]江苏海洋大学药学院,江苏省海洋药物活性分子筛选重点实验室,连云港222005 [2]江苏海洋大学海洋工程学院,海洋工程技术研究中心,连云港222005 [3]南京农业大学理学院,江苏省农药学重点实验室,南京210095

出　　处：《高等学校化学学报》2024年第2期54-62,共9页Chemical Journal of Chinese Universities

基　　金：国家自然科学基金(批准号:32202334);江苏省高等学校自然科学基金(批准号:22KJB210009);江苏海洋大学人才引进项目(批准号:KQ21031);江苏海洋大学研究生科研与实践创新计划项目(批准号:KYCX202340)资助.

摘　　要：为开发出新型杀菌剂候选分子,通过柔性改造吡唑甲酰胺杀菌剂结构中的二元酰胺键得到了一系列潜在靶向真菌琥珀酸脱氢酶(SDH)的新型吡唑乙酰胺分子.借助菌丝生长速率法发现了其中具有广谱抑菌特性的二苯醚联吡唑乙酰胺分子(6l),其在药剂质量浓度为50μg/mL时对水稻纹枯病菌、小麦赤霉病菌和草莓灰霉病菌的抑制效果均优于对照药剂噁霉灵.化合物6l对水稻纹枯病菌的半最大效应浓度(EC_(50)值)为19.92μg/mL,抑菌活性明显优于对照药剂噁霉灵和氟吡菌酰胺(EC_(50)分别为76.74和40.36μg/mL).SDH酶活力测试结果表明,真菌体内的SDH是化合物6l抑制水稻纹枯病菌生长的潜在作用靶标.分子对接研究结果显示,化合物6l分子结构中的二苯醚单元能以多种方式与靶标口袋的关键残基结合,对分子发挥抑菌活性起到了关键作用.研究结果表明,二苯醚联吡唑乙酰胺分子对植物病原真菌具有较显著的抑制作用,在其结构基础上进行深度的优化和改造有望得到可有效防控植物病原真菌的新型杀菌剂候选分子.Aiming to search for novel fungicide candidates,a series of novel pyrazolyl acetamides potentially targeting fungal succinate dehydrogenase(SDH)were constructed by flexibly reinventing the dualistic amide linkage that emerges in the structure of pyrazole-4-carboxamide fungicides.The diphenylether-containing pyrazole-4-acetamide(6l)featuring broad-spectrum antifungal effects was screened via a mycelium growth rate method.The above molecule exhibited the conspicuous inhibitory effect against Rhizoctonia solani,Fusarium graminearum and Botrytis cinerea at 50μg/mL,with the inhibitory rates that were slightly better than that of hymexazol.Strikingly,the median effective concentration(EC_(50))of compound 6l against R.solani was estimated as 19.92μg/mL that is better than that of hymexazol(76.74μg/mL)and fluopyram(40.36μg/mL).The bioactive evaluations against SDH indicated that a fungal SDH was the potential target of compound 6l for inhibiting R.solani.Subsequently,molecular docking studies implied that the diphenylether unit emerging in the structure of compound 6l could multiply interact with the pivotal residues locating at SDH protein pockets,which plays a critical role in guaranteeing the antifungal effect of diphenylether-containing pyrazole-4-acetamides.The above researches indicated that the diphenylethercontaining pyrazole-4-acetamides exhibit obviously inhibitory effects against phytopathogenic fungi,and could be further optimized for developing novel fungicide candidates that could effectively control phytopathogenic fungi.

关 键 词：抑菌先导发现 吡唑乙酰胺 植物病原真菌 琥珀酸脱氢酶抑制剂 

分 类 号：O625.42[理学—有机化学]