新型吡唑-喹唑啉二酮类对羟基苯丙酮酸双加氧酶抑制剂的设计、合成及生物活性

Design,synthesis and biological activity of novel pyrazole-quinazoline-2,4-diones as 4-hydroxyphenylpyruvate dioxygenase inhibitors

对羟基苯丙酮酸双加氧酶(HPPD)抑制剂近年来因其高活性和低抗性风险成为了除草剂领域的研究热点。喹唑啉二酮被证明是一类具有潜力的骨架结构,为了继续发挥该骨架的优势,在前期工作的基础上,结合已有的构效关系研究结果,设计并合成了30个新型含喹唑啉二酮结构的吡唑类HPPD抑制剂,其结构均经过了高分辨质谱(HRMS)、核磁共振氢谱(^(1)H NMR)和碳谱(^(13)C NMR)的表征。酶水平和活体活性测试结果表明,大部分目标化合物展现出了与对照药剂喹草酮相当甚至更优异的酶抑制活性。温室除草活性测试结果表明,目标化合物对6种供试杂草均有一定的生长抑制作用,特别是化合物9-28,在有效成分150 g/hm^(2)剂量下,对6种杂草的防治效果均在80%以上,其中对稗草和马唐的防治效果达100%。最后,培养了代表性化合物9-28与拟南芥HPPD的复合物晶体结构,从分子层面说明了该类抑制剂与靶标的结合模式,也为后续该类抑制剂的开发提供了一定的分子基础和设计思路。

In recent years,inhibitors targeting 4-hydroxyphenylpyruvate dioxygenase(HPPD)have become the hot research in the field of herbicide due to their high activity and low risk of resistance.Quinazoline-2,4-dione has been proved to be a potent scaffold.To further exploit its advantage,30 novel pyrazole-quinazoline-2,4-dione derivatives were designed and synthesized based on the previous work and existing structure-activity relationship,all the structure of which were determined by HRMS,^(1)H NMR and ^(13)C NMR.Furthermore,the in vitro and in vivo activity of the synthesized compounds were evaluated.The result indicated that most of the synthesized compounds exhibited comparable or even better enzyme inhibitory activity than that of the positive control benquitrione.The greenhouse herbicidal activity experiments revealed that the tested compounds showed growth inhibition against the six tested weeds,especially for compound 9-28,which achieved more than 80%inhibition against the six species of target weeds at the dosage of 150 g/hm^(2) and 100%inhibition against Echinochloa crus-galli and Digitaria sanguinalis.Furthermore,the AtHPPD-9-28 complex was obtained,which explained the binding mode between the inhibitor and target enzyme,and brought a novel thought to facilitate a detailed understanding for the discovery of new HPPD inhibitors with improved performance.