【作者】 孔新刚；

【导师】 李华；

【作者基本信息】 新疆农业大学 ， 动物营养与饲料学， 2008， 硕士

【摘要】 本论文根据1,4-二氧喹喔啉类化合物具有毒副作用小及多种生物活性的特点,合成出了三种新的1,4-二氧喹喔啉衍生物,通过元素分析、MS、IR、1H NMR对其结构进行了表征。采用滤纸片抑菌圈试验法、最小抑菌浓度法对合成的新化合物进行了抑菌活性试验,初步研究了三种新化合物的抑菌活性。并根据生物大分子与药物小分子相互作用的位点模型,采用光谱技术研究了三种新化合物与牛血清白蛋白(BSA)的相互作用机制。以邻硝基苯胺为起始原料,经过次氯酸钠氧化反应、贝鲁特(Beirut)反应、二氧化硒(SeO2)氧化反应、缩合反应四步,得到目标1,4-二氧化喹喔啉衍生物(CⅠ～CⅢ)。第三步反应在前人的基础上加以改进,以1,4-二氧六环为溶剂,一次性加入所需量的二氧化硒,在100℃油浴中氧化反应5h,反应中间体2-甲酰基-3-乙氧羰基-1,4-二氧喹喔啉不必分离,直接用于第四步反应,总产率可达76%。抑菌实验表明,CⅠ～CⅢ对六种供试细菌(大肠杆菌、枯草杆菌、金黄色葡萄球菌、巨大芽孢杆菌、八叠球菌、苏云金杆菌)都均有明显抑菌活性,而对三种供试真菌(青霉菌、根霉菌、黑曲霉菌)没有抑菌作用;CⅠ对大肠杆菌和巨大芽孢杆菌的MIC分别达到20μg·mL-1、l5μg·mL-1;CⅡ对大肠杆菌和金黄色葡萄球菌的MIC分别达到10μg·mL-1、15μg·mL-1;CⅢ对大肠杆菌和苏云金杆菌的MIC达到15μg·mL-1、20μg·mL-1。采用荧光光谱和紫外光谱研究了牛血清白蛋白(BSA)与新合成的化合物(CⅠ～CⅢ)分子之间的结合作用机制。以荧光猝灭法测定了该反应的结合常数K,结合位点数n;并依据F?rster非辐射能量转移机制,得到CⅠ～CⅢ和BSA的色氨酸残基之间结合距离r和能量转移效率E;并用同步荧光技术考察了CⅠ～CⅢ对BSA构象的影响,BSA与CⅠ～CⅢ分子之间都有较强的疏水作用力,而且CⅠ～CⅢ对BSA的构象都有一定影响。由此可以推得三种新化合物进入动物体内后都可以通过血浆贮存与运输到达受体部位,进而发生药效作用。更多还原

【Abstract】 According to little adverse reaction and more bioactivity of the derivatives of quinoxaline-1,4-dioxide, the thesis has synthesized three new derivatives of quinoxaline-1,4-dioxide, and had been characterized by means of elemental analyses, MS, IR and 1H NMR. The antibacterial activity experiment of CⅠ～CⅢwas carried by disk diffusion method and minimum inhibitory concentration(MIC) method to study the antibacterial activity. And the interaction between CⅠ～CⅢand bovine serum albumin (BSA) was studied by means of spectra on the basis of the binding site of biology big molecule and medicine small molecule interaction.Use o-nitroaniline as raw material, and aquire the target derivatives of quinoxaline-1,4-dioxide (CⅠ～CⅢ) though NaClO oxidizing reaction, Beirut reaction, SeO2 oxidizing reaction and condensation reaction. We improved SeO2 oxidizing reaction on the basis of predecessor , which use 1,4-dioxane as resolution, add required amount of SeO2 at one time, took 5 hours in the 100℃oil bath. And the intermediate product (2-ethylformate-3-formaldehyde quinoxaline-1,4-dioxide) was not necessary to been purified, was directly made use of condensation reaction, total yield was 76%.The antibacterial results showed that CⅠ～CⅢhad strong inhibitory activity against six trialed bacteria (i.e. Escherichia coli、Bacillus subtilis、Staphlococcus aureus、Bacillus megaterium、Sporosarcina urea、Bacillus thuringiensis), but no inhibitory activity against fungi(Penicillium、Phizopussp、Aspergillus niger) was observed. MIC of CⅠto Escherichia coli is 20μg·mL-1 and to Bacillus megaterium is l5μg·mL-1; MIC of CⅡto Escherichia coli is 10μg·mL-1 and to Staphlococcus aureus is l5μg·mL-1; MIC of CⅢto Escherichia coli is 15μg·mL-1 and to Bacillus thuringiensis is 20μg·mL-1.The interaction between Quinoxaline-1,4-dioxide(CⅠ～CⅢ) and bovine serum albumin (BSA) was studied by fluorescence spectra and ultraviolet spectra. The binding constant K and the binding sites n were found by fluorescence quenching method. The binding distance r and energy-transfer efficiency E between CⅠ～CⅢand BSA were also obtained according to the Forster-type dipole-dipole non-radiative energy-transfer mechanism. The effect of CⅠ～CⅢon the conformation of BSA was also analyzed by using synchronous fluorescence spectroscopy. In additional, the impact of CⅠ～CⅢon conformation of BSA was examined by synchronized spectrum, the hydrophobic interaction between CⅠ～CⅢand BSA is strong, and CⅠ～CⅢcan effect the conformation of BSA in some degree. According to it, we will obtain that CⅠ～CⅢmay reach to recipient and take an action by storing and carrying of blood plasm.更多还原