新型喹诺酮类化合物的合成及其协同超声抑菌活性研究

发布时间：2018-10-19 20:39

【摘要】：在课题组前期工作基础上,结合相关文献报道,设计合成了一系列环丙沙星C-3wei羧基的杂环取代物。通过其与超声共同下抑菌效果研究,考察产物的声敏性,期望通过本课题的研究对于化合物声敏性与其结构间关系进行初步探讨。首先,本文采用了混合酸酐法成功合成了三种环丙沙星目标化合物,1-环丙基-6-氟-1,4-二氢-4-氧代-7-[1-(4-乙氧羰基)哌嗪基]喹啉-3-[N-(2-吡啶)]甲酰胺(C1),1-环丙基-6-氟-1,4-二氢-4-氧代-7-[1-(4-乙氧羰基)哌嗪基]喹啉-3-[N-(6-氯-2-吡啶)]甲酰胺(C2),1-环丙基-6-氟-1,4-二氢-4-氧代-7-[1-(4-乙氧羰基)哌嗪基]喹啉-3-[N-(5-甲基-2-噻唑)]甲酰胺(C3)。其次,采用胞外检测手段,对3种目标化合物在超声条件下活性氧(ROS)的产量和种类进行检测。同时,探讨了目标化合物浓度对超声溶液体系中产生活性氧(ROS)产量影响以及ROS种类。结果显示,目标化合物在超声体系中产生的ROS数量远高于单独产生ROS的数量。即C1、C2和C3均具有声敏性。此外,随着目标化合物浓度增大,超声溶液体系中产生ROS的能力逐渐增强。其中,C3产生ROS的能力最强。对于产生ROS种类的检测中可以看出,C1产生的ROS为羟自由基为主不排除其他类型活性氧,C2产生的ROS为羟自由基和其他类型活性氧而C3产生的ROS中既有单线态氧也有羟自由基。最后,为了进一步验证目标化合物的声敏性,选取了金黄色葡萄球菌和大肠杆菌为研究对象,抑菌率为考察指标,从细胞水平上进一步考察3种目标化合物的声敏性与结构间的关系。同时,为了探究各因素对目标化合物与超声共同抑菌效果的影响,分别改变药物加入顺序、超声时间、药物浓度、超声溶液介质以及超声温度等实验条件。结果显示:目标化合物具有声敏性,与超声共同作用下对细菌体现出了协同抑菌作用。且随着超声照射时间和目标化合物浓度的增加,抑菌率逐渐增加。但超声介质与超声温度对抑菌率的影响比较复杂。综上所述,本实验设计合成的三个目标化合物均具有较强的声敏活性,且对于大肠杆菌的超声协同抑菌效果要优于对金黄色葡萄球菌。其中,C3的声敏性要明显强于C1和C2,这可能是由于C3的分子活泼性大于C1和C2所致。
[Abstract]:A series of heterocyclic substituents of ciprofloxacin C-3wei carboxyl group were designed and synthesized on the basis of previous work and related literature reports. Through the study of the bacteriostatic effect of the compound with ultrasound, the sound sensitivity of the product was investigated, and the relationship between the sound sensitivity and the structure of the compound was expected to be preliminarily discussed through the study of this subject. First Three ciprofloxacin target compounds, 1-cyclopropyl-6-fluoro-4-dihydro-4-oxo-7- [1- (4-ethoxycarbonyl) piperazinyl] quinoline-3- [N- (2-pyridine)] formamide (C1), 1-cyclopropyl-6fluoro-4H-4oxo-7- [1- (4- (4-) ethoxycarbonyl) piperazine] formamide (C1), 1-cyclopropyl-6-fluoro-1H-4H-7- [1- (4- (4-) -ethoxycarbonyl)] formamide (C1) were successfully synthesized by mixed anhydride method. Ethoxycarbonyl) piperazinyl] quinoline-3- [N- (6-chloro-2-pyridine)] formamide (C2), 1-cyclopropyl-6-fluoro-4-dihydro-4-oxo-7- [1- (4-ethoxycarbonyl) piperazine] -3- [N- (5-methyl-2-thiazole)] formamide (C3). Secondly, the production and species of reactive oxygen species (ROS) of three target compounds under ultrasonic conditions were detected by extracellular detection. At the same time, the effect of the concentration of target compounds on the production of reactive oxygen species (ROS) in ultrasonic solution system and the types of ROS were discussed. The results show that the amount of ROS produced by the target compound in ultrasonic system is much higher than that produced by ROS alone. C _ 1 C _ 2 and C _ 3 have sound sensitivity. In addition, the ability to produce ROS in ultrasonic solutions increases with the increase of the concentration of the target compounds. Among them, C3 has the strongest ability to produce ROS. It can be seen that the ROS produced by C1 is hydroxyl radical, while ROS produced by C2 is hydroxyl radical and other active oxygen species, while ROS produced by C3 has both hydroxyl radical and hydroxyl radical. Finally, in order to further verify the sound sensitivity of the target compounds, Staphylococcus aureus and Escherichia coli were selected as the research objects, and the bacteriostasis rate was used as the index. The relationship between the sound sensitivity and the structure of the three target compounds was further investigated at the cellular level. At the same time, in order to explore the influence of various factors on the bacteriostatic effect of the target compound and ultrasound, the experimental conditions such as drug addition order, ultrasonic time, drug concentration, ultrasonic solution medium and ultrasonic temperature were changed respectively. The results showed that the target compound had sound sensitivity and synergistic bacteriostatic effect on bacteria under the action of ultrasound. With the increase of ultrasound irradiation time and the concentration of the target compound, the bacteriostasis rate increased gradually. But the influence of ultrasonic medium and ultrasonic temperature on bacteriostatic rate is complex. To sum up, the three target compounds designed and synthesized in this experiment all have strong acoustic-sensitive activity, and the synergistic bacteriostatic effect on Escherichia coli is better than that on Staphylococcus aureus. The sound sensitivity of C3 is obviously stronger than that of C1 and C2, which may be due to the fact that C3 is more active than C1 and C2.
【学位授予单位】：辽宁大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96

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