噻唑类新化合物的设计与合成及其抗微生物活性研究
发布时间：2021-04-05 14:33
噻唑环是一类含有氮硫杂原子的重要五元芳香杂环,具有富电子性,易通过氢键、配位键、π-π堆积、范德华力、静电和疏水作用等多种非共价键与生物体内的多种酶、蛋白质、核酸及其他活性位点发生作用,表现出多种生物活性,因此噻唑环被广泛用于药物设计与开发。随着众多噻唑类化合物成功用于临床,如抗生素药物头孢、抗癌药物达沙替尼、消炎药物美洛昔康、抗寄生虫药物硝唑尼特等均作为临床首选一线药物,基于噻唑类药物的研发几乎涵盖了整个医药领域,并取得了杰出成果。更为重要的是噻唑类化合物在抗细菌、抗真菌领域发挥了尤为重要的作用,已有大量研究针对噻唑类化合物多靶点活性分子的研发,为临床提供了越来越多的耐受性好、高活性、广谱、低毒性、生物利用度高、药代动力学性质好的噻唑类化合物作为候选药物或药物分子,显示出了其在医药领域的巨大开发价值和潜在的宽广应用前景。基于近年来国内外关于噻唑类药物的研究与开发现状,以及课题组对噻唑类化合物抗微生物研究工作的延续,本论文基于以下思想设计合成了一系列结构新颖的噻唑类化合物,以期得到具有多靶向性且更好生物活性的新型噻唑类化合物。主要对其进行了体外抗细菌抗真菌活性评估及构效关系的研究,并对...
【文章来源】：西南大学重庆市 211工程院校 教育部直属院校
【文章页数】：415 页
【学位级别】：博士
【文章目录】：
中文摘要
ABSTRACT
第一章 噻唑类化合物在医药领域研究新进展及论文选题 Chapter 1 Recent Research in Thiazoles as Antimicrobial Agents and Strategy of Thesis
本章详细中文摘要
1.1 Introduction
1.2 Thiazole-based antibacterial agents
1.2.1 Aminothiazoles as antibacterial agents
1.2.2 Other thiazoles as antibacterial agents
1.2.3 Benzothiazoles as antibacterial agents
1.3 Thiazole-based antifungal agents
1.3.1 Hydrazone-combined thiazoles as antifungal agents
1.3.2 Amide-derived thiazoles as antifungal agents
1.3.3 Other thiazoles as antifungal agents
1.4. Conclusion and outlooks
1.5 Strategy of this thesis
References
第二章 新型黄连素类噻唑化合物的设计合成及其抗微生物作用研究 Chapter 2 Design, Synthesis and Antimicrobial Evaluation of Berberine Thiazole Derivatives
本章详细中文摘要
2.1 Introduction
2.2 Results and discussion
2.2.1 Chemistry
2.2.2 Biological activity
2.2.3 Aqueous solubility
2.2.4 Cytotoxicity
2.2.5 Bactericidal kinetics
2.2.6 Drug resistance development
2.2.7 Bacterial membrane permeabilization
2.2.8 Supramolecular docking study
2.2.9 Preliminary antibacterial mechanism study
2.2.10 Drug combination use of compound II-9c with norfloxacin
2.3 Conclusion
2.4 Experimental protocols
2.4.1 General methods
2.4.2 Synthesis
2.4.3 Antimicrobial assay
2.4.4 Aqueous solubility assay
2.4.5 Cytotoxicity assay
2.4.6 Bactericidal kinetic assay
2.4.7 Resistance assay
2.4.8 Bacterial membrane permeabilization assay
2.4.9 Isolating genomic DNA from drug-resistant A. baumanii strain
2.4.10 Drug-resistant A. baumanii DNA cleavage assay
2.4.11 Assay for drug combination use
References
APPENDIX Ⅰ
第三章 新型香豆素类噻唑化合物的设计合成及其抗微生物活性研究 Chapter 3 Design, Synthesis and Antimicrobial Evaluation of Coumarin Thiazoles
本章详细中文摘要
3.1 Introduction
3.2 Results and discussion
3.2.1 Chemistry
3.2.2 Biological activity
3.2.3 Cytotoxicity
3.2.4 Bactericidal kinetics
3.2.5 Drug resistance development
3.2.6 Preliminary antibacterial mechanism study
3.2.7 Supramolecular docking study
3.3 Conclusion
3.4 Experimental protocols
3.4.1 General methods
3.4.2 Synthesis
3.4.3 Antimicrobial assay
3.4.4 Cytotoxicity assay
3.4.5 Bactericidal kinetic assay
3.4.6 Resistance assay
3.4.7 Isolating genomic DNA from drug-resistant E. faecalis strain
3.4.8 UV absorption spectra
3.4.9 Fluorescence emission spectra of compound III-11b
3.4.10 Drug-resistant E. faecalis DNA cleavage experment
3.4.11 Bacterial membrane permeabilization assay
References
APPENDIX Ⅱ
第四章 新型喹诺酮类噻唑化合物的设计合成及其抗微生物活性研究 Chapter 4 Design, Synthesis and Antimicrobial Evaluation of Quinolone Thiazoles
本章详细中文摘要
4.1 Introduction
4.2 Results and discussion
4.2.1 Chemistry
4.2.2 Biological activity
4.2.3 Mammalian cytotoxicity
4.2.4 Bactericidal kinetics
4.2.5 Drug resistance development
4.2.6 Bacterial membrane permeabilization
4.2.7 Supramolecular docking study
4.2.8 Preliminary antibacterial mechanism study
4.3 Conclusion
4.4 Experimental
4.4.1 General methods
4.4.2 Synthesis
4.4.3 Antibacterial and antifungal assays
4.4.4 Cytotoxicity assay
4.4.5 Bactericidal kinetic assay
4.4.6 Resistance assay
4.4.7 Bacterial membrane permeabilization assay
4.4.8 Isolating genomic DNA from drug-resistant S. aureus strain
4.4.9 UV absorption spectra
4.4.10 Topoisomerase IV Inhibition Assay
References
APPENDIX Ⅲ
第五章 新型有机膦咪唑类化合物的设计合成及其抗微生物研究 Chapter 5 Design, Synthesis and Biological Evaluation of Organophosphorus Imidazoles
本章详细中文摘要
5.1 Introduction
5.2 Results and discussion
5.2.1 Chemistry
5.2.2 Spectral analysis
5.2.3 Biological activity
5.2.4 Drug combination study
5.2.5 Resistance study
5.2.6 Bactericidal kinetic study
5.2.7 Bacterial membrane permeabilization study
5.2.8 Interaction with calf thymus DNA
5.2.9 Partition coefficient and computational analysis
5.2.10 Supramolecular interactions of compound V-3f with HSA
5.3 Conclusion
5.4 Experimental protocols
5.4.1 General methods
5.4.2 Synthesis
5.4.3 Biological assay
5.4.4 Drug combination assay
5.4.5 Resistance assay
5.4.6 Bactericidal kinetic assay
5.4.7 Bacterial membrane permeabilization assay
5.4.8 UV absorption and fluorescence emission spectra
References
APPENDIX Ⅳ
结果与展望（Results and prospects）
基金支持（Financial support）
致谢（Acknowledgments）
作者简介（A brief introduction to the author）
成果（Achievements）
本文编号：3119810
【文章来源】：西南大学重庆市 211工程院校 教育部直属院校
【文章页数】：415 页
【学位级别】：博士
【文章目录】：
中文摘要
ABSTRACT
第一章 噻唑类化合物在医药领域研究新进展及论文选题 Chapter 1 Recent Research in Thiazoles as Antimicrobial Agents and Strategy of Thesis
本章详细中文摘要
1.1 Introduction
1.2 Thiazole-based antibacterial agents
1.2.1 Aminothiazoles as antibacterial agents
1.2.2 Other thiazoles as antibacterial agents
1.2.3 Benzothiazoles as antibacterial agents
1.3 Thiazole-based antifungal agents
1.3.1 Hydrazone-combined thiazoles as antifungal agents
1.3.2 Amide-derived thiazoles as antifungal agents
1.3.3 Other thiazoles as antifungal agents
1.4. Conclusion and outlooks
1.5 Strategy of this thesis
References
第二章 新型黄连素类噻唑化合物的设计合成及其抗微生物作用研究 Chapter 2 Design, Synthesis and Antimicrobial Evaluation of Berberine Thiazole Derivatives
本章详细中文摘要
2.1 Introduction
2.2 Results and discussion
2.2.1 Chemistry
2.2.2 Biological activity
2.2.3 Aqueous solubility
2.2.4 Cytotoxicity
2.2.5 Bactericidal kinetics
2.2.6 Drug resistance development
2.2.7 Bacterial membrane permeabilization
2.2.8 Supramolecular docking study
2.2.9 Preliminary antibacterial mechanism study
2.2.10 Drug combination use of compound II-9c with norfloxacin
2.3 Conclusion
2.4 Experimental protocols
2.4.1 General methods
2.4.2 Synthesis
2.4.3 Antimicrobial assay
2.4.4 Aqueous solubility assay
2.4.5 Cytotoxicity assay
2.4.6 Bactericidal kinetic assay
2.4.7 Resistance assay
2.4.8 Bacterial membrane permeabilization assay
2.4.9 Isolating genomic DNA from drug-resistant A. baumanii strain
2.4.10 Drug-resistant A. baumanii DNA cleavage assay
2.4.11 Assay for drug combination use
References
APPENDIX Ⅰ
第三章 新型香豆素类噻唑化合物的设计合成及其抗微生物活性研究 Chapter 3 Design, Synthesis and Antimicrobial Evaluation of Coumarin Thiazoles
本章详细中文摘要
3.1 Introduction
3.2 Results and discussion
3.2.1 Chemistry
3.2.2 Biological activity
3.2.3 Cytotoxicity
3.2.4 Bactericidal kinetics
3.2.5 Drug resistance development
3.2.6 Preliminary antibacterial mechanism study
3.2.7 Supramolecular docking study
3.3 Conclusion
3.4 Experimental protocols
3.4.1 General methods
3.4.2 Synthesis
3.4.3 Antimicrobial assay
3.4.4 Cytotoxicity assay
3.4.5 Bactericidal kinetic assay
3.4.6 Resistance assay
3.4.7 Isolating genomic DNA from drug-resistant E. faecalis strain
3.4.8 UV absorption spectra
3.4.9 Fluorescence emission spectra of compound III-11b
3.4.10 Drug-resistant E. faecalis DNA cleavage experment
3.4.11 Bacterial membrane permeabilization assay
References
APPENDIX Ⅱ
第四章 新型喹诺酮类噻唑化合物的设计合成及其抗微生物活性研究 Chapter 4 Design, Synthesis and Antimicrobial Evaluation of Quinolone Thiazoles
本章详细中文摘要
4.1 Introduction
4.2 Results and discussion
4.2.1 Chemistry
4.2.2 Biological activity
4.2.3 Mammalian cytotoxicity
4.2.4 Bactericidal kinetics
4.2.5 Drug resistance development
4.2.6 Bacterial membrane permeabilization
4.2.7 Supramolecular docking study
4.2.8 Preliminary antibacterial mechanism study
4.3 Conclusion
4.4 Experimental
4.4.1 General methods
4.4.2 Synthesis
4.4.3 Antibacterial and antifungal assays
4.4.4 Cytotoxicity assay
4.4.5 Bactericidal kinetic assay
4.4.6 Resistance assay
4.4.7 Bacterial membrane permeabilization assay
4.4.8 Isolating genomic DNA from drug-resistant S. aureus strain
4.4.9 UV absorption spectra
4.4.10 Topoisomerase IV Inhibition Assay
References
APPENDIX Ⅲ
第五章 新型有机膦咪唑类化合物的设计合成及其抗微生物研究 Chapter 5 Design, Synthesis and Biological Evaluation of Organophosphorus Imidazoles
本章详细中文摘要
5.1 Introduction
5.2 Results and discussion
5.2.1 Chemistry
5.2.2 Spectral analysis
5.2.3 Biological activity
5.2.4 Drug combination study
5.2.5 Resistance study
5.2.6 Bactericidal kinetic study
5.2.7 Bacterial membrane permeabilization study
5.2.8 Interaction with calf thymus DNA
5.2.9 Partition coefficient and computational analysis
5.2.10 Supramolecular interactions of compound V-3f with HSA
5.3 Conclusion
5.4 Experimental protocols
5.4.1 General methods
5.4.2 Synthesis
5.4.3 Biological assay
5.4.4 Drug combination assay
5.4.5 Resistance assay
5.4.6 Bactericidal kinetic assay
5.4.7 Bacterial membrane permeabilization assay
5.4.8 UV absorption and fluorescence emission spectra
References
APPENDIX Ⅳ
结果与展望（Results and prospects）
基金支持（Financial support）
致谢（Acknowledgments）
作者简介（A brief introduction to the author）
成果（Achievements）
本文编号：3119810
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