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Synthesis, in Vitro Characterization and Applications of Novel 8-Aminoquinoline Fluorescent Probes Adonis Mcqueen University of South Florida, [email protected]

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Synthesis, in Vitro Characterization and Applications of Novel 8-Aminoquinoline Fluorescent Probes Adonis Mcqueen University of South Florida, Amcquee1@Health.Usf.Edu University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School October 2017 Synthesis, in vitro Characterization and Applications of Novel 8-Aminoquinoline Fluorescent Probes Adonis McQueen University of South Florida, [email protected] Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the Medicine and Health Sciences Commons, Organic Chemistry Commons, and the Parasitology Commons Scholar Commons Citation McQueen, Adonis, "Synthesis, in vitro Characterization and Applications of Novel 8-Aminoquinoline Fluorescent Probes" (2017). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/7062 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]. Synthesis, in vitro Characterization and Applications of Novel 8-Aminoquinoline Fluorescent Probes by Adonis McQueen A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Molecular Medicine Department of Molecular Medicine College of Medicine University of South Florida Major Professor: Dennis E. Kyle, Ph.D. Burt Anderson, Ph.D. Yu Chen, Ph.D. Lynn Wecker, Ph.D. Date of Approval: October 13, 2017 Keywords: Malaria, Primaquine, Drug Discovery, Mechanism of Action, Parasitology, Medicinal Chemistry Copyright © 2017, Adonis McQueen ACKNOWLEDGMENTS This research is a culmination of everyone I’ve interacted with, everyone who’s taught me and everyone I’ve ever taught. I thank my Creator for allowing me to make it this far. As far as people go, I owe my first thanks to Dr. Dennis Kyle. Without your mentorship, patience and guidance, I wouldn’t have been able to complete this project. You are an amazing scientist and an even greater man. I am privileged to have known you and to work in your lab. My time in your lab has provided me with the skills necessary to pursue any era of research I wish. For that, and for your countless lab meeting jabs, I will always be grateful. To Dr. Roman Manetsch, you too have been an excellent mentor and professor. Our interactions have taught me to not let setbacks weigh me down, and that any progress is good progress. I am grateful for your attentiveness, honesty, wisdom, and light hearted nature. Working in your lab made me re-discover why I enjoy chemistry so much. To my scholarship and fellowship mentors Ms. Edna Cofield and Mr. Bernard Batson. You both have made sure that my life stayed balanced and informed during my professional transitions. Both of you have helped me develop my professional network in ways I still cannot even imagine. I am blessed to know the both of you. The progress made by thousands of students can be directly or indirectly attributed to your commitment to your work. I only hope I can have the same impact on students as the two of you. To my family: Gloria McQueen (Mom), Monica, Lisa, Jasper and Ocie. You all have been a huge help not just in graduate school, but throughout my entire education as I reached for this goal. Now that I’ve attained it, each of your individual inputs over time have all had a great impact on my life and success. I couldn’t have done this without any of you, especially Mom. You always encouraged me, helped me when I needed it, and told me your truth even when I didn’t want to hear it. I am truly blessed and privileged to have such loving people in my family. To my lab mates and friends, there are so many of you to thank I couldn’t even begin to list you all (but I’m going to try!!!). Sasha, Lynn, Marvin, Debbie, Tina, Miles, TJ, Beatrice, Samantha, Steve and Amanda from the Kyle lab; all of you have helped me in one way or another to complete my goal. I literally couldn’t have done this without any of you. Niranjan, Kurt, Cindy, Iredia, Jordainy, David and Andrii from the Manetsch lab; each of you have been instrumental in helping me refine my rough organic chemistry skills. I hope that we all can continue to learn from each other in the years to come. To my close friends Jamarr, Liz, Jennifer, Kyle, Ahmad, Chris, Geoff, Krishna, Jessica, Stephanie, Brian, Jerome and Kali, thank you for keeping me sane in between the rough shores of endless experiments and information dense classes. You all have literally helped me maintain my sanity, and each of you has been vital in my physical and mental transformation. I couldn’t have asked for a better group of people to associate myself with. I love and appreciate every single person listed in this acknowledgement. “Alone we can accomplish so little, but together we can accomplish so much”. This quote means so much more to me now than it ever did before, and I know it’s because of the impact you all have had on my life. I pray that I am able to exceed all of your expectations as well as my own. Let us all create the future together. TABLE OF CONTENTS List of Tables .............................................................................................................................................. iii List of Figures .............................................................................................................................................. iv Abstract ........................................................................................................................................................ vi vi Chapter 1: Introduction ................................................................................................................................. 1 1 Malaria History ............................................................................................................................... 1 Life Cycle ........................................................................................................................................ 1 1 Pathology ......................................................................................................................................... 3 3 Immunization and Human Host Protection Mechanisms................................................................. 5 Immunity and Immunization............................................................................................... 5 Human Host Protection Mechanisms .................................................................................. 7 Glucose 6-Phosphate Dehydrogenase Deficiency ................................................. 7 Thalassemias .......................................................................................................... 8 Sickle Cell Anemia ................................................................................................ 9 Malaria Chemotherapeutics: Mechanisms of Action and Resistance ............................................ 10 Arylamino Alcohols .......................................................................................................... 10 Quinine ................................................................................................................ 10 Mefloquine ........................................................................................................... 11 Antifolates and Atovaquone ............................................................................................. 11 Sulfadoxine and Pyrimethamine .......................................................................... 11 Proguanil .............................................................................................................. 12 Atovaquone .......................................................................................................... 13 Antibiotics ................................................................................................................ 14 Clindamycin ......................................................................................................... 14 Doxycycline ......................................................................................................... 14 4-Aminoquinolines ........................................................................................................... 15 Chloroquine ......................................................................................................... 15 Amodiaquine ........................................................................................................ 17 Piperaquine .......................................................................................................... 18 Endoperoxides ................................................................................................................ 18 Methylene Blue and 8-Aminoquinolines .......................................................................... 20 Methylene Blue .................................................................................................... 20 8-Aminoquinlines: Primaquine and Tafenoquine ................................................ 21 Project Specific Background .......................................................................................................... 25 Focus of Study ............................................................................................................................... 26 27 Chapter 2: Synthesis and Characterization of Novel 8-Aminoquinoline Fluorescent Probes .................... 31 Introduction ...................................................................................................................................
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