本文關鍵詞： 噻唑酰胺 合成 硝唑尼特 查爾酮 最小抑菌濃度　出處：《中國農(nóng)業(yè)科學院》2015年碩士論文　論文類型：學位論文

【摘要】：寄生蟲作為一類非常重要的病原,侵害著人類和動物的健康,給人類和畜牧養(yǎng)殖業(yè)帶來了嚴重的損失,然而目前市場上使用的寄生蟲藥物品種少、毒副作用大、部分藥物耐藥性嚴重等問題,不能滿足人類和畜牧養(yǎng)殖業(yè)的需求。開發(fā)高效、低毒的抗寄生蟲藥物是當前獸藥開發(fā)工作者的追求目標。硝唑尼特是一種新型廣譜抗寄生蟲藥物,對寄生蟲、細菌、病毒等顯示出較高的生物活性。有研究表明,硝基噻唑環(huán)是其發(fā)揮藥效的重要基團。查爾酮類化合物是植物中一類廣泛存在的天然產(chǎn)物,具有豐富的生物活性,部分查爾酮類化合物抗寄生蟲的作用顯著。根據(jù)藥效基團的拼接原理,我們設計合成了兩類化合物——雙酰胺類化合物和查爾酮噻唑酰胺類化合物。由于厭氧細菌和厭氧寄生蟲都具有能量代謝的關鍵酶——丙酮酸:鐵氧化還原蛋白酶(PFOR),硝唑尼特的作用機制與抑制PFOR的活性有關。通過考察化合物的體外抑菌活性,以期篩選出高效抑制厭氧菌艱難梭菌的化合物,為后續(xù)抗寄生蟲活性的研究奠定基礎。1、雙酰胺類化合物的合成。以二乙醇胺為起始原料,與不同取代位置的溴(氯)甲基吡啶反應生成N-吡啶甲基二乙醇胺;芳香胺與氯乙酰氯發(fā)生酯化反應生成不同的氯乙酸芳香酰胺。N-吡啶甲基二乙醇胺與不同的酰胺反應得到最終的雙酰胺化合物6a-c、7a-c、8a-c。合成的化合物的結(jié)構(gòu)通過高分辨質(zhì)譜、1H-NMR、13C-NMR進行了確證。2、查爾酮噻唑酰胺類化合物的合成。苯環(huán)不同位置取代基的苯甲醛與4-乙酰基苯甲酸發(fā)生羥醛縮合反應生成相應的取代苯基丙烯�；郊姿徕c鹽A1-A12,然后與2-氨基-5-硝基噻唑在1-羥基苯并三唑(HOBt)、1-乙基-(3-二甲基氨基丙基)碳酰二亞胺鹽酸鹽(EDCI)、N,N-二異丙基乙胺(DIPEA)的作用下發(fā)生縮合反應,生成相應的查爾酮噻唑酰胺類化合物B1-B12。合成的化合物的結(jié)構(gòu)通過高分辨質(zhì)譜、1H-NMR進行了確認。3、化合物的體外抑菌活性評價。用瓊脂稀釋法測定了化合物6a-c、7a-c、8a-c、A1-A12、B1-B12對厭氧菌艱難梭菌和產(chǎn)氣莢膜梭菌的最小抑菌濃度。用微量肉湯稀釋法測定了化合物6a-c、7a-c、8a-c、A1-A12、B1-B12對豬大腸桿菌以及金黃色葡萄球菌的最小抑菌濃度。實驗結(jié)果顯示:大部分雙酰胺類化合物對于四種細菌的抑菌活性均較差,MIC值大于64μg/mL;部分A1~A12、B1-B12對艱難梭菌、產(chǎn)氣莢膜梭菌有一定的抑制作用,其中化合物B10和B11對艱難梭菌MIC值分別為2μg/mL和1μg/mL,與對照藥物硝唑尼特、甲硝唑相當;除了A9和A12外,其余查爾酮噻唑酰胺類化合物對大腸桿菌、金黃色葡萄球菌無明顯抑制作用。
[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.
【學位授予單位】：中國農(nóng)業(yè)科學院
【學位級別】：碩士
【學位授予年份】：2015
【分類號】：S859.795

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