两个柠檬苦素类似物的结构优化、杀虫活性及3D-QSAR研究

By using two limonoids (fraxinellone and obacunone), the naturally occurring products, as the lead compounds, the extensive structural modifications were carried out: (1) on the B-ring and the C-8 furyl ring of fraxinellone; (2) the endocyclic double bond and seven-membered-lactone of A-ring, carbonyl group of B-ring, six-membered-lactone of D-ring, and C-17 furyl ring of obacunone. The insecticidal activities of a series of fraxinellone and obacunone derivatives were tested against pre-third-instar larvae of Mythimna separata Walker. Moreover, their quantitative structure and activity relationship (QSAR) was further investigated. Based upon the above results, we would know which parts of fraxinellone, such as the B-ring and the C-8 furyl ring, are the important factors to the insecticidal activities; and which parts of obacunone, such as endocyclic double bond and seven-membered-lactone of A-ring, carbonyl group of B-ring, six-membered-lactone of D-ring, and furyl ring at the C-17 position are the important factors to the insecticidal activities. Then the suitable and important modification location of fraxinellone and obacunone will be found, and the most promising fraxinellone and obacunone derivatives will be discovered. Additionally, 3D-QSAR model of limonoids will be developed and obtained. Finally, the optimization model for limonoids bearing good insecticidal activity will be constructed, and it will pave the way for further design, structural modification, and development of fraxinellone and obacunone derivatives as insecticidal agents.

本申请拟以两个具杀虫活性的柠檬苦素类似物梣酮与黄柏酮为先导化合物，对梣酮B环及碳8位的呋喃环等官能团进行结构改造；在黄柏酮A环的环内双键及七元内酯环、B环的羰基、D环的六元内酯环、碳17位的呋喃环等官能团上进行结构改造；制备出系列梣酮及黄柏酮类衍生物，用东方粘虫为标准试虫考察其杀虫活性；同时进行三维定量构效关系的研究。从而确证梣酮碳8位呋喃环及B环大小对其杀虫活性的影响；确证黄柏酮A环的环内双键及七元内酯环、B环的羰基、D环的六元内酯环、碳17位呋喃环等官能团对其杀虫活性的影响；找到梣酮及黄柏酮分子骨架上关键的结构修饰位点；筛选出高杀虫活性的候选化合物；构建出柠檬苦素类似物具高杀虫活性的理想结构模型，为今后开发利用梣酮及黄柏酮类化合物作为天然产物农药提供理论依据。

基于梣酮、黄柏酮等柠檬苦素类化合物为先导化合物进行结构优化，找到了梣酮呋喃环上卤代反应及酰基化反应的规律，并提出了可能的卤代或多卤代反应机理；发现了梣酮呋喃环上的肟磺酸酯化反应与其在呋喃环上的取代位置密切相关；摸索出柠檬苦素C-7位羰基的还原产物比例与反应溶剂间相互关系；并找到了一条可简便顺利地分离纯化一对差向异构体的方法；建立了立体选择性地合成了系列C-7β酰氧基柠檬苦素类衍生物；证明柠檬苦素类化合物C-7位的立体空间位阻可以控制其酯化反应的立体选择性；利用Baeyer-Villiger氧化重排反应，构筑了结构新颖的B环含七元内酯环的黄柏酮及柠檬苦素类衍生物。获得了具有高杀虫、杀螨及抗TMV活性的化合物。构效关系表明：在梣酮肟片段上引入1-萘乙酰基有利杀虫活性的提高；梣酮呋喃环C2’位上醚类衍生物的杀虫活性较其5’位上的好，及引入4-硝基苯氧基或4-氯苯氧基有利于杀虫活性提高；柠檬苦素C-7位羰基还原成羟基能改善其杀虫/螨和抗TMV活性，在其C-7β位引入苯丙烯酰氧基和2-呋喃丙烯酰氧基能明显提高其杀虫/螨和抗TMV活性，及含七元内酯B环的柠檬苦素类衍生物具有较好的杀虫和抗TMV活性。同时，研究了鬼臼毒素等天然产物的结构优化及农用活性，发现了具有较好的杀虫和杀螨活性的化合物，并进一步阐明了鬼臼毒素类天然产物诱导粘虫产生残翅的可能原因。上述研究结果发表在农药学权威刊物Journal of Agricultural and Food Chemistry、重要刊物ACS Sustainable Chemistry & Engineering、 Industrial Crops and Products、 Bioorganic & Medicinal Chemistry Letters、Chinese Chemical Letters等12篇SCI论文上。上述研究结果为今后进一步结构优化梣酮等柠檬苦素类衍生物与鬼臼毒素等天然产物，以及研究其农用活性与作用机理等奠定了基础。