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Design, Synthesis, and Evaluation of Small Molecules in the Discovery of Novel Antimicrobial Agents Kimberly D

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Design, Synthesis, and Evaluation of Small Molecules in the Discovery of Novel Antimicrobial Agents Kimberly D University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 5-2008 Design, Synthesis, and Evaluation of Small Molecules in the Discovery of Novel Antimicrobial Agents Kimberly D. Grimes University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Other Medical Sciences Commons, and the Pharmaceutics and Drug Design Commons Recommended Citation Grimes, Kimberly D. , "Design, Synthesis, and Evaluation of Small Molecules in the Discovery of Novel Antimicrobial Agents" (2008). Theses and Dissertations (ETD). Paper 114. http://dx.doi.org/10.21007/etd.cghs.2008.0119. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. Design, Synthesis, and Evaluation of Small Molecules in the Discovery of Novel Antimicrobial Agents Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Medicinal Chemistry Research Advisor Richard E. Lee, Ph.D. Committee John K. Buolamwini, Ph.D. Isaac O. Donkor, Ph.D. Duane D. Miller, Ph.D. Jie Zheng, Ph.D. DOI 10.21007/etd.cghs.2008.0119 This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/114 DESIGN, SYNTHESIS, AND EVALUATION OF SMALL MOLECULES IN THE DISCOVERY OF NOVEL ANTMICROBIAL AGENTS A Dissertation Presented for The Graduate Studies Council The University of Tennessee Health Science Center In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy From The University of Tennessee By Kimberly D. Grimes May 2008 Copyright © 2008 by Kimberly D. Grimes All rights reserved ii DEDICATION I would like to dedicate this body of work to my greatest supporter and idol, my mother Mrs. Debora A. Stewart. iii ACKNOWLEDGEMENTS I would first like to acknowledge my mentor and advisor, Dr. Richard E. Lee for giving me a chance to advance professionally. He eagerly welcomed me into the Medicinal Chemistry program and into his lab without hesitation. In the last 5 ½ years, I’ve matured into a better scientist. I have also become a better person because of his guidance and mentorship. I would also like to give special thanks to my committee members, Dr. John K. Buoalmwini, Dr. Isaac O. Donkor, Dr. Duane D. Miller, and Dr. Jie Zheng for your support and guidance throughout my graduate tenure. I give special thanks to the past and present members of the “Lee lab”: Dr. Kerim Babaoglu, Dr. Kristopher Virga, Dr. Rajendra Tangallapally, Dr. Jianjun Qi, Dr. Raghunandan Yendapally, Dr. Kirk Hevener, Dr. Dianqing Sun, Dr. Julian Hurdle, Dr. Sucheta Kudrimoti, Dr. Rakesh, Robin Lee, Elizabeth Carson, Engy Maharous, Joshua Brown, Jerrod Scarborough, Jason Wilson, AnTawan Daniels, Neena Joshi, and David Ball for their support, assistance, and friendship. Special thanks go to Dr. Qi, Dr. Kudrimoti, Dr. Baboglu, Dr. Virga, Dr. Tangalapally, Dr. Yendapally, and Dr. Hurdle for their assistance, advice, and expertise. I would also like to extend thanks to our collaborators on the research projects in this dissertation: Dr. Michael NcNeil (Colorado State University), Dr. James Naismith (St. Andrew’s University), Dr. Charles Rock (St. Jude Children’s Research Hospital), Dr. Vicki Luna (University of South Florida) and their lab members. I would like to thank the general body of the Black Graduate Student Association, as they have been pivotal to my overall growth as an individual and providing me with a great support system. I’d also like to give special thanks to my friends at the University of Tennessee, especially Ms. Ja’Wanda Grant. Without Ja’Wanda, I’m not sure I would have made it this far. I thank her dearly for being my sounding board and encouraging me to make it through to the end. Last, but certainly not least, I’d like to thank my family who has supported me and kept me encouraged so that I could complete the task at hand. iv ABSTRACT The increasing prevalence of antibiotic-resistant bacteria, including Mycobacterium tuberculosis, Streptococcus pneumoniae, Staphylococcus aureus, and Enterococcus faecalis, pushes us to discover new antibacterial agents to maintain adequate patient coverage. This body of work highlights the use of medicinal chemistry methodologies that encompass cross-disciplinary fields of study. Chapter 1 gives an introduction to the antibacterial drug targets, resistance, and how scientists are working to overcome obstacles encountered with drug-resistant bacteria. It also details modern medicinal chemistry applications in antimicrobial drug discovery. Chapter 2 details the use of a structure-guided library approach to drug design, in which large virtual libraries against the target are generated and filtered, based on pharmacophoric and structural constraints, to produce smaller and more structurally complex libraries prioritized for synthesis. In this work, bi-aryl sulfonamide libraries using contemporary medicinal chemistry techniques were synthesized as potential inhibitors of Mycobacterium tuberculosis cell wall biosynthesis via the rhamnose pathway. Chapter 3 describes the discovery of novel inhibitors of the PlsX/PlsY pathway to phosphatidic acid, a key intermediate in the biosynthesis of phospholipids in Gram-positive bacteria. Substrate mimics, incorporating various bioisosteric replacement head groups, were discovered demonstrating good enzyme inhibition and good antimicrobial activity against clinically relevant bacteria. Finally, Chapter 4 provides an overall discussion of the work detailed in this dissertation and future directions that will continue the advancement of these projects. v TABLE OF CONTENTS CHAPTER 1. INTRODUCTION ....................................................................................1 Introduction to Antibiotics and Antimicrobial Agents....................................................1 Inhibitors of Folic Acid Metabolism ...........................................................................1 Inhibitors of Cell Wall Biosynthesis ...........................................................................3 Inhibitors of Protein Biosynthesis ...............................................................................7 Inhibitors of Nucleic Acid Biosynthesis .....................................................................9 Inhibitors of DNA-Directed RNA Polymerase .........................................................11 Resistance to Antibiotic Chemotherapy ........................................................................11 Limiting Uptake ........................................................................................................13 Efflux Pumps.............................................................................................................13 Antibiotic-Altering Enzymes ....................................................................................13 Modification of the Target ........................................................................................14 Bypass Pathways .......................................................................................................14 Overcoming Resistance.................................................................................................14 Inhibiting Drug-Destroying Enzymes .......................................................................15 Inhibiting Multi-Drug Efflux Pumps.........................................................................15 Introducing New Chemical Entities (NCE)...............................................................17 Pursuing Novel Targets with Novel Modes of Action ..............................................20 Medicinal Chemistry Applications in Antimicrobial Drug Discovery .........................24 Structure-Based Drug Design....................................................................................24 Combinatorial Chemistry and HTS...........................................................................25 Filters for Drug Likeness...........................................................................................26 Research Objectives ......................................................................................................27 Sulfonamide Libraries as Inhibitors of Mycobacterium tuberculosis Cell Wall Biosynthesis...............................................................................................................27 Discovery of Novel Inhibitors in Phospholipid Biosynthesis ...................................28 CHAPTER 2: STRUCTURE-GUIDED SULFONAMIDE LIBRARIES AS INHIBITORS OF MYCOBACTERIUM TUBERCULOSIS CELL WALL BIOSYNTHESIS .............................................................................................................29 Introduction to Tuberculosis .........................................................................................29 Tuberculosis Treatment.............................................................................................29 Need for New Therapeutic Agents............................................................................33 Targeting the Mycobacterium Cell Wall.......................................................................33 Introduction ...............................................................................................................33
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