以钙离子-ATP酶为导向的天然杀螨先导东莨菪内酯结构修饰与改造

Scopoletin is a natural coumarin compound, which has a variety of biological activity. The earlier researches indicated that scopoletin also has pronounced acaricidal activity, but further researches have found that the toxicity of scopoletin was not as good as the commercial acaricides, thus it is urgent to modified the structure of scopoletin for increasing the acaricidal potency. This project will take scopoletin as lead compound and modify the structure of phenolic hydroxy group to design and synthesis the derivatives of aryl oxide, aromatic ester and 3 substituted derivatives by using molecular hybridization method. The acaricidal activity of synthesized compounds will be evaluated, and the structure-activity relationship also will be investigated to screen more desirable acaricidal active compounds as candidate compounds for further research and development. Acaricidal activity improved mechanism of modified scopoletin will be compared and validated by enzymatic and bioinformatics methods. The research findings are significant for revealing the pleiotropy of physiological activity of scopoletin, creating new acarides of independent intellectual property rights and effectively controlling of the harm been done by phytophagous mites on agriculture, and reducing the amount of pesticide in our country.

莨菪内酯是一种源于植物具有多种生物活性的天然香豆素类化合物，前期研究结果表明其对植食性螨类也表现出显著的触杀活性，但深入研究发现其杀螨效力仍不及市售优秀杀螨药剂，亟需对其结构进行修饰和改造，以期提高杀螨活性，改善生物利用度。本项目以东莨菪内酯为先导，采用分子杂交法，对其酚羟基活性部位及3位进行优化与改造，分子设计合成东莨菪内酯芳醚、芳酯及3位取代衍生物，对合成的目标化合物进行杀螨活性评价，构效关系研究，并采用酶学及生物信息学等手段比较验证东莨菪内酯结构修饰改造后杀螨活性提高的机制，筛选出更为理想的杀螨活性化合物供进一步开发研究。该项研究对于揭示东莨菪内酯生物活性的多效性，创制出拥有自主知识产权的新型高效杀螨剂，有效控制农业上植食性螨类的危害，减少我国农药使用量具有重要意义。

东莨菪内酯是一种源于植物具有多种生物活性的天然香豆素类化合物，前期研究结果表明其对植食性螨类也表现出显著的触杀活性，但深入研究发现其杀螨效力仍不及市售优秀杀螨药剂，亟需对其结构进行修饰和改造，以期提高杀螨活性，改善生物利用度。.本项目以东莨菪内酯为先导，采用分子杂交法，设计并合成了东莨菪内酯酚醚、芳酯及3位取代三个系列化合物，并分离纯化及采用IR, 1H NMR, 13C NMR, MS等进行结构鉴定；采用玻片浸渍法进行杀螨活性评价，构建了2D-QSAR模型：pLC50=log1/LC50=4.243（±0.704）-1.045（±0.218）R8e+12.920（±1.921）HATS5p +0.313（±0.062）Depressant-80-1.351（±0.385）MATS6e-1.274（±0.401）HNar（F=26.527，R2=0.875）；使用SYBYL6.9软件，构建了CoMFA和CoMSIA 3D- QSAR模型，研究得到的CoMFA模型（q2=0.802，r2=0.993），最佳主成分数n为6，立体场的贡献70.8%，静电场的贡献29.2%；研究得到的CoMSIA模型（q2=0.735，r2=0.965），最佳主成分数n为6，立体场的贡献21.5%，静电场的贡献28.5%，疏水场的贡献为44.9%，氢键受体场占5.0%，并预测了测试集化合物的活性，预测能力较好；采用I-TASSER在线服务器构建了Ca2+-ATP酶（TcPMCA1）三维模型，autodock软件对接了合成的目标化合物与Ca2+-ATP酶（TcPMCA1）的结合模式，结合生测结果，比较验证东莨菪内酯结构优化改造修饰后杀螨活性提高机制。.筛选出东莨菪内酯7甲氧基酚醚和3-乙酰氨基7异丙基酚醚的LC50分别为0.171 mg/mL和0.095 mg/mL分别比先导化合物东莨菪内酯（1.059 mg/mL）提高了6.19倍和11.15倍，比商品药剂炔螨特原药提高了1.95倍和3.52倍，可供进一步研究开发的候选化合物或者先导化合物。该项研究对于揭示东莨菪内酯生物活性的多效性，创制出拥有自主知识产权的新型高效杀螨剂，有效控制农业上植食性螨类的危害，减少我国农药使用量具有重要意义。

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