抗植物病原真菌药物：苯并（氧化）呋咱类化合物的发现与甲氧基丙烯酸酯类化合物的设计与合成

发布时间：2018-01-26 11:26

本文关键词： 抗真菌植物病原真菌苯并氧化呋咱苯并呋咱甲氧基丙烯酸酯类杀菌剂　出处：《苏州大学》2016年博士论文　论文类型：学位论文

【摘要】：植物病原真菌一直以来威胁着食物安全以及人类的健康:一方面直接造成农作物产量损失以及质量下降;另一方面,部分病原真菌在侵染农作物过程中,可分泌产生多种对人畜有害的毒素与代谢物,对农产品的安全性构成极大威胁。应用化学小分子药物一直是防治植物病原真菌的主要措施。目前几种常用的杀菌剂中除了甲氧基丙烯酸酯类杀菌剂以外,其它杀菌剂的应用时间都较久。由于作用靶点单一,已有的杀菌剂均出现耐药性现象。因此开发具有不同结构特征的化合物作为新型杀菌剂是抗植物病原真菌工作的重点之一。本文首先通过筛选得到具有很好抗植物病原真菌活性的母核苯并氧化呋咱,并合成了系列苯并(氧化)呋咱衍生物。再通过测定菌丝生长抑制率的方法评价所有化合物的体外活性,主要考察对水稻纹枯病菌、油菜菌核病菌、小麦赤霉病菌以及辣椒疫霉病菌的抑制效果。体外实验结果表明该类化合物具有很好的抗植物病原真菌效果,例如:化合物A17对油菜菌核病菌、小麦赤霉病菌和辣椒疫霉病菌的IC50值分别为0.81μg/mL、0.77μg/mL和4.88μg/mL,与阳性对照多菌灵(0.15μg/mL、0.50μg/mL)或者百菌清(4.48μg/mL)基本相当。B类化合物对水稻纹枯病菌有很好的抑制作用(其中16个化合物的IC50值为1.05-7.32μg/mL之间),且细胞毒性较小,所以该类化合物值得进一步研究成为针对水稻纹枯病菌的杀菌剂。另一类苯并呋咱化合物与苯并氧化呋咱相比之下,保留了一定的抗菌活性,尤其是化合物D10(R1取代基为对氟间氯苯胺)对四株菌都有很好的抑制效果,且细胞毒性明显低于苯并氧化呋咱系列化合物。同时,本文对部分化合物进行体内防治效果的实验研究,发现化合物A5对油菜菌核病菌有较好的防治效果,500 ppm的浓度下用药36小时后防治效果可达到46.1%。甲氧基丙烯酸酯类(Strobilurins)杀菌剂是一类抗菌谱广并且低毒的新型农用杀菌剂。该类杀菌剂作用于线粒体呼吸链复合物Ⅲ上的Qo位点,阻断细胞色素b与c1之间的电子传递,妨碍ATP的生成而干扰真菌的能量循环。本文依据药物化学中骨架跃迁原理以及生物电子等排理论,设计合成系列嘧菌酯类似物、吡唑醚菌酯类似物、唑嘧菌胺类似物以及恶唑菌酮类似物。体外抗真菌实验结果表明:将吡唑醚菌酯中的苯环桥链换成亲水性更好的吡啶环而设计合成的吡唑醚菌酯类似物具有很好的抗植物病原真菌效果,化合物56f,56k和56s都表现出很好的抗真菌活性,尤其对番茄灰霉病菌与油菜菌核病菌IC50值与阳性对照吡唑醚菌酯相当。其中化合物56s在100μM的浓度下对猪心细胞色素bc1复合物抑制效果(抑制率99.9%)优于相同浓度下的吡噻菌胺(抑制率95%),且与吡唑醚菌酯相当(抑制率99.9%)。上述苯并(氧化)呋咱衍生物可作为一类新型的抗植物病原真菌潜在的药物进行更深入的研究开发。吡唑醚菌酯类似物与细胞色素bc1复合物相互作用更深入全面的生物实验正在进行中。
[Abstract]:Plant pathogenic fungi have been threatening food safety and human health: on the one hand, a direct result of decreased crop yield losses and quality; on the other hand, some pathogenic fungi in crop infection process, can secrete toxins and metabolites of harmful to human beings and animals, poses a great threat to the safety of agricultural products. The application of chemistry small molecule drugs has been the main measures for the prevention and treatment of plant pathogenic fungi. At present, several commonly used fungicides in addition to strobilurin fungicides, application time of other fungicides are relatively long. As for a single target, fungicides have all of the emergence of drug resistance phenomenon. Therefore the development of compounds with different structural characteristics as a new type of fungicide resistance is one of the key work of plant pathogenic fungi. This paper firstly screened with good antifungal activity of the parent Nuclear benzofuroxan, and synthesized a series of benzo (oxidation) of furazan derivatives. And through determination of mycelial growth inhibition rate of in vitro activity of all compounds, the main study of Rhizoctonia solani, Sclerotinia sclerotiorum, Fusarium graminearum and Phytophthora capsici inhibition effect in vitro experiments. Show that the compound has the effect of plant pathogenic fungi resistance good example: compound A17 on Sclerotinia sclerotiorum, Fusarium graminearum and Phytophthora capsici IC50 values were 0.81 g/mL, 0.77 g/mL and 4.88 g/mL, and the positive control of carbendazim (0.15 g/mL, 0.50 g/mL) or chlorothalonil (4.48 g/mL) similar.B compounds have a good inhibitory effect on Rhizoctonia solani (of which 16 compounds are IC50 1.05-7.32 between g/mL) had low toxicity, so the compounds deserve further research into As for fungicide R.solani. Under another kind of benzene and compared furazan compounds and benzofuroxan, retains certain antibacterial activity, especially compound D10 (R1 substituent of fluorine m-chloroaniline) has good inhibition effect on four strains of bacteria, and cell toxicity was significantly lower than that of benzofuroxan compounds. At the same time, the experimental study on Control effect of some compounds in vivo, we found that compound A5 has good control effect to Sclerotinia sclerotiorum, the concentration of 500 ppm after 36 hours treatment the control effect can reach 46.1%. strobilurin fungicide (Strobilurins) is a kind of the antibacterial spectrum of new agricultural fungicide widely and low toxicity. The effect of fungicides to Qo site in the mitochondrial respiratory chain complex III, blocking electrons between cytochrome b and C1 transfer, ATP and hinder the generation of fungi can interference The amount of circulation. On the basis of medicinal chemistry skeleton transition principle and biosostere theory, design and synthesis of a series of azoxystrobin analogues, pyraclostrobin analogues of azoxystrobin amine analogues and Famoxadone analogues. The in vitro antifungal experiment results show that the benzene ring bridge chain pyraclostrobin in the pyridine ring more hydrophilic and pyraclostrobin synthetic analogues has good anti effect, plant pathogenic fungi compound 56f, 56K and 56S showed good antifungal activity, especially to Botrytis cinerea and Sclerotinia sclerotiorum IC50 was comparable with the positive control of pyrazole kresoxim. Compound 56S at a concentration of 100 M of porcine cytochrome bc1 complex inhibitory effect (inhibition rate 99.9%) pyrazole amine is better than that of thiazide bacteria at the same concentration (inhibition rate 95%), and pyraclostrobin equivalent (inhibition rate 99.9%). The benzene and oxygen ( Furozan derivatives can be further researched and developed as a new potential drug against plant pathogenic fungi. A more thorough and comprehensive biological experiment is being carried out for the interaction of pyrazole ether ester analogues with cytochrome bc1 complex.

【学位授予单位】：苏州大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：S482.2

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