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Design, Synthesis, and Biological Evaluation of Potent Hiv-1 Protease Inhibitors with Novel Bicyclic Oxazolidinone and Bis Squaramide Scaffolds

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Design, Synthesis, and Biological Evaluation of Potent Hiv-1 Protease Inhibitors with Novel Bicyclic Oxazolidinone and Bis Squaramide Scaffolds DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF POTENT HIV-1 PROTEASE INHIBITORS WITH NOVEL BICYCLIC OXAZOLIDINONE AND BIS SQUARAMIDE SCAFFOLDS by Jacqueline N. Williams A Dissertation Submitted to the Faculty of Purdue University In Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy Department of Chemistry West Lafayette, Indiana August 2019 2 THE PURDUE UNIVERSITY GRADUATE SCHOOL STATEMENT OF COMMITTEE APPROVAL Dr. Arun K. Ghosh, Chair Department of Chemistry Dr. Andrew Mesecar Department of Biochemistry Dr. Christopher Uyeda Department of Chemistry Dr. Abram Axelrod Department of Chemistry Approved by: Dr. Christine Hyrcyna Head of the Graduate Program 3 To my loving grandmother, for her constant support and encouragement. 4 ACKNOWLEDGMENTS First and foremost, I would like to express my gratitude to Professor Arun K. Ghosh - thank you for your guidance and mentorship. It was truly an honor to learn from you throughout my graduate career. To my thesis committee members, Professor Andrew Mesecar, Professor Christopher Uyeda, and Professor Bram Axelrod - a special thanks for your support and advice. I would like to sincerely thank our collaborators Dr. Irene T. Weber and Dr. Hiroaki Mitsuya for their work on X-ray crystallography and biological studies. To the NMR facility staff, Dr. John Harwood, Dr. Huaping Mo, Jerry Hirschinger, and Donna Bertram - thank you for your advice, words of encouragement and support during my NMR appointment. I would like to thank the department staff, Dr. Christine Hyrcyna, Betty Dexter, Lynn Ryder, and Debra Packer for their guidance throughout my graduate studies. A special thanks to Suzanne Snoeberger for your constant assistance and direction. To the current and past Ghosh group members - thank you for your advice, and support during my time in the Ghosh group, particularly Dr. Anthony Tomaine, Dr. Anindya Sarkar, Dr. Chandu Guddeti Dr. Garth Parham, Dr. Heather Osswald, Dr. Luke Kassekert, Dr. Margherita Brindisi, Dr. Sidhu Akasapu, Dr. Vasudeva Dodda, Dr. Vasu Garidi, Dr. Satish Kovela, Dr. Zilei Xia, Hannah Simpson, Megan Johnson, and Rachel Ho. 5 TABLE OF CONTENTS LIST OF TABLES ......................................................................................................................8 LIST OF FIGURES ....................................................................................................................9 LIST OF SCHEMES ................................................................................................................. 11 LIST OF ABBREVIATIONS.................................................................................................... 13 ABSTRACT ............................................................................................................................. 16 DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF HIV-1 PROTEASE INHIBITORS WITH A P2 BICYCLIC OXAZOLIDINONE LIGAND ................ 17 1.1 The History of Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome ............................................................................................................................... 17 1.2 Taxonomy of HIV ......................................................................................................... 18 1.3 The HIV Life Cycle ....................................................................................................... 18 1.4 Treatments of HIV/AIDS ............................................................................................... 24 1.4.1 Entry and Fusion Inhibitors ..................................................................................... 28 1.4.2 Reverse Transcriptase Inhibitors ............................................................................. 30 1.4.2.1 Nucleoside Reverse Transcriptase Inhibitors ...................................................... 31 1.4.2.2 Non-Nucleoside Reverse Transcriptase Inhibitors .............................................. 32 1.4.3 Integrase Inhibitors ................................................................................................. 34 1.4.4 Protease Inhibitors .................................................................................................. 35 1.5 HIV-1 Protease .............................................................................................................. 35 1.5.1 First Generation HIV Protease Inhibitors ................................................................ 39 1.5.2 Second Generation HIV Protease Inhibitors ............................................................ 41 6 1.5.3 The Fight Against Drug Resistance ......................................................................... 42 1.5.3.1 Backbone Binding Concept ................................................................................ 43 1.5.3.2 Darunavir........................................................................................................... 43 1.6 Design, Synthesis, and Biological Evaluation of HIV-1 Protease Inhibitors with an Oxazolidinone P2 ligand ........................................................................................................ 44 1.6.1 Introduction ............................................................................................................ 44 1.6.2 Design of HIV Protease Inhibitors with an Oxazolidinone P2 Ligand ..................... 45 1.6.3 Results .................................................................................................................... 48 1.6.3.1 Synthesis of Inhibitors ....................................................................................... 49 1.6.3.2 Biological Evaluation......................................................................................... 65 1.6.3.3 X-ray Crystallographic Analysis ........................................................................ 73 1.6.4 Discussion .............................................................................................................. 73 1.7 Conclusion .................................................................................................................... 81 1.8 Experimental Section ..................................................................................................... 82 DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF HIV-1 PROTEASE INHIBITORS WITH A NOVEL BIS SQUARAMIDE SCAFFOLD .................. 113 2.1 Introduction ................................................................................................................. 113 2.2 Design, Synthesis, and Biological Evaluation of HIV-1 Protease Inhibitors with a Novel Bis Squaramide P2 Ligand ................................................................................................... 114 2.2.1 Design of HIV Protease Inhibitors with a Bis Squaramide P2 Ligand ................... 114 2.2.2 Results .................................................................................................................. 118 2.2.2.1 Synthesis of Inhibitors ..................................................................................... 118 2.2.2.2 Biological Evaluation....................................................................................... 127 7 2.2.3 Discussion ............................................................................................................ 129 2.3 Conclusion .................................................................................................................. 129 2.4 Experimental Section ................................................................................................... 130 APPENDIX: NMR Spectra ..................................................................................................... 138 REFERENCES ....................................................................................................................... 193 VITA ...................................................................................................................................... 206 PUBLICATION ...................................................................................................................... 207 8 LIST OF TABLES Table 1.1: FDA Approved HIV/AIDS Drugs ............................................................................. 27 Table 1.2: HIV-1 Proteases Inhibitory and Antiviral Activity of Inhibitors 1.65a and 1.65b with N-Hydride Group ..................................................................................................... 65 Table 1.3: HIV-1 Proteases Inhibitory and Antiviral Activity of Inhibitors 1.65c, 1.65d, 1.65f, and 1.65h with N-Alkyl Group ....................................................................................... 66 Table 1.4: HIV-1 Proteases Inhibitory and Antiviral Activity of Inhibitors 1.65e and 1.65g with Saturated N-Alkyl Group ......................................................................................... 67 Table 1.5: HIV-1 Proteases Inhibitory and Antiviral Activity of Inhibitors 1.65i-l with N-Aryl Group ...................................................................................................................... 68 Table 1.6: HIV-1 Proteases Inhibitory and Antiviral Activity of Inhibitors 1.65m with N-MOM Group ...................................................................................................................... 69 Table 1.7: HIV-1 Proteases Inhibitory and Antiviral Activity of Inhibitor 1.65n with Varying P2’ ...............................................................................................................................
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