基于蜡梅碱的新型杀菌剂的构建及作用机理研究

Creating novel fungicides with independent intellectual property based on leading compounds is an effective way for pesticide innovation and an urgent task for the researcher and developer of the pesticide industry in China.There are little reports about the synthesis of fungicides based on the folicanthine skeleton and its structure-activity relationship. Folicanthine has significant fungicidal activites which was found during our early study. It has research and develop value to be potentially novel fungicides. The project plan to use folicanthine which was found to be an fungicidal skeleton by our group as a precursor structure to design and synthesize series of folicanthine analogues. Structures of the synthetized compounds were elucidated by various spectral data.Their fungicidal activities will be assayed by the methods of mycelial growth and spore germination and the pot experiment, structure-activity relationships will be studied by the software of Syby L7.0, Pharmacophore model will be constructed based on the study results of structure-activity relationship. New folicanthine analogues will be designed and synthetized based on the pharmacophore model and its fungicidal mechanism will be researched. Novel compounds with simpler structure and more stronger activity and good to the enviroment will be found. Three to five novel candidates compounds with significant fungical activity will be assayed and their fungicidal bioactivities and mechanism will be determinated and explored. All these will promote the progress in novel fungicides creation and plant diseases control and modern agriculture science and technology in China.

以天然产物为先导创制具有自主知识产权的新型杀菌剂是农药创新的有效途径。蜡梅碱具有显著的杀菌活性，但以蜡梅碱为杀菌剂先导结构的合成与构效关系研究未见报道。课题组前期研究显示，蜡梅碱对多种农业致病菌有强烈的抑制作用，具有作为潜在新型杀菌剂的研发价值。 本项目以蜡梅碱为先导结构，设计合成系列蜡梅碱类似物，采用波谱技术进行结构表征，采用菌丝生长速率法、孢子萌发法和盆栽试验定量测定其杀菌活性，采用Syby L7.0软件研究其构效关系，构建药效团模型，据此设计合成、筛选出3-5个高活性候选化合物，测定其杀菌活性，探讨其作用机理。期望获得结构更简单、活性更高的新化合物，并且保持天然产物环境相容性好的特性，进而创制新型杀菌剂，这对促进我国的新农药创制、农作物病害防治及提升现代农业的高科技含量均有积极的科学和实际意义。

以天然产物为先导创制具有自主知识产权的新型杀菌剂是农药创新的有效途径。蜡梅碱具有显著的杀菌活性，但以蜡梅碱为杀菌剂先导结构的合成与构效关系研究未见报道。蜡梅碱对多种农业致病菌有强烈的抑制作用，具有作为潜在新型杀菌剂的研发价值。本项目以蜡梅碱为先导结构，设计合成系列蜡梅碱类似物，采用波谱技术进行结构表征，采用菌丝生长速率法、孢子萌发法和盆栽试验定量测定其杀菌活性，采用 Syby L7.0 软件研究其构效关系，构建药效团模型，据此设计合成、筛选出 3-5 个高活性候选化合物，测定其杀菌活性，探讨其作用机理。以期获得结构更简单、活性更高的新化合物，并且保持天然产物环境相容性好的特性，进而创制新型杀菌剂，这对促进我国的新农药创制和农作物病害生物防治均有积极的科学和实际意义。. 本课题设计合成表征了209个新的目标化合物，其中206个为半蜡梅碱类似物、3个为蜡梅碱类似物，测定了合成化合物对棉花黄萎（V.dahliae）、棉花枯萎（F.oxysperium sp. vasinfectum）、核桃腐霉（Cytospora juglandis）、黄曲霉（A.sflavu）、桔青霉（P.citrinum）、尖孢镰刀菌（F. oxysporum）、黄瓜枯萎（C.orbiculare）、黑曲霉（A.niger）、灰葡萄孢（B.cinerea Pers）等10余种植物病原真菌、2种革兰氏阳性菌和3种格兰斯阴性菌等细菌、3种人体致病真菌菌的杀菌活性与乙酰胆碱酯酶抑制活性。明确了合成化合物的抑菌活性，研究了筛选出的4个较高抑菌活性化合物的抑菌机理，并对合成的化合物的构效关系进行了分析探讨，其中182个目标化合物对乙酰胆碱酯酶均有不同程度的抑制活性。建立的半腊梅碱化合物库为进一步的生物活性筛选、活性谱研究、作用机理与构效关系研究奠定了基础。. 本项目共发表SCI论文5篇，撰写专利3项，其中授权实用新型专利2项、公开实审发明专利1项。培养硕士研究生4名，本科生1名。

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