柠檬醛衍生物抗油茶炭疽病菌活性与QSAR研究

Anthracnose (Glomerella cingulata) is one of common pathogens that may jeopardize the growth of camellia oleifera, an important economic species in China. Using traditional pesticides may lead to serious environmental problems and food safety concerns. The exploration of new environment-friendly and highly-efficient antimicrobials through the structure modification of natural products becomes urgent and strategically important. The key problem in the exploration of antimicrobial is structure-activity relationship (SAR) of antibacterial activity and antimicrobial mechanism. In our preliminary study, the antimicrobial activity of essential oils and citral from plants (Litsea cubeba) has been investigated and some citral derivatives have been synthesized. Results show that these derivatives show an enhanced bioactivity. In this study, natural citral structures will be used as the lead compounds, followed by structure modifications during the chemical synthesis process. Structures of derivatives will be characterized by using NMR, FTIR and MS. The antimicrobial activities of those derivatives will be investigated against Glomerella cingulata by the growth speed method so compounds with powerful antibacterial activities can be screened from them. For the selected compounds, their physicochemical properties and safety will be evaluated in order to find ones with optimal performance. In addition, the effects of chemical groups, atoms, and loop system on antimicrobial activity will be elucidated and the structure-activity relationship will be discussed using pharmacophore and computational chemistry methods. The quantitative structure-activity relationship ( QSAR) model was obtained using Gaussian, Ampac and Codessa. This study will provide theory basis for the exploration of new antimicrobials and antimicrobial mechanism.

炭疽病是危害我国重要经济树种油茶的常见病，目前防治该病的传统抗菌剂易带来环境污染和食品安全等问题，寻找安全高效的新型抗菌剂是当前重要课题。创制新型抗菌剂的关键是活性、构效关系与作用机理研究。申请者前期研究发现天然柠檬醛对油茶炭疽病有一定抑制作用，继而开展了衍生物的合成与活性测定工作，结果显示活性呈增强趋势。本项目拟继续以天然柠檬醛为先导物，有针对性地进行结构修饰与衍生物合成，利用核磁、质谱和红外等进行结构鉴定；以油茶炭疽病菌为对象，采用生长速率法，进行抗菌活性分析，筛选高活性化合物，并对其理化性质、安全性进行系统测试和全面评估，获得综合评价均优的抗菌剂；采用药效团和化学计量分析法，研究各种化学基团、原子、环系结构等对抗菌活性的影响，并运用Gaussian、Ampac和Codessa，采用启发式回归方法建立定量计算模型，掌握构效关系。研究成果可为创制新型抗菌剂和认识抗菌作用机理提供理论依据。

油茶是我国大面积种植的油料作物，炭疽病是危害油茶生长的最重要病害之一，传统抗菌剂易带来环境污染和食品安全等问题，寻求和开发有利于环境和人类健康的新型抗菌剂迫在眉睫。.项目通过筛选获得了精油得率最高达9.71%，精油中柠檬醛的含量为73.46%；精油得率达到6.22%，精油中柠檬醛的含量为86.59%；精油得率达到2.39%，精油中柠檬醛的含量最高为87.17%的优良山苍子资源，为将来开发利用奠定良好基础。.以天然柠檬醛为先导化合物，在酸催化回流反应合成得到香茅醛二甲缩醛、二乙缩醛、二丙缩醛及乙二缩醛、1,2-丙二缩醛、1,3-丙二缩醛、1,2-丁二缩醛、1,3-丁二缩醛等8个缩醛类化合物；将醛与盐酸羟胺反应，生成相应的肟，再将肟与卤代烷反应生成了柠檬醛的甲基醚、乙基醚、正丙基醚、正丁基醚、异丁基醚、仲丁基醚、正戊基醚、正己基醚等8种肟醚，香茅醛的乙基醚、丙基醚、正丁基醚、正戊基醚以及羟基香茅醛肟及其肟醚（乙基醚、丙基醚、正丁基醚、正戊基醚）等8种化合物；将醛肟脱水生成腈，合成得到香茅腈和羟基香茅腈。采用红外、气质联用和核磁共振等分析手段进行化学结构分鉴定析。经检索，26种为新化合物，极大地提高了柠檬醛的附加值。.通过比较分析，橙花素、柠檬腈和柠檬醛1,2-丙二醇缩醛对油茶炭疽病菌的抑制效果优于或类似于广谱抗菌农药。橙花素、柠檬腈和柠檬醛1,2-丙二醇缩醛的抑制中浓度EC50分别为12.28 mg/L、14.09 mg/L、42.78 mg/L。4种广谱农药多菌灵、百菌清、甲基硫菌灵、代森锰锌的抑制中浓度EC50分别为4.37 mg/L、29.86 mg/L、37.98 mg/L、14.62 mg/L。从毒力活性测定和防效试验结果观察，这几种化合物具有较好的开发前景。.总结分析抗油茶炭疽病的化合物分子结构，结构中含有-C=C-，-C=O，=C-CN，-OH，=C-C-O-O等结构，碳原子数大于10，碳氧原子数之和可以大于20；构建抑制油茶炭疽病的化合物结构特征，探讨了抗菌活性的定性构效关系。利用Gaussian 03W，Ampac 8.16优化结构，Codessa 2.7.10计算结构参数，采用启发式回归方法初步建立化合物的结构与活性的定量计算模型。.项目的开展，为解决抗菌活性与构效关系的科学问题奠定基础，为山苍子资源精深加工利用提供科学依据，具有重要理论和现实意义。