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Anti-Parasitic and Anti-Bacterial Agents University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School January 2013 Anti-parasitic and anti-bacterial agents: Studies on 1,4-dihydropyridines and 2,4-diaminoquinazolines Kurt Steven Van Horn University of South Florida, [email protected] Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the Chemistry Commons Scholar Commons Citation Van Horn, Kurt Steven, "Anti-parasitic and anti-bacterial agents: Studies on 1,4-dihydropyridines and 2,4-diaminoquinazolines" (2013). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/4784 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Anti-parasitic and anti-bacterial agents: Studies on 1,4-dihydropyridines and 2,4- diaminoquinazolines by Kurt Steven Van Horn A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Chemistry College of Arts and Sciences University of South Florida Major Professor: Roman Manetsch, Ph.D. Bill J. Baker, Ph.D. Wayne Guida, Ph.D. Dennis E. Kyle, Ph.D. Lindsey Shaw, Ph.D. Date of Approval: 11 June 2013 Keywords: Malaria, Leishmaniasis, methicillin-resistant Staphylococcus aureus, Acinetobacter baumannii, antimicrobial, structure-activity relationship, structure-property relationship Copyright © 2013, Kurt Steven Van Horn Acknowledgements First and foremost I would like to acknowledge Roman Manetsch. He has been my mentor and friend these last eight years and without him I would never have accomplished what I have. Thank you, Roman, it has been a real pleasure. Working in a medicinal chemistry lab, it is impossible to get anything done without collaborations. Within the Manetsch lab, Niranjan Namelikonda was a great help and most of the lactone work in Chapter 2 would not have occurred without him. He has also been a great help with chemical discussions and has provided much insight that otherwise would not have been found. Within the chemistry department at the University of South Florida, the help of Edwin Rivera and the NMR TA’s including David Badger, Will Tay, Andrii Monastyrskii and Arthur Maknenko has indeed been beneficial for all of the projects within. Their support and commitment to keeping the instruments serviced and running and providing proper education to the users has enabled the smooth characterization of numerous compounds. Along this same line, the HPLC facility has been well run by Ted Gautier and most recently Mohanraja Kumar. Without their help much of the reactions run herein would not have been followed as well as has been shown within. Lukasz Wojtas also played an important role, facilitating the X-ray crystallography and allowing for the determination of stereochemistry in the 1,4-dihydropyridine project. Collaborations at USF began with the lab of Dennis Kyle, with Brian Vesely and Anuradha Srivastava performing the initial tests for the leishmaniasis project. Without their time and studies the quinazoline class would not have been investigated in as much depth. A great help in the Kyle lab has been Tina Mutka, who has peformed all of the in vitro Plasmodium falciparum assays using the TM90-C2B and W2 strains. Her work has provided numerous points of data that has truly allowed the growth of the 1,4- dihydropyridine project. Another collaboration at USF has been in the lab of Lindsey Shaw. Whittney Burda has performed the bulk of the work concering the MRSA and Acinetobacter baumannii projects and has been able to provide any and all information that I have requested in regards to the project. Another person in the Shaw lab, Renee Fleeman, has been a great help and was involved early on in the chemistry portion of the quinazoline class so she must be thanked two-fold. The Ohio State University has provided a highly beneficial collaboration with Kyle Werbovetz. The Werbovetz lab has led the majority of the testing for the leishmaniasis project and I am extremely grateful to the help of Xiaohua Zhu and Trupti Pandharkar for their enthusiasm for the project and the ability to accomplish their work. None of the pharmacokinetic studies would have been done without the work of Zhuo Michael Wang at the University of Kansas. In the Wang group, Siyung Yang performed the work and was able to reliably show PK data for the leishmaniasis project. The malaria project involving the 1,4-dihydropyridines has been a godsend for me as a highly enjoyable project filled with lofty chemistry goals and great achievements. I would truly like to thank R. Kiplin Guy for involving us on the project, and the rest of his team at the St. Jude Children’s Research Hospital. Martina Sigal has been my go to person and helped me throughout the project. Julie Clark has performed much of the testing and Amy Matheny has been a leader with oversight on the biological side of the project. Again, I am truly grateful for all of the collaborations in which I have been able to take part. Without them, my graduate career could not have been what you see written within. Table of Contents List of Figures .................................................................................................................... ix List of Tables ................................................................................................................... xiv List of Abbreviations ....................................................................................................... xvi Abstract ............................................................................................................................ xix Chapter 1: Introduction to Anti-microbials..........................................................................1 1.1 Overview ......................................................................................................1 1.2 Protozoa .......................................................................................................2 1.2.1 Genus Plasmodium ..........................................................................2 1.2.1.1 Anti-Malarials ..................................................................................5 1.2.2 Genus Leishmania ............................................................................8 1.2.2.1 Anti-leishmanials ...........................................................................11 1.3 ESKAPE Pathogens ...................................................................................12 1.3.1 Staphylococcus aureus ...................................................................14 1.3.1.1 Staphylococcal Toxins ...................................................................15 1.3.1.2 Antibiotics for Staphylococcus aureus ..........................................17 1.3.2 Acinetobacter baumannii ...............................................................25 1.3.2.1 Antibiotics for Acinetobacter baumannii.......................................26 Chapter 2: 1,4-Dihydropyridines as Anti-Malarials ..........................................................29 2.1 Hantzsch Pyridine Synthesis ......................................................................29 2.1.1 Enantioselective Syntheses of 1,4-Dihydropyridines ....................30 2.1.2 Biological Activity of 1,4-Dihydropyridine Derivatives ...............36 2.2 1,4-Dihydropyridine Syntheses..................................................................38 2.2.1 Synthetic Plan ................................................................................39 2.2.1.1 Comparison of Methylene and Oxygen Derivatives ......................40 v 2.2.1.2 Synthetic Scheme with Chiral Auxiliaries .....................................44 2.2.1.3 Synthetic Schemes for Chiral β-Ketolactones ...............................56 2.2.2 Structure-Activity Relationship of 1,4-Dihydropyridines .............62 2.2.2.1 Structure-Activity Relationship at 4- and 7-Positions ...................62 2.2.2.2 Structure-Activity Relationship of the 2- and 3-Positions .............66 2.2.2.3 A Few Polyhydroquinoline Derivatives.........................................68 2.2.2.4 Role of Stereochemistry in Activity ..............................................69 2.2.2.5 Role of Stereochemistry on Solubility and Permeability ...............70 2.3 Summary ....................................................................................................71 Chapter 3: Quinazolines as Anti-Leishmanials..................................................................73 3.1 Chemistry of the Quinazoline Class ..........................................................73 3.2 Medicinal Importance of the Quinazoline Class ........................................74 3.2.1 Quinazolines in the Literature as Anti-Leishmanials.....................76 3.3 Anti-Leishmanial Testing ..........................................................................77 3.3.1 Synthetic Chemistry .......................................................................77 3.3.2 In vitro Anti-Leishmanial Efficacy and Cytotoxicity ....................78 3.3.2.1 Structure-Activity Relationship Studies. .......................................79 3.3.2.2 Cytotoxicity....................................................................................83 3.3.3 Mechanism of Action .....................................................................84
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