【摘要】：在課題組前期工作基礎(chǔ)上,結(jié)合相關(guān)文獻(xiàn)報(bào)道,設(shè)計(jì)合成了一系列環(huán)丙沙星C-3wei羧基的雜環(huán)取代物。通過其與超聲共同下抑菌效果研究,考察產(chǎn)物的聲敏性,期望通過本課題的研究對(duì)于化合物聲敏性與其結(jié)構(gòu)間關(guān)系進(jìn)行初步探討。首先,本文采用了混合酸酐法成功合成了三種環(huán)丙沙星目標(biāo)化合物,1-環(huán)丙基-6-氟-1,4-二氫-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-環(huán)丙基-6-氟-1,4-二氫-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-環(huán)丙基-6-氟-1,4-二氫-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,采用胞外檢測(cè)手段,對(duì)3種目標(biāo)化合物在超聲條件下活性氧(ROS)的產(chǎn)量和種類進(jìn)行檢測(cè)。同時(shí),探討了目標(biāo)化合物濃度對(duì)超聲溶液體系中產(chǎn)生活性氧(ROS)產(chǎn)量影響以及ROS種類。結(jié)果顯示,目標(biāo)化合物在超聲體系中產(chǎn)生的ROS數(shù)量遠(yuǎn)高于單獨(dú)產(chǎn)生ROS的數(shù)量。即C1、C2和C3均具有聲敏性。此外,隨著目標(biāo)化合物濃度增大,超聲溶液體系中產(chǎn)生ROS的能力逐漸增強(qiáng)。其中,C3產(chǎn)生ROS的能力最強(qiáng)。對(duì)于產(chǎn)生ROS種類的檢測(cè)中可以看出,C1產(chǎn)生的ROS為羥自由基為主不排除其他類型活性氧,C2產(chǎn)生的ROS為羥自由基和其他類型活性氧而C3產(chǎn)生的ROS中既有單線態(tài)氧也有羥自由基。最后,為了進(jìn)一步驗(yàn)證目標(biāo)化合物的聲敏性,選取了金黃色葡萄球菌和大腸桿菌為研究對(duì)象,抑菌率為考察指標(biāo),從細(xì)胞水平上進(jìn)一步考察3種目標(biāo)化合物的聲敏性與結(jié)構(gòu)間的關(guān)系。同時(shí),為了探究各因素對(duì)目標(biāo)化合物與超聲共同抑菌效果的影響,分別改變藥物加入順序、超聲時(shí)間、藥物濃度、超聲溶液介質(zhì)以及超聲溫度等實(shí)驗(yàn)條件。結(jié)果顯示:目標(biāo)化合物具有聲敏性,與超聲共同作用下對(duì)細(xì)菌體現(xiàn)出了協(xié)同抑菌作用。且隨著超聲照射時(shí)間和目標(biāo)化合物濃度的增加,抑菌率逐漸增加。但超聲介質(zhì)與超聲溫度對(duì)抑菌率的影響比較復(fù)雜。綜上所述,本實(shí)驗(yàn)設(shè)計(jì)合成的三個(gè)目標(biāo)化合物均具有較強(qiáng)的聲敏活性,且對(duì)于大腸桿菌的超聲協(xié)同抑菌效果要優(yōu)于對(duì)金黃色葡萄球菌。其中,C3的聲敏性要明顯強(qiáng)于C1和C2,這可能是由于C3的分子活潑性大于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.
【學(xué)位授予單位】：遼寧大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R914;R96

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