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Synthesis and Antifungal Evaluation of Barbiturate Saponins and Progress Towards Cysteinyl Metal Peptides

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Synthesis and Antifungal Evaluation of Barbiturate Saponins and Progress Towards Cysteinyl Metal Peptides University of New Orleans ScholarWorks@UNO University of New Orleans Theses and Dissertations Dissertations and Theses Spring 5-17-2013 Synthesis and Antifungal Evaluation of Barbiturate Saponins And Progress Towards Cysteinyl Metal Peptides Monika Madhav University of New Orleans, [email protected] Follow this and additional works at: https://scholarworks.uno.edu/td Part of the Medicinal-Pharmaceutical Chemistry Commons, and the Organic Chemistry Commons Recommended Citation Madhav, Monika, "Synthesis and Antifungal Evaluation of Barbiturate Saponins And Progress Towards Cysteinyl Metal Peptides" (2013). University of New Orleans Theses and Dissertations. 1649. https://scholarworks.uno.edu/td/1649 This Dissertation is protected by copyright and/or related rights. It has been brought to you by ScholarWorks@UNO with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in University of New Orleans Theses and Dissertations by an authorized administrator of ScholarWorks@UNO. For more information, please contact [email protected]. Synthesis and Antifungal Evaluation of Barbiturate Saponins And Progress Towards Cysteinyl Metal Peptides A Dissertation Submitted to the Graduate Faculty of the University of New Orleans in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry By Monika Madhav B.Pharm. MDU, India, 2000 M.S. National Institute of Pharmaceutical Education and Research, Mohali, India, 2004 May, 2013 i Dedicated to my dear daughter Nyasa Madhav. ii ACKNOWLEDGEMENTS I would like to express my deep gratitude to my research advisor, Professor Branko S. Jursic, for his patient guidance, enthusiastic encouragement, unwavering support and useful critiques throughout the years. His kindness and generosity made me feel very comfortable working with him. He has always been supportive and provided the freedom to pursue independent work. Without his encouragement and constant inspiration, it would have not been possible to achieve this stage in my life. My deep gratitude and sincere appreciation also goes to the members of my research advisory committee, Dr. Lee Roy Morgan, Dr. Mark L. Trudell and Dr. Ed Stevens, for all of their advice, help and guidance throughout this process. Additionally, I would like to recognize all the former of Dr. Jursic’s group -Dr Ravi Pingali, Dr. Sarada Sagiraju and Dr. Sunil Kumar Upadhyay, for being supportive, cooperative and having a friendly environment in the lab. I would also like to thank all current members of Dr. Jursic’s group- Rajesh Komati and Rebecca Rhon for their support and help. I would like to acknowledge the UNO Department of Chemistry, Department Chair Dr. Matthew Tarr for providing me a wonderful opportunity to use all the facilities at all the times to pursue my research. I am thankful to all the former and current faculty members Dr. Wiley, Dr. Rick, Dr. Cole and Dr. Gibb for all their support and advice. I can never forget how helpful Dr. Corrine was for solving NMR problems. I am very thankful to her for giving me NMR training. Completion of this dissertation and subsequent PhD has been a long journey. During this period, I came across many people who helped me succeed in one or the other way. All their support is invaluable. Without these supporters, especially the select few I am about to mention, I may not have gotten to where I am today, at least not sanely. My special thanks go to Ms. Blanca iii and her family for helping me during the toughest of the time. I cannot imagine writing this thesis without her help. I feel deep gratitude in knowing such a kind and generous person who offered selfless help to me and my daughter when we needed it the most. I extend my thanks to all my friends who filled my heart with joy and encouraged me throughout these days. I have been very fortunate to surround by such great people. I would like to thank my father Mr. R. S. Singhal, mother Mrs. Veena Singhal and grandmother late Shrimati Darshan Devi, for their tremendous emotional support. My special thank to them for constantly motivating me and being much more than supportive through my entire journey. They are always there when I need them and have provided the best of everything. Most of all they gave me the wings of freedom and roots of responsibility so strong, that I never stopped believing in myself. My sister Shalini, brother Piyush have always filled my life with great joy, enthusiasm and stood by me for every moment in my life. Thanks to Jiju Vikas, neice Riya and nephew Aryan for filling our lives with tremendous joy and being there for us always. Great appreciation goes to my husband Maj. D B Madhav, for his love, encouragement and constant support. Acknowledgements are incomplete with the mention of our lovely daughter Nyasa for making our world so beautiful. She is a constant inspiration and encouragment for me to go on and never look back. Huge thanks to her for being there with me always. Waking up every day by my side with a bright smile and innocent eyes make each day very special and fill me with new energy to go on despite all the odds. At the end, I would like to thank God for bestowing his blessings on me, giving me this opportunity and being so kind to me. iv TABLE OF CONTENTS List of Figures .................................................................................................................... ix List of Tables ..................................................................................................................... xi List of Scheme .................................................................................................................. xii Abbreviations .....................................................................................................................xv Abstract ............................................................................................................................ xvi v Chapter 1: Introduction ........................................................................................................1 1.1 Systemic antifungals development ..................................................................................5 1.2 Pharmacological Targets for antifungal agents................................................................6 1.3 Antifungal Agents Chemical Classification .....................................................................7 1.3.1 Polyenes Antibiotics .....................................................................................................7 1.3.2 Azoles ...........................................................................................................................11 1.3.3 Pyrimidines ...................................................................................................................15 1.3.4 Echinocandins ...............................................................................................................16 1.3.5 Sordarins .......................................................................................................................20 1.3.6 Saponins ........................................................................................................................21 1.4 Resistance to antifungal agents ........................................................................................27 1.5 Prevention and Control of Antifungal Resistance ...........................................................29 1.6 Clinical need for New Antifungal Agents .......................................................................29 1.7 Fungal Strains for Antifungal studies ..............................................................................31 1.8 Aim of project ..................................................................................................................38 1.9 References........................................................................................................................41 Chapter 2: Synthesis of Steroidal barbiturate saponins .......................................................50 2.1 Glycosylation methods.....................................................................................................56 2.1.2 Synthesis of barbiturate glycosides ..............................................................................64 2.2 Synthesis of steroid linker derivative ...............................................................................69 2.2.1 Ether linked steroid derivative synthesis ......................................................................71 2.2.2 Synthesis of steroid linker containing carbonate, carbamate and ester ........................83 2.3 Synthesis of novel saponin barbiturates as antifungal compounds ..................................93 vi 2.4 Antifungal studies ............................................................................................................99 2.5 Conclusions ......................................................................................................................101 2. 6 Experimental ...................................................................................................................103
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