新型噻唑酰胺类化合物的合成及体外抑菌活性研究

发布时间：2018-01-26 09:23

本文关键词： 噻唑酰胺合成硝唑尼特查尔酮最小抑菌浓度　出处：《中国农业科学院》2015年硕士论文　论文类型：学位论文

【摘要】：寄生虫作为一类非常重要的病原,侵害着人类和动物的健康,给人类和畜牧养殖业带来了严重的损失,然而目前市场上使用的寄生虫药物品种少、毒副作用大、部分药物耐药性严重等问题,不能满足人类和畜牧养殖业的需求。开发高效、低毒的抗寄生虫药物是当前兽药开发工作者的追求目标。硝唑尼特是一种新型广谱抗寄生虫药物,对寄生虫、细菌、病毒等显示出较高的生物活性。有研究表明,硝基噻唑环是其发挥药效的重要基团。查尔酮类化合物是植物中一类广泛存在的天然产物,具有丰富的生物活性,部分查尔酮类化合物抗寄生虫的作用显著。根据药效基团的拼接原理,我们设计合成了两类化合物——双酰胺类化合物和查尔酮噻唑酰胺类化合物。由于厌氧细菌和厌氧寄生虫都具有能量代谢的关键酶——丙酮酸:铁氧化还原蛋白酶(PFOR),硝唑尼特的作用机制与抑制PFOR的活性有关。通过考察化合物的体外抑菌活性,以期筛选出高效抑制厌氧菌艰难梭菌的化合物,为后续抗寄生虫活性的研究奠定基础。1、双酰胺类化合物的合成。以二乙醇胺为起始原料,与不同取代位置的溴(氯)甲基吡啶反应生成N-吡啶甲基二乙醇胺;芳香胺与氯乙酰氯发生酯化反应生成不同的氯乙酸芳香酰胺。N-吡啶甲基二乙醇胺与不同的酰胺反应得到最终的双酰胺化合物6a-c、7a-c、8a-c。合成的化合物的结构通过高分辨质谱、1H-NMR、13C-NMR进行了确证。2、查尔酮噻唑酰胺类化合物的合成。苯环不同位置取代基的苯甲醛与4-乙酰基苯甲酸发生羟醛缩合反应生成相应的取代苯基丙烯酰基苯甲酸钠盐A1-A12,然后与2-氨基-5-硝基噻唑在1-羟基苯并三唑(HOBt)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)、N,N-二异丙基乙胺(DIPEA)的作用下发生缩合反应,生成相应的查尔酮噻唑酰胺类化合物B1-B12。合成的化合物的结构通过高分辨质谱、1H-NMR进行了确认。3、化合物的体外抑菌活性评价。用琼脂稀释法测定了化合物6a-c、7a-c、8a-c、A1-A12、B1-B12对厌氧菌艰难梭菌和产气荚膜梭菌的最小抑菌浓度。用微量肉汤稀释法测定了化合物6a-c、7a-c、8a-c、A1-A12、B1-B12对猪大肠杆菌以及金黄色葡萄球菌的最小抑菌浓度。实验结果显示:大部分双酰胺类化合物对于四种细菌的抑菌活性均较差,MIC值大于64μg/mL;部分A1~A12、B1-B12对艰难梭菌、产气荚膜梭菌有一定的抑制作用,其中化合物B10和B11对艰难梭菌MIC值分别为2μg/mL和1μg/mL,与对照药物硝唑尼特、甲硝唑相当;除了A9和A12外,其余查尔酮噻唑酰胺类化合物对大肠杆菌、金黄色葡萄球菌无明显抑制作用。
[Abstract]:Parasites as a very important pathogen, affecting the health of human beings and animals, to the human and livestock breeding industry has brought serious losses, but at present, there are fewer kinds of parasitic drugs used in the market, and the side effects are large. Some drug resistance and other serious problems, can not meet the needs of human beings and livestock breeding industry, the development of high efficiency. Low-toxicity antiparasitic drugs are the goal of current veterinary drug developers. Nizonide is a new broad-spectrum antiparasitic drug for parasites and bacteria. Some studies have shown that nitrothiazole ring is an important group to play its drug effect. Chalcone compounds are a kind of widespread natural products in plants and have rich biological activity. Some of the chalcone compounds have remarkable antiparasitic effects. According to the splicing principle of pharmacodynamic groups. We have designed and synthesized two kinds of compounds, diamides and chalcone thiazolamide, because both anaerobic bacteria and anaerobic parasites have the key enzyme of energy metabolism-pyruvate:. Iron Redox Protease (. PFOR. The mechanism of niazonide action is related to the inhibition of PFOR activity. By studying the antibacterial activity of the compounds in vitro, the aim of this study was to screen out the compounds that could inhibit the anaerobes of Clostridium difficult. To lay a foundation for the further study of antiparasitic activity. 1. Synthesis of diamides. Diethanolamine was used as the starting material. N-pyridine methyl diethanolamine was synthesized by reaction with bromine (chloromethyl) pyridine at different sites. Aromatic amines reacted with chloroacetyl chloride to form different chloroacetic acid aromatic amides. N-pyridine diethanolamine reacted with different amides to obtain the final dicamides 6a-cf7a-c. The structure of the synthesized compounds was confirmed by high resolution mass spectrometry (HRMS) 1H-NMR-13C-NMR. Synthesis of chalcone thiazolamide compounds. Benzaldehyde with different substituents of benzene ring reacted with 4-acetylbenzoic acid to form corresponding substituted phenyl acryloyl benzoate A _ 1-A _ 12. Then with 2-amino-5-nitrothiazole in 1-hydroxybenzo triazolium (HOBtl) 1-ethyl-3-dimethyl-aminopropyl) carbodiimide hydrochloric acid salt EDCIZN. The condensation reaction of N-diisopropylethylamine (DIPEAA) was carried out to form the corresponding Chalcone thiazolamide compounds B1-B12.The structure of the synthesized compounds was obtained by high resolution mass spectrometry. The antibacterial activity of the compounds was evaluated by 1H-NMR in vitro. Agar dilution method was used to determine the antibacterial activity of the compounds 6a-cf7a-cf8a-cfA1-A12. The minimal inhibitory concentration of B1-B12 on Clostridium diffracta and Clostridium perfringens was determined by broth dilution method. The minimal inhibitory concentration of B1-B12 on Escherichia coli and Staphylococcus aureus. The results showed that most of the diamides had poor bacteriostatic activity against four kinds of bacteria. MIC > 64 渭 g / mL; Some of A1A12 B1-B12 had some inhibitory effects on Clostridium diffractatus and Clostridium perfringens. The MIC values of compound B10 and B11 were 2 渭 g / mL and 1 渭 g / mL, respectively, which were similar to those of the control drugs, niazonide and metronidazole. Except for A9 and A12, the other charketothiazolamide compounds had no inhibitory effect on Escherichia coli and Staphylococcus aureus.
【学位授予单位】：中国农业科学院
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：S859.795

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