喹諾酮是一類重要的以DNA回旋酶和拓?fù)洚悩?gòu)酶為靶點(diǎn)的合成類抗菌藥物。其強(qiáng)的抗菌能力、廣的抗菌譜、不良反應(yīng)小以及藥代動(dòng)力學(xué)性質(zhì)好等優(yōu)點(diǎn)吸引著眾多的科學(xué)工作者致力于喹諾酮結(jié)構(gòu)藥物的研發(fā),相繼開發(fā)出四代喹諾酮抗菌藥物并廣泛應(yīng)用于臨床,在治療呼吸道感染、前列腺炎、慢性支氣管炎以及泌尿系統(tǒng)感染等細(xì)菌性感染疾病發(fā)揮著重要作用,是迄今為止最重要的合成類抗感染藥物。大量文獻(xiàn)和臨床結(jié)果表明基于喹諾酮結(jié)構(gòu)的修飾是研發(fā)新型、高效、抗耐藥性強(qiáng)抗菌藥的高效途徑之一。此外,唑類化合物如三唑、咪唑、噻唑等含氮芳雜環(huán)以其獨(dú)特的結(jié)構(gòu)易與生物體內(nèi)多種酶和受體等作用靶點(diǎn)發(fā)生相互作用,在藥物開發(fā)中發(fā)揮著重要的作用,相關(guān)工作眾多,且已取得豐碩的研究成果。然而,隨著近些年來抗生素、喹諾酮類抗感染藥物在臨床上的廣泛使用甚至濫用導(dǎo)致全球性的耐藥菌株頻發(fā),嚴(yán)重危及人類健康,因此新型抗耐藥性的抗菌藥物的研發(fā)迫在眉睫。鑒于此,本文基于喹諾酮類化合物在國內(nèi)外抗菌領(lǐng)域的研發(fā)現(xiàn)狀與本課題組有關(guān)喹諾酮和唑類化合物的前期工作,設(shè)計(jì)合成了一系列新型的喹諾酮唑類抗菌化合物,探索了目標(biāo)化合物的制備方法與條件,并對(duì)其體外抗菌活性、理化性質(zhì)以及構(gòu)效關(guān)系的進(jìn)行... 

【文章來源】：西南大學(xué)重慶市 211工程院校 教育部直屬院校

【文章頁數(shù)】：242 頁

【學(xué)位級(jí)別】：博士

【文章目錄】：
中文摘要
ABSTRACT
第一章 喹諾酮類化合物在抗菌領(lǐng)域研究新進(jìn)展及論文選題
    本章詳細(xì)中文摘要
    1.1 Introdution
    1.2 Development history of quinolone antibacterial drugs
    1.3 Action mechanism of quinolone antibacterial drugs
    1.4 Structure-activity relationship of quinolone antibacterial drugs
    1.5 Structural modification based on quinolone skeleton
        1.5.1 Hybrids of clinical quinolones and antibacterial drugs
        1.5.2 Hybrids of quinolones and β-lactams
        1.5.3 Hybrids of quinolones and macrolides
        1.5.4 Hybrids of quinolones and other clinical drugs
        1.5.5 Structural modification of the C-7 position in quinolone ring
        1.5.6 Structural modification of N-1 position in quinolone ring
    1.6 Conclusions
    1.7 Strategy of this thesis
    References
第二章 喹諾酮三唑新結(jié)構(gòu)的設(shè)計(jì)合成及其抗菌作用研究
    本章詳細(xì)中文摘要
    2.1 Introduction
    2.2 Results and discussion
        2.2.1 Chemistry
        2.2.2 Spectral analysis
        2.2.3 Pharmacology
        2.2.4 Interaction of compound Ⅱ-6b with CT DNA
    2.3 Conclusion
    2.4 Experimental
        2.4.1 Chemistry
        2.4.2 Antibacterial and antifungal assays
        2.4.3 Interaction of DNA with compound Ⅱ-6b assay
    References
    APPENDIX Ⅰ
第三章 喹諾酮甲硝唑新雜化體的設(shè)計(jì)合成及其抗菌作用研究
    本章詳細(xì)中文摘要
    3.1 Introduction
    3.2 Results and discussion
        3.2.1 Chemistry
        3.2.2 Analysis of spectra
        3.2.3 Biological activity
        3.2.4 Effect of metal ions on the transportation of compound Ⅲ-7d by HSA
        3.2.5 Molecular modeling
        3.2.6 Interaction with DNA
    3.3 Conclusion
    3.4 Experimental
        3.4.1 General methods
        3.4.2 Antibacterial and antifungal assays
        3.4.3 Cytotoxicity assays
        3.4.4 Assays of pKa values
        3.4.5 Assays of effect of metal ions to compounds-HSA complex
    References
    APPENDIX Ⅱ
第四章 喹諾酮氨基噻唑新骨架結(jié)構(gòu)的設(shè)計(jì)合成及其抗菌作用機(jī)制研究
    本章詳細(xì)中文摘要
    4.1 Introduction
    4.2 Chemistry
    4.3 Biological evaluation and discussion
        4.3.1 In vitro antibacterial activity
        4.3.2 Cell toxicity and DNA gyrase inhibitory activity
        4.3.3 Development of resistance to compound Ⅳ-12b
        4.3.4 Structure-activity relationship
        4.3.5 Binding behavior with HSA
        4.3.6 Preliminary antibacterial mechanism of 3-aminothiazolquinolones
    4.4 Conclusion
    4.5 Experimental
        4.5.1 General methods
        4.5.2 Cytotoxicity assay
        4.5.3 DNA gyrase supercoiling inhibition assay
        4.5.4 Antibacterial assay
        4.5.5 Compound Ⅳ-12b-HSA complex assay
        4.5.6 Compound Ⅳ-12b-DNA-Cu~(2+)complex assay
    References
    APPENDIX Ⅲ
Financial Support
Acknowledgements
A bilef introduction to the author
Achievements


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