Discovery of Piperidine--linked Quinazoline Derivatives as Potent HIV--1 NNRTIs and HIV--1 Latent Reservoir Activators

目录

声明

TABLE OF CONTENTS

ABSTRACT

ABBREVIATIONS

CHAPTER 1．INTRODUCTION

1．1 The Human Immunodeficiency Virus

1．1．1 HIV-1 Structure

1．1．2 HIV-1 Replication Cycle and Drug Targets

1．1．3 U．S FDA Approved HIV Drugs

1．2 HIV-1 Reverse Transcriptase and Non-nucleoside Reverse Transcriptase Inhibitors

1．2．1 HIV-1 Reverse Transcriptase Structure and Functions

1．2．2 HIV-1 Reverse Transcriptase lnhibitors

1．2．3 Non-nucleoside Reverse Transcriptase Inhibitors

1．2．4 Drawbacks of Available NNRTIs

1．2．5 Structural Optimization Strategies of NNRTIs

CHAPTER 2．DESIGN，SYNTHESIS AND BIOLOGICAL EVALUATION OF PIPERIDINE-LINKED QUINAZOLINE DERIVATIVES AS POTENT HIV-1 NNRTIs

2．1．Binding Modes of Diaryipyrimidines

2．2 Recent Structural Modification of DAPY-lead Compounds Reported by Our Group

2．3 Design of Target Compounds

2．4 Synthesis of Target Compounds

2．4．1 Instruments and Reagents

2．4．2 Synthetic Procedure of Target Compounds

2．4．3 List of Synthesized Compounds

2．5 Anti-HIV Evaluation of Target Compounds

2．5．1 Method of Anti-HIV Activity Assay

2．5．2 Results and Discussion

2．6 HIV-1 RT Inhibition Assay of Target Compounds

2．6．1 Method of Recombinant HIV-1 RT Inhibitory Assays

2．6．2 Results and Discussion

2．7 Molecular Simulation and Physicochemical Properties Prediction of Representative Compounds

2．7．1 Molecular Simulation of Representative Compound

2．7．2 In silico Physicochemical Properties Prediction of Representative Compounds

2．8 Conclusion

CHAPTER 3．DISCOVERY OF HIV-1 LATENT RESERVOIR ACTIVATORS：DESIGN，SYNTHESIS，AND EVALUATION

3．1 HIV-1 Latent Reservoirs

3．2 Establishment and Maintenance of HIV-1 Latent Reservoirs

3．3 Therapeutics Strategies for an HIV-1 Cure

3．3．1 Histone Deacetylase Inhibitors(HDACIs)

3．3．2 Histone Methyltransferase Inhibitors(HMTIs)

3．4 Design of Target Compounds

3．5 Synthesis of Target Compounds

3．5．1 Instruments and Reagents

3．5．2 Synthetic Route of Target Compounds

3．6．Latent HIV-1 Activation Assay of Target Compounds

3．6．1 Method of Latent HIV-1 Activation Assay

3．6．2 Results and Discussion

3．6 Conclusion

CHAPTER 4．CONCLUSIONS AND RECOMMENDATIONS

4．1 Conclusions

4．2 Recommendations

REFERENCES

APPENDIX

ACKNOWLEDGEMENTS

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