5-硝基亚氨基[1,4-2H]-1,2,4-三唑啉烯式吡虫啉类似物的合成及生物活性研究

Synthesis and Bioactivities of 5-Nitroimino-[1,4-2H]-1,2,4-triazolines as Olefin-Imidacloprid Mimics

烯式吡虫啉是吡虫啉的高活性代谢产物.为解决烯式吡虫啉的高蜂毒问题,根据生物电子等排原理,合成了一系列烯式吡虫啉的类似物1,3-二取代-5-硝基亚氨基三唑啉化合物,研究了该系列化合物对蚜虫、褐飞虱和西花蓟马的杀虫活性和离体杀菌活性.结果表明,这些化合物在400μg/mL浓度下表现出一定的杀虫活性,其中化合物Ⅱ-7在100μg/mL浓度对西花蓟马的致死率达100%.用admetSAR预测了部分化合物对蜜蜂的毒性,结果均表现为低毒.目标化合物在50μg/mL浓度下对9种植物病原真菌均表现出不同程度的抑菌活性,其中化合物I-15对5种病原菌的抑菌率高于或等同于对照药恶霉灵.构效关系分析发现,3-位脂肪烃基取代的化合物的杀虫活性高于芳香烃取代,提高3号位取代基的亲脂性也可明显提高化合物的抑菌活性,1-位吡啶环和噻唑环的取代对化合物抑菌活性没有影响.与乙酰胆碱结合蛋白(Ach BP)的分子对接结果表明,化合物Ⅱ-7与吡虫啉(IMI)的结合模式相似,说明该类化合物也具有与AChBP结合的潜力,为进一步分子优化提供了新的借鉴.

Olefin-imidacloprid is a highly active metabolite of imidacloprid.To solve the problem of high bee toxicity of olefin-imidacloprid,according to the bioisosterism,a series of novel olefin-imidacloprid mimics containing 1,3-disubstituted-1,2,4-triazoline were designed and synthesized.The insecticidal activity of these compounds against A.craccivora,Nilaparvata lugens and F.occidentalis and in vitro antifungal activity were determined.The results showed that these compounds showed certain insecticidal activity at 400μg/mL and 100%lethal rate was obtained from compoundⅡ-7 at 100μg/mL against F.occidentalis.The toxicity of some compounds to bees was predicted by admetSAR,and they showed low level of toxicity.On the other hand,the target compounds showed different degrees of antifungal activity against 9 plant pathogenic fungi at the concentration of 50μg/mL.Compound I-15 exhibited the highest activity with the inhibition rate higher or equal to hymexazol against five pathogens.The structure-activity relationship analysis showed that the compounds bearing alkyl substituent at site 3 in triazoline unit displayed higher insecticidal activity than that of an aryl substitution,meanwhile,the more lipophilic groups,the higher fungicidal activity.The substitution of pyridine ring or thiazole ring at site 1 in triazoline unit had little effect on their antifungal activity.The molecular docking results showed that the binding pattern of compoundⅡ-7 to acetylchol ine binding protein(AChBP)was similar to that of imidacloprid(IMI),indicating that these compounds also had the potential to bind to AChBP,which provided a new reference for further molecular optimization.