N-(1-苯胺基-2,2,2-三氯乙基)-1H-吡唑酰胺类抑制剂的设计、合成及生物活性研究  

Design, synthesis and biological evaluation of N-(1-phenylamino-2,2,2-trichloro)-1H-pyrazole-4-carboxamide as the inhibitor of succinateubiquinone oxidoreductase

作　　者：朱晓磊[1] 胡生全 蒋莉娜 杨文超[1] 杨光富 

机构地区：[1]华中师范大学化学学院,农药与化学生物学教育部重点实验室,武汉430079 [2]化学化工协同创新中心,天津300071

出　　处：《中国科学：化学》2016年第11期1188-1194,共7页SCIENTIA SINICA Chimica

基　　金：国家公益性行业(农业)科研专项(编号:201203022);国家自然科学基金(编号:21272092;21332004;21272092)资助项目

摘　　要：线粒体呼吸链复合体II(EC 1.3.5.1)又称为线粒体琥珀酸脱氢酶(succinate dehydrogenase,SDH)和琥珀酸-泛醌氧化还原酶(succinate:ubiquinone oxidoreductase,SQR),它是一种重要的杀菌剂靶标,作用于该靶标的商业化品种已有19个.本文以本课题组前期通过虚拟筛选得到的先导化合物为起点,设计并合成了一系列新型的N-(1-苯胺基-2,2,2-三氯乙基)-1H-吡唑酰胺类化合物4a^4z和5,其中化合物4r和5对猪心来源SQR的半抑制浓度(IC_(50)值)分别达到了0.106μM和15.01nM.采用分子模拟技术研究了它们的构效关系,结合自由能的理论计算值(△G_(cal))与实验测定值(△G_(exp))之间的相关性(R^2)为0.95,表明基于分子对接得到的结合模式是可信的,化合物活性的提高在很大程度依赖于侧链部分与受体的相互作用能的提高.Mitochondrial respiratory complex II（EC 1.3.5.1）, also known as succinate dehydrogenase（SDH） or succinate ubiquinone oxidoreductase（SQR）, has been identified as a novel target of a large family of agricultural fungicides. Till now, there are about 19 commercial fungicides. Based the lead compound obtained from virtual screening, the derivative compounds 4a–4z and 5 were designed and synthesized. The structure-activity relationship was studied. The correlation coefficient between △G_（cal） and △G_（exp） was 0.951, proving that the virtual binding mode for titled compounds is correct. The compounds 4r and 5 have the higher activity with the IC_（50） value of 0.106 μM and 15.01 nM, respectively. The binding mode obtained from molecular docking indicated that the compound would show higher potency with more interaction between the sub-amine and the active site of protein.

关 键 词：琥珀酸泛醌氧化还原酶 分子设计 杀菌剂 分子对接 吡唑酰胺 

分 类 号：TQ455.4[化学工程—农药化工]