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A Dissertation entitled Design, Synthesis, and Inhibition Studies of Compounds Targeting the Enzymes in the Trehalose Utilization Pathway of Mycobacterium Tuberculosis by Sunayana Kapil Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Chemistry Dr. Steven J. Sucheck, Committee Chair Dr. Donald R. Ronning, Committee Member Dr. Peter R. Andreana, Committee Member Dr. James T. Slama, Committee Member Dr. Cyndee Gruden, Dean College of Graduate Studies The University of Toledo August 2019 Copyright 2019, Sunayana Kapil This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Design, Synthesis and Inhibition Studies of Compounds Targeting the Enzymes in the Trehalose Utilization Pathway of Mycobacterium tuberculosis by Sunayana Kapil Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Chemistry The University of Toledo August 2019 Tuberculosis (TB) is an infectious disease that is responsible for more deaths worldwide than any other contagious disease. TB treatment is challenging, which often results in poor adherence to medications, leading to the development of drug-resistant strains of Mycobacterium tuberculosis (Mtb), the bacteria responsible for the disease. The increasing drug-resistance of Mtb has made it necessary to develop new therapeutics. Thus, this dissertation involves the design, synthesis, and inhibition studies of compounds targeting the enzymes involved in the trehalose utilization pathway (TUP) of Mtb. The first chapter introduces the history of TB, the Mtb cell wall, and the role of trehalose dimycolate (TDM) in pathogenesis. The second chapter details the synthesis of a library of 2-aminothiophenes as potential inhibitors of polyketide synthase 13 (Pks13)1 and also introduces the synthesis of mycolic acids in Mtb. The thiophene cores were synthesized by the Gewald reaction and the cores were subsequently treated with different acid chlorides and alkyl amines to yield 2-alkylamido and 3-carboxamide compounds, respectively. These compounds were evaluated for their inhibitory activity against Mtb H37Rv, and one of the compounds containing a perfluorobenzamido group showed excellent inhibition with a minimum inhibitory concentration (MIC) of 0.69 µM. Other literature reports have iii indicated that related compounds containing a perfluorobenzamido group act as potential Pks13 inhibitors.2 Hence, it is assumed that the 2-aminothiophenes prepared in this work can also inhibit Pks13 or target enzymes involved in the biosynthesis of mycolic acids. The third chapter discusses the design and synthesis of mimetic trehalose-6-phosphate (T6P) substrates as inhibitors for Mtb trehalose phosphate phosphatase, which is found in TUP.3 The 6-position of T6P was modified to produce 6-phosphonic acid- (TMP, 2), 6- (methylene) phosphonic acid- (TEP, 3), 6-N-phosphonamide- (TNP, 4) and 6-oxirane trehalose as non-hydrolyzable inhibitors. The obtained compounds were evaluated for their inhibitory activities against homologs of TPP from Mtb, M. lentiflavum (Mlt) and M. triplex (Mtx). The results showed that all compounds strongly inhibited Mtx with IC50 values of 288 ± 32 µM, 421 ± 24 µM, and 1959 ± 261 µM for TMP, TNP, and TEP respectively. The results also indicated that the presence of an atom bearing a lone pair of electrons at the 6-position of trehalose played an important role in binding to TPP. The fourth chapter discusses glycoside hydrolase (GH) enzymes and the targeting of the GH-like enzyme, Mtb GlgE. The section also reviews the classification of GHs into subfamilies based on their mechanistic actions, as well as the importance of targeting Mtb GlgE, as it is a genetically validated drug target. Three different classes of inhibitors were synthesized for targeting Mtb GlgE. First, glycoconjugate-based inhibitors were synthesized via the glycosylation of thioglycoside donor with phenols and cyclohexanols with different substituents. Second, pyrrolidine-based inhibitors were synthesized which mimicked the charge of the substrate in the transition state (TS)-catalyzed reaction with Mtb GlgE. Third, cyclitol-based inhibitors were synthesized which were anticipated to form covalent adducts with GlgE. iv The compounds were tested for their inhibitory activity against Streptomyces coelicolor (Sco) GlgE1-V279S, a GlgE homolog. The results indicated that the glycoconjugate in which the first glucose unit was replaced with a phenyl group bearing a carboxylic acid and amine at the ortho position showed a Ki of 659 µM, and the pyrrolidine-based compound with a propyl group containing a benzyl chloroformate-protected amine showed a Ki of 132.6 ± 8 µM. In contrast, the cyclitol-based inhibitor containing a cyclopropyl ring did not show any inhibition, possibly due to its Michalis conformation which placed the aglycone moiety in an equatorial position. It can thus be concluded that in addition to mimicking the TS, a similar Michaelis conformation is necessary to develop inhibitors for GH enzymes. v Dedicated to my mother. Acknowledgments First and foremost, I express my immense gratitude to my advisor Dr. Steve Sucheck for giving me this opportunity to conduct research in his lab. I am thankful for his invaluable guidance and constant support throughout my PhD. His constant motivation to carry out work in the lab is the most driving force for me to move ahead. I deeply thank our collaborator and committee member Dr. Donald Ronning for his valuable inputs and contribution in various projects. I would like to thank Dr. Richard A. Slayden and Dr. Mary Jackson for their contribution to one of the projects. I sincerely thank my graduate committee members Dr. Peter Andreana and Dr. James Slama for their constant support and insightful comments. My sincere thanks to Dr. Sandeep Thanna, Dr. Cecil Petit, Victoria N. drago and Dr. Christopher M. Goins for their contribution in accomplishing the projects. I thank my fellow labmates past and present for maintaining a cordial atmosphere in the lab especially, Dr. Sandeep Thanna and Dr. Sri Kumar Veleti for guiding me initially through lab techniques. I am grateful to Dr. Yong Wah Kim for training me on NMR and MS. I thank my friends Shriraj, Shivani, Abhishek, Vidhisha, Abhijeet, Yousaf and Sarmad for always cheering me up. Finally, I express my profound gratitude to my family: my mother for her unconditional love, support and motivation, my brother for always supporting me. Last but not least, I would like to thank my husband for his patience and encouragement throughout my PhD. vii Contents Abstract ...……………………………………………………………………………….. iii Acknowledgment ………………………………………………………………………. vii Contents ……………………………………………………………………………….. viii List of Tables …………………….………………………………………………………. x List of Figures …………………………………………………………………………… xi 1. Introduction to Tuberculosis ……………………………………………………….…. 1 1.1 History of Tuberculosis ………………………………………………….…....... 1 1.1.1 Treatment of TB …………………………………………………………. 2 1.2 Mtb cell wall ……………………………………………………………………. 3 1.3 Role of TDM …………………………………………………………………… 6 1.4 Importance of Trehalose ……………………………………………………....... 7 2. Synthesis and evaluation of 2-aminothiophenes against Mtb ………………………..... 9 2.1 Introduction ……………….……………………………………………………. 9 2.2 Mycolic acid synthesis …….……………………………………………………. 9 2.2.1 Mechanistic action of Pks13 …………….……………………………... 10 2.3 Background ….………………………………………………………………… 13 2.4 Results ….……………………………………………………………………... 15 2.4.1 Chemistry ……………………………………………………………….. 15 2.4.2 Inhibition studies ……………………………………………………….. 17 2.5 Experimental …………………………………………………………………... 19 3. Synthesis and invitro characterization of trehalose-based inhibitors of mycobacterial trehalose-6-phosphate phosphatase …………………………………………………….. 29 3.1 Introduction ….………………………………………………………………... 30 viii 3.2. Results and discussion …………….…………………………………………. 32 3.2.1 Chemistry studies ……………………………………………………… 32 3.2.2 Discussion ……….……..……………………………………………… 36 3.3 Experimental …………………….…………..………………………………… 40 4. Targeting Glycoside Hydrolase enzyme GlgE ……………………………….………. 51 4.1 Introduction …………………………...………………………………………. 52 4.2 Classification of GH …………………………………………………………… 53 4.2.1 Based on substrate specificity …………………………...……………… 53 4.2.2 Based on mechanistic action ……………………………...…………….. 53 4.2.3 Based on mode of action ………………………………...……………… 54 4.2.4 Based on amino acid sequence ………………………………………….. 54 4.3 Mechanism for GH …………………………………………………….……… 55 4.4 Targeting GH enzyme GlgE ………………………………………….……….. 57 4.5 Glycoside Hydrolase inhibitors …………………………….…………………. 60 4.5.1 Glyco-conjugate as inhibitors ………………………...…………………. 60 4.5.1.1 Chemistry …………….…………………………………………… 62 4.5.1.2 Experimental for glyco-conjugates ….………………...………….. 65 4.5.2 Iminosugars as Inhibitors ……….………………………………………. 71 4.5.2.1 Experimental for iminosugar-based inhibitors ………...…………. 73 4.5.3 Inhibition studies ………….…………………………………………….. 74 4.5.4 Result and discussion ………….………………………………………... 75 4.5.5 Carbasugars as inhibitors …………….…………………………………. 76 4.5.5.1 Chemistry studies …………………………………………………. 81 4.5.5.2 Results ……………………………………………………………. 85 4.5.5.3 Discussion ………………………………………………………… 86 4.5.5.4 Experimental ……………………………………………………… 88 References …………………………………………………………………………….. 103 ix Appendix A Supporting Information-Chapter 2 …..…………………………………... 125 Appendix B Supporting Information-Chapter 3 ……..………………………………..
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