基于Ugi反应的含芳氨基甲酰基1-氰基-1-环丙烷甲酰胺类新化合物的合成、结构和生物活性研究  

Studies on the Synthesis, Structure and Biological Activities of Novel Arylaminoformyl-containing 1-Cyano-1-cycloproane Carboxylic Acid Amides Based on Ugi Reaction

作　　者：詹益周 王宝雷[1] 张丽媛[1] 张燕[1] 张晓[1] 李正名[1] 宋海斌[1] 

机构地区：[1]南开大学元素有机化学国家重点实验室天津化学化工协同创新中心,天津300071

出　　处：《化学学报》2015年第11期1173-1181,共9页Acta Chimica Sinica

基　　金：国家自然科学基金面上项目(No.21372133);高等学校学科创新引智计划(No.B06005)资助~~

摘　　要：酮醇酸还原异构酶(KARI;EC 1.1.1.86)是植物和微生物(细菌、真菌)体内支链氨基酸生物合成过程中起催化作用的关键酶之一,可作为设计除草剂或杀菌剂的靶标.本工作在前期工作基础上,以1-氰基-1-环丙烷甲酸,芳基异腈,醛和胺为反应物,通过Ugi反应设计合成了一系列含芳氨基甲酰基1-氰基-1-环丙烷甲酰胺类新化合物8a^8p,经1H NMR,13C NMR,IR和元素分析或HRMS确证了结构,并解析了化合物8m的晶体结构.初步生物活性测试结果表明,这些环丙烷双酰胺类衍生物是结构新颖的KARI酶抑制剂,其中8a^8c,8m,8n和8j在200 mg/L浓度下对水稻KARI酶具有94%~98%的抑制活性,8m的Ki为(77.91±30.15)μmol/L.化合物在50 mg/L浓度下对黄瓜枯萎病菌、花生褐斑病菌、苹果轮纹病菌、番茄早疫病菌和小麦赤霉病菌等5种植物病菌表现出显著抑制活性,整体来看8e和8p具有相对宽泛的抑菌谱,可作为新型抑菌剂苗头化合物进行深入研究.As one of key enzymes that catalyze the biosynthesis of branched-chain amino acids in plants and microorganisms（bacteria, fungi）, ketol-acid reductoisomerase（KARI; EC 1.1.1.86） can be regarded as a promising target for designing herbicides or fungicides. Previously, we have found that N-aryl-1-cyano-1-cyclopropane carboxamides and cyclopropylformyl thioureas exhibit favorable KARI inhibitory activity and can be made further structure modification for discovery more new inhibitors. In this continuous work, a series of novel 1-cyano-1-cycloproane carboxylic acid amides containing arylaminoformyl moity 8a^8p were designed accordingly and synthesized via one-pot Ugi reaction with 1-cyano-1-cyclopropane carboxylic acid, aryl isonitrile, aldehyde and amine as reactants. The structures of the new compounds were confirmed by 1H NMR, 13 C NMR, IR spectra and elemental analysis or HRMS. Meanwhile the crystal structure of 8m was reported, which provided comprehensive structure information for this kind of compounds. From a continuous assay method that following the consumption of NADPH（involved in the KARI-catalyzed reaction） at 340 nm, it was found that most of these cyclopropane diamide derivatives exhibit obvious KARI inhibitory activities and are new KARI inhibitors, among which 8a^8c, 8m, 8n and 8j possessed inhibition rate of 94%~98% at a test concentration of 200 mg/L against rice KARI, and 8m had a Ki value of（77.91±30.15） μmol/L. These new inhibitors synthesized in this paper can inhibit KARI enzyme effectively at the same level with those of N-aryl-1-cyano-1-cyclopropane carboxamides reported previously. In addition, the preliminary bioassay results also showed that several compounds exhibit significant in vitro fungicidal activities at a test concentration of 50 mg/L against Ftasarium omysporum, Cercospora arachidicola, Physalospora piricola, Alternaria solani and Gibberella sanbinetti by using the mycelium growth rate test method, and 8e and 8p, which have comparatively broad fungicidal spectru

关 键 词：环丙烷甲酰胺 Ugi反应 酮醇酸还原异构酶 抑菌活性 

分 类 号：O621.3[理学—有机化学] TQ450.1[理学—化学]