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Dedicated to My Parents, Augustine and Rosemary Nti-Addae

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Dedicated to My Parents, Augustine and Rosemary Nti-Addae Dedicated to my parents, Augustine and Rosemary Nti-Addae. Acknowledgements My sincere appreciation goes to my parents, Augustine and Rosemary Nti-Addae for their relentless support and loving care through out my life, and making my education a success. In addition I send my appreciation to my brothers, Yaw Appiah Nti-Addae and Akwasi Kay Nti-Addae for being my support away from home and always being there for me when ever I needed them. I would like to acknowledge my research advisor, Dr. Valentino J. Stella, for opportunity to study under his leadership. I will forever be grateful for the mentorship and contribution towards my scientific education and for his guidance to both my academic and personal life. I would also like to acknowledge my committee members and the entire faculty of the University of Kansas Pharmaceutical Chemistry Department for their contributions. Special thanks to Siegfried Lindenbaum Predoctoral Fellowship, Higuchi Biosciences Center, The University of Kansas Center for Research (KUCR), and the University of Kansas Pharmaceutical Chemistry Department for providing the much needed financial support through out the course of my studies. Special thanks also go to Nancy Helm, Karen Hall, Ann Heptig and Nicole Brooks for all the administrative help. I would like to especially acknowledge Bill Marinaro, Sundeep Dhareshwar, Jeff Hemenway, Victor Guarino, Svetlana Silchenko, Serena Tongiani-Pacor, Na Sun, Jian Lu, Hedeki Kohita and Alex Grill for their constant support in and out of the lab. I extend my appreciation to my friends Justin Pennington, Joseph Lubach, Sumit Majumdar Rosemary Ndolo, Alana Toro Ramos, Natalie Ciaccio, Elodie K. Dempah, and all the students of the Pharmaceutical chemistry department, past and present. I would also like to say a big thank you to Kofi and Tina Boye-Doe, Samuel and Naa Britwum, and Gloria Akyeampong for their love, friendship and kindness to me during my time in Lawrence KS. Finally, my appreciation goes to my Uncle, Kojo Nsiah Amanquah, without whom my move to the USA to continue my education would have not been possible. ii The synthesis, physicochemical characterization and evaluation of sulfenamide derivatives of antimicrobial oxazolidinones as prodrugs are described in this dissertation. Synthesis of sulfenamide derivatives described in this work involves the use of thiophthalimide intermediates. These thiophthalimide intermediates allow for a clean one step reaction, which requires less purification steps resulting in higher yields of sulfenamide products compared to a previously described synthetic route that incorporated the use of unstable sulfuryl chloride intermediates. The sulfenamide prodrugs undergo chemical conversion through the hydrolytic cleavage of the N-S bond during aqueous stability studies to release the parent drug molecule. However, insufficient aqueous stability characteristics may pose potential problems for future development of sulfenamide prodrugs as ready to use liquid formulations. The stability of the sulfenamide prodrugs was studied in the presence of small molecule thiols with varying thiol pKa. These studies showed that the thiolate ion was the species responsible for the nucleophilic attack on the sulfur atom of the N-S bond, leading to the cleavage of the bond to release the parent molecule and a mixed disulfide. Reactions of the sulfenamide prodrugs with thiol containing proteins such as human serum albumin and PRL-1 also resulted in the nucleophilic cleavage of the sulfenamide bond to release the parent molecule. The reactions of the sulfenamide prodrugs with small molecule thiols and thiol containing proteins led to the conclusion that in vivo conversion will occur via the nucleophilic attack of thiolate species. Attempts to study the permeability of the sulfenamide derivatives were hindered by the rapid conversion of the sulfenamide prodrugs to the parent molecule in the transport study setup. This rapid conversion is believed to be caused by the presence of thiol containing proteins on the surface of the Caco-2 cell monolayer and also within the cells. However, analysis of the initial permeability data shows that the sulfenamide prodrugs are contributing to the slight improvement of the permeability of the parent molecule. iii Outline Chapter 1: Application of sulfenamides as potential prodrugs to improve the physicochemical properties of amide containing drug molecules 1. Introduction and Background 1.1. Statement of goals 1.2. Prodrugs 1.3. -NH acids (amides) and their prodrugs 1.4. Advantages and disadvantages of some -NH acid prodrugs 1.4.1. N-Acyl prodrugs 1.4.2. N-Mannich base prodrugs 1.4.3. N-Hydroxymethyl prodrugs 1.4.4. N-Acyloxymethyl prodrugs 1.5. Sulfenamides 1.6. Chemistry of sulfenamides 1.7. Applications in the chemical and pharmaceutical industry 1.7.1. Applications in organic synthesis. 1.7.2. Applications in the agricultural industry. 1.7.3. Other applications of sulfenamides. 1.8. Sulfenamide Prodrugs 1.8.1. Origin of sulfenamide prodrug idea. 1.8.2. Previously studied sulfenamide prodrugs. 1.9. Summary and Specific Aims 1.10. References. Chapter 2: Synthesis and physicochemical characterization of sulfenamide prodrugs from novel antibacterial oxazolidinones. 2.1. Introduction 2.1.1. Overall objective 2.1.2. Sulfenamides: Definition and Background. 2.1.3. Oxazolidinones; Definition and background iv 2.2. Materials and Methods 2.2.1. Solvents, Chemicals and Instruments 2.2.2. Synthesis and characterization of oxazolidinones 2.2.2.1. General 2.2.2.2. (R)-[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5 oxazolidinyl]methyl methanesulfonate (2.2) 2.2.2.3. (R)-5-(azidomethyl)-3-(3-fluoro-4-thiomorpholinophenyl) oxazolidin-2-one (2.3) 2.2.2.4. (S)-5-(aminomethyl)-3-(3-fluoro-4-thiomorpholinophenyl) oxazolidin-2-one. (2.4) 2.2.2.5. N-((3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5- yl)methyl)acetamide (U-100480) (2.5) 2.2.2.6. (S)-N-((3-(3-fluoro-4-(1-oxothiomorpholin-4-yl)phenyl)-2- oxo-5-oxazolidinyl) methyl)acetamide (U101603) (2.6) 2.2.3. Synthesis and characterization of sulfenamides 2.2.3.1. Ethylthiophthalimide. (2.7) 2.2.3.2. Ethyl 3-(1,3-dioxoisoindolin-2-ylthio)propanoate. (2.8) 2.2.3.3. (R)-N-((3-(3-fluoro-4-morpholinophenyl)-2- oxo oxazolidin- 5-yl)methyl)-N-(phenylthio)acetamide. (2.9) 2.2.3.4. (R)-N-((3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxa zolidin-5-yl)methyl)-N-(phenylthio)acetamide. (2.10) 2.2.3.5. (R)-N-((3-(3-fluoro-4-(1-oxothiomorpholin-4-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)-N-(phenylthio)acetamide. (2.11) 2.2.3.6. (R)-N-(ethylthio)-N-((3-(3-fluoro-4-morpholinophenyl) oxooxazolidin-5-yl) methyl)acetamide.(2.12) 2.2.3.7. Ethyl 3-(N-((3-(3-fluoro-4-morpholinophenyl)-2-oxo oxazolidin-5-yl)methyl)acetamidothio)propanoate. (2.13) 2.2.3.8. Attempted Synthesis of (R)-tert-butyl 4-(N-((3-(3-fluoro-4- morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamidothio) butanoate (2.15) 2.2.4. Determining aqueous stability of sulfenamide prodrugs models. v 2.2.4.1. Solvents and chemicals 2.2.4.2.Aqueous stability sample preparation 2.2.4.3.HPLC conditions 2.2.4.4.Determination of degradation products by LCMS 2.3. Results and Discussion 2.3.1. Synthetic results 2.3.2. Hydrolytic degradation of N-(phenylsulfenyl)linezolid (2.9) and N-(ethylsulfenyl) linesolid (2.12). 2.4. Conclusions 2.5. References Chapter 3: Degradation of sulfenamides in the presence of small molecule thiols 3.1. Introduction 3.1.1. Overall Objective 3.1.2. Reactivity of Sulfenamides 3.1.3. Proposed reaction of sulfenamides prodrugs with thiols 3.2. Experimental Materials and Methods 3.2.1. Solvents and chemicals 3.2.2. Aqueous stability sample preparation 3.2.3. HPLC conditions 3.2.4. Determination of degradation products by LCMS 3.3. Results and discussion 3.3.1. LCMS analysis. 3.3.2. Pseudo 1st order reactions of sulfenamide prodrug models in molar excess of thiols. 3.3.3. Kinetic Analysis of sulfenamides prodrug reactions with thiols. 3.3.4. Mathematical determination of 2nd order rate constants 3.4. Conclusions 3.5. References vi Chapter 4: Degradation of sulfenamide prodrugs in the presence of thiol containing proteins 4.1. Introduction 4.1.1. Overall objective 4.1.2. Background 4.1.2.1. Thiol containing proteins and their significance 4.2. Experimental, Material and Methods 4.2.1. Solvents and chemicals 4.2.2. Determination of the free thiol concentration in HSA. 4.2.3. Degradation of 4.1 in the presence of HSA 4.2.4. Degradation of 4.1 in the presence of PRL-1 C170-171S Mutant. 4.2.5. Degradation of 4.1 and 4.2 in the presence of Human Plasma. 4.3. Results and Discussions 4.3.1. Degradation of 4.1 in the presence of HSA and PRL-1 C170-171S. 4.3.2. Degradation of sulfenamide prodrugs in the presence of Human Plasma 4.4. Conclusions. 4.5. References Chapter 5: The Determination of the Permeability Characteristics of Sulfenamide Prodrugs of Antimicrobial Oxazolidinones across Caco-2 Cells. 5.1. Introduction 5.1.1. Overall Objective 5.1.2. Permeability 5.2. Experimental Materials and Methods 5.2.1. Solvents and chemicals 5.2.2. Caco-2 Permeability Assay: 5.2.2.1. Media preparation. 5.2.2.2. Cell culture. 5.2.2.3. Sub culturing cells 5.2.2.4. Permeability Experiments 5.2.2.5. Control studies. 5.3. Results and Discussions 5.3.1. Cell transport studies vii 5.3.2. Permeability of Linezolid 5.3.3. Permeability studies of 5.1 and 5.2 5.4. Conclusions 5.5. References Chapter 6: Overall Summary, Conclusions and Future Work 6.1. Summary and Conclusions 6.1.1. Synthesis and aqueous stability of sulfenamide prodrugs of oxazolidinones.
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