【作者】 邓杉；

【导师】 高锦明； 陈新；

【作者基本信息】 西北农林科技大学 ， 化学生物学， 2017， 硕士

【摘要】 对具有生物活性的天然产物进行修饰改造是新药创制的重要方法。吲哚二酮哌嗪类化合物在自然界分布广泛,尤其作为微生物的次生代谢产物存在,由于其同时含有吲哚和二酮哌嗪两个药效基团,所以具有多种多样的生物活性。bervianamide F是一个吲哚二酮哌嗪类化合物,来源于烟曲霉的次生代谢产物,是多种具有良好生物活性天然产物的生物合成前体,本课题组在前期研究中发现该化合物具有良好的化感活性,有开发成为绿色除草剂的潜能。本研究以bervianamide F为先导化合物,利用计算机药物辅助设计技术,对bervianamide F进行针对性的改造,合成了20个化合物,包括先导化合物bervianamide F,5-Br-bervianamide F以及18个bervianamide F二酮哌嗪环上五元吡咯环被取代的衍生物。所有化合物通过GC-MS,¹HNMR,¹³CNMR等波谱学方法鉴定了结构,通过检索,确认合成的衍生物都是新化合物。在合成过程中通过探索,优化了一条简洁有效的合成路线,一锅法得到了目标化合物,大大缩短了反应步骤,节约了反应时间。对所测定化合物进行了TIR1抑制活性测试,抗植物病原菌活性评价和化感活性测试,活性测试结果表明,所合成的化合物不具备生长素抑制活性,不能抑制TIR1;化合物对植物病原菌的抑制作用也有限,在50μΜ浓度下,只有bervianamide F对马铃薯干腐病菌表现出一定的抑制作用,抑制率为63.41%。2.1b对马铃薯干腐病菌和苹果炭疽病菌有微弱的有抑制作用,抑制率分别为62.57%,51.31%。2.3h对番茄灰霉病菌有轻微的抑制作用,抑制率为49.34%;化感活性测试结果表明所有的化合物对稗草的根均有不同程度的抑制作用,有继续研究的潜力,其中化合物2.2e,2.3a均能抑制莴苣和稗草的生长,对莴苣和稗草根和茎的化感效应指数（RI）与阳性对照草甘膦相近。综上所述,我们通过计算机药物辅助设计技术,设计合成了一批吲哚二酮哌嗪化合物bervianamide F的衍生物,合成过程中探索优化了一条简洁的合成路线,并测定了所合成化合物的生物活性,发现了两个具有良好化感抑制活性的化合物。这为吲哚二酮哌嗪类化合物的衍生合成提供了新的方法和思路,为开发新型除草剂提供了支持。更多还原

【Abstract】 The modification of natural bioactive products has been an important way of drug discovery.Indole diketopiperazine derivatives are widely distributed in nature,especially as the secondary metabolites of microorganisms.It has a wide variety of biological activity for possessing both indole and diketopiperazine pharmcophore.Bervianamide F,an indole diketopiperazine compound from the secondary metabolites of aspergillus,as biosynthesis precursor microbes in a variety of good bioactive natural products.In previous studies,we found that the compound has potent allelopathic activity,so futher research will be carried out.By the technology of computer-aided drug design,Twenty target compounds were synthesized including lead compounds bervianamide F,5-Br-bervianamide F and eighteen bervianamide F derivatives whose pyrrole ring are replaced.All novel synthetic compounds are verified by GC-MS,¹HNMR,¹³CNMR spectroscopy methods.A concise and effective synthetic route was exploited.by a pot method to get the target compounds which greatly shortens the reaction steps and the reaction time.All the compounds were tested against TIR1,anti-phytopathogenic fungi and allelopathic activity.The results showed that the compounds do not have TIR1inihibiton;At 50μM concentration,bervianamide F exhibited Farium sulphureum inhibition activity with a inhibition rate of 63.41%.2.1 b exhibited Farium sulphureumand and Colletotrichum gloeosporiodes inhibition with a inhibition rate of62.57%,51.31%.The inhibition rate of 2.3 h against Farium sulphureum was 49.34%;Allelopathic activity test results showed that all compounds exhibitweed roots inhibition.The compound 2.2e,2.3a can inhibit the growth of lettuce and weed,have an stem index（RI）comparable with positive control of glyphosate.Above all,we use the technology of computer-aided drug design to synthesize a serious of indole diketopiperazine derivatives,and explore a concise synthetic routeThebiological assay indicated two compounds has good allelopathic activity which have the potential to become a novel potent herbicides.更多还原