化学学报 ›› 2015, Vol. 73 ›› Issue (11): 1173-1181.DOI: 10.6023/A15050333 上一篇    下一篇

研究论文

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

詹益周, 王宝雷, 张丽媛, 张燕, 张晓, 李正名, 宋海斌   

  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
  • 收稿日期:2015-05-20 出版日期:2015-11-15 发布日期:2015-11-19
  • 通讯作者: 王宝雷, 李正名 E-mail:nkwbl@nankai.edu.cn;nkzml@vip.163.com
  • 基金资助:

    项目受国家自然科学基金面上项目(No. 21372133)和高等学校学科创新引智计划(No. B06005)资助.

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

Zhan Yizhou, Wang Baolei, Zhang Liyuan, Zhang Yan, Zhang Xiao, Li Zhengming, Song Haibin   

  1. State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071
  • Received:2015-05-20 Online:2015-11-15 Published:2015-11-19
  • Supported by:

    Project supported by the National Natural Science Foundation of China (No. 21372133) and “111” Project of Ministry of Education of China (No. B06005).

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8a8p, 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8a8c, 8m, 8n8j在200 mg/L浓度下对水稻KARI酶具有94%~98%的抑制活性, 8mKi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8e8p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.

关键词: 环丙烷甲酰胺, Ugi反应, 酮醇酸还原异构酶, 抑菌活性

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 8a8p were designed accordingly and synthesized via one-pot Ugi reaction with 1-cyano-1-cyclo- propane carboxylic acid, aryl isonitrile, aldehyde and amine as reactants. The structures of the new compounds were confirmed by 1H NMR, 13C 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 8a8c, 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 spectrum on the whole and are comparable with the contrast Triadimefon during the present study, could be used as novel hit compounds for further structural optimization in fungicide innovations.

Key words: cyclopropane carboxylic acid amides, Ugi reaction, KARI, fungicidal activity