University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 5-2010 The esiD gn and Synthesis of Novel Antimicrobial Agents for Use in the Battle Against Bacterial Resistance Joshua Randal Brown University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Brown, Joshua Randal , "The eD sign and Synthesis of Novel Antimicrobial Agents for Use in the Battle Against Bacterial Resistance" (2010). Theses and Dissertations (ETD). Paper 31. http://dx.doi.org/10.21007/etd.cghs.2010.0035. 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]. The esiD gn and Synthesis of Novel Antimicrobial Agents for Use in the Battle Against Bacterial Resistance Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Pharmaceutical Sciences Research Advisor Richard Lee, Ph.D. Committee James Bina, Ph.D. Isaac Donkor, Ph.D. Wei Li, Ph.D. Duane Miller, Ph.D DOI 10.21007/etd.cghs.2010.0035 This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/31 THE DESIGN AND SYNTHESIS OF NOVEL ANTIMICROBIAL AGENTS FOR USE IN THE BATTLE AGAINST BACTERIAL RESISTANCE 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 Joshua Randal Brown May 2010 Copyright © 2010 by Joshua R. Brown All rights reserved ii ABSTRACT There is an ever increasing need to develop new antimicrobial agents with novel mechanisms of action. These new agents will help to combat the steady rise of antibiotic- resistant bacteria which are becoming more and more difficult to treat due to the dwindling number of antibiotics available to treat such organisms. This body of work brings to light the many ways in which medicinal chemistry plays a vital role in the discovery of novel antimicrobial agents. Chapter 1 is an introduction into antimicrobial agents. It provides a brief history of the discovery of antimicrobial agents, and delves into reasons why new agents are urgently needed. It also examines the recent antimicrobial agents approved by the Food and Drug Administration for use in the United States, and looks into the current antimicrobial drug pipeline. Chapter 2 explores the current therapy regime for combating tuberculosis and expresses the need for novel agents in this arena. It also shows how current medicinal chemistry techniques are being utilized to develop a novel class of potential anti-tuberculosis agents with novel mechanisms of action. Chapter 3 discusses the treatment of gram-negative bacterial infections with novel hybrid antimicrobial agents. These agents afford current antimicrobial agents, which have difficulty penetrating the gram-negative cell wall, a way into the gram-negative cell in order to exert their intended mechanism of action. This chapter explores the rationale and design behind the making of such agents. Chapter 4 provides an overview of the work detailed in the dissertation; as well as future directions that will help further the scope of these projects. iii TABLE OF CONTENTS CHAPTER 1: INTRODUCTION .................................................................................... 1 Introduction to Antibacterial Agents .............................................................................. 1 Inhibitors of Bacterial Cell Wall Biosynthesis ........................................................... 1 Inhibitors of Protein Biosynthesis ............................................................................... 3 Inhibitors of DNA and RNA Synthesis ...................................................................... 8 Inhibitors of Folate Synthesis ..................................................................................... 8 The Need for Novel Antibacterial Agents .................................................................... 11 New Antibiotics ............................................................................................................ 13 Recently Approved Antibiotics ................................................................................ 13 Antibiotics in the Pipeline: Gram-Positive ............................................................... 18 Antibiotics in the Pipeline: Gram-Negative .............................................................. 29 Concluding Introductory Remarks ................................................................................ 34 CHAPTER 2: NOVEL UREA DERIVATIVES AS ANTI-TUBERCULOSIS AGENTS .......................................................................................................................... 35 Introduction to Tuberculosis ......................................................................................... 35 Treating Tuberculosis ............................................................................................... 35 Need for Novel Anti-Tuberculosis Agents ............................................................... 38 Targeting Epoxide Hydrolase ....................................................................................... 38 Chemistry ...................................................................................................................... 39 Results and Discussion ................................................................................................. 41 Conclusions ................................................................................................................... 47 Experimental Section .................................................................................................... 52 Chemistry .................................................................................................................. 52 General Method for the Synthesis of Urea Compounds ........................................... 52 MIC Determination ................................................................................................... 59 Cytotoxicity Study .................................................................................................... 59 CHAPTER 3: DESIGN OF NOVEL SIDEROPHORE ANTIMICROBIAL AGENTS FOR THE TREATMENT OF GRAM-NEGATIVE BACTERIA ........... 60 Introduction to Gram-Negative Bacteria ...................................................................... 60 Composition .............................................................................................................. 60 Quorum Sensing ....................................................................................................... 60 Tetramic Acids .............................................................................................................. 61 Synthesis of Quorum Sensing Molecule 1 and Its Degradation Product ...................... 61 Significance of the Tetramic Acid Degradation Product as a Siderophore .................. 64 Synthesis of Iron(III) Chelation Product of Tetramic Acids ........................................ 65 Siderophores as Antibacterial Agents ........................................................................... 68 Background ............................................................................................................... 68 TonB Transport System ............................................................................................ 68 Application ................................................................................................................ 69 Synthesis of Tetramic Acid Core .................................................................................. 71 Conclusions ................................................................................................................... 71 Experimental Section .................................................................................................... 73 iv CHAPTER 4: OVERALL DISCUSSION OF DISSERTATION ............................... 76 Introduction ................................................................................................................... 76 Urea Project .................................................................................................................. 76 Tetramic Acid Project ................................................................................................... 78 Final Thoughts .............................................................................................................. 80 LIST OF REFERENCES ............................................................................................... 82 VITA................................................................................................................................. 95 v LIST OF FIGURES Figure 1.1: Activation of Prontosil to Sulfanilamide ...................................................... 2 Figure 1.2: General Structures of the Four Classes of β-Lactam Antibiotics .................. 2 Figure 1.3: Structures of Vancomycin and Teicoplanin .................................................. 4 Figure 1.4: Structures of Aminoglycoside Antibiotics ...................................................