DOCSLIB.ORG

Development of Open Lactam and Captopril Analogues for the Covalent Inhibition of Metallo-Β-Lactamases

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Development of Open Lactam and Captopril Analogues for the Covalent Inhibition of Metallo-Β-Lactamases University of New Hampshire University of New Hampshire Scholars' Repository Doctoral Dissertations Student Scholarship Spring 2021 DEVELOPMENT OF OPEN LACTAM AND CAPTOPRIL ANALOGUES FOR THE COVALENT INHIBITION OF METALLO-β-LACTAMASES Marie-Josiane Ohoueu University of New Hampshire, Durham Follow this and additional works at: https://scholars.unh.edu/dissertation Recommended Citation Ohoueu, Marie-Josiane, "DEVELOPMENT OF OPEN LACTAM AND CAPTOPRIL ANALOGUES FOR THE COVALENT INHIBITION OF METALLO-β-LACTAMASES" (2021). Doctoral Dissertations. 2588. https://scholars.unh.edu/dissertation/2588 This Dissertation is brought to you for free and open access by the Student Scholarship at University of New Hampshire Scholars' Repository. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of University of New Hampshire Scholars' Repository. For more information, please contact [email protected]. DEVELOPMENT OF OPEN LACTAM AND CAPTOPRIL ANALOGUES FOR THE COVALENT INHIBITION OF METALLO-β-LACTAMASES BY MARIE-JOSIANE OHOUEU B.S., American International College, 2013 M.S., New Mexico Highlands University, 2015 DISSERTATION Submitted to the University of New Hampshire in Partial Fulfillment of the Requirement for the Degree of Doctor of Philosophy in Chemistry May, 2021 This dissertation was examined and approved in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry by: Dissertation Director, Marc A. Boudreau, Assistant Professor, Department of Chemistry Arthur Greenberg, Professor, Department of Chemistry Richard P. Johnson, Professor, Department of Chemistry Christopher Bauer, Professor, Department of Chemistry Krisztina Varga, Associate Professor, Department of Molecular, Cellular, and Biomedical Sciences On April 12th, 2021 Approval signatures are on file with the University of New Hampshire Graduate School. ii DEDICATION To my parents, brothers, Drou, and all my family members, For their constant support and encouragements. Thank you. iii ACKNOWLEDGMENTS I would like to thank my research advisor, Marc Boudreau, for his support and guidance. He has helped me grow as a chemist and expand my knowledge and understanding in the field of chemistry. Also, I thank my committee members for the time and support they have dedicated me during this process. To my friends close and far, all across the globe, thank you for making grad school what it has been with your messages and calls of encouragement. And a special thanks to Dr. Deisy Pena-Romero and Dr. Sharon Song for always being there to guide and cheer me up during grad school. I would like to acknowledge the past and present Boudreau group members for making these years in lab fun. I thank especially my parents, my brothers, Drou and his family for being there during these years whenever I needed them. Cindi and Laura, I would like to thank you for the support you have provided me during my time at UNH and helping in every way you could to make it smooth administratively but also with all the kind and supportive words and gestures you had. It was always greatly appreciated. To the university instrument center, particularly Dr. Patricia Wilkinson and Jon Wilderman, thank you for providing help to set up NMR experiments and troubleshooting any related issues whenever I needed it. iv TABLE OF CONTENTS DEDICATION ……………………………………………………………………..……………………...iii ACKNOWLEDGEMENTS ………………………………………………….…………………..……….iv LIST OF SCHEMES ……………………………………………………………..…………..…………..x LIST OF FIGURES ……………………………………………………………………….………….…xii LIST OF TABLES ………………………………………………………………………………………xv ABSTRACT……………………………………………………………………………..………………xvi GENERAL INTRODUCTION……………………………………………………………………………1 CHAPTER I. INTRODUCTION TO β-LACTAMASES AND ANTIMICROBIAL RESISTANCE..…2 Bacterial infections: a life-threatening issue …………………………………………………………….2 Antibiotics and their modes of action against bacteria ………………………...………………………3 Mechanisms of antimicrobial resistance in bacteria ……………………………………………………8 β-Lactam antibiotics and β-lactamases enzymes……………………………………………………..11 Metallo-β-lactamases (MBLs)….………………………………………………...……………………...14 Inhibitors of metallo-β-lactamases……………………………………..………………………………..18 Overall research goal …………………………………………………………………………………….24 CHAPTER II. OPEN β-LACTAM ANALOGUES AS COVALENT INHIBITORS TARGETING METALLO- β-LACTAMASES…………………………………………..………………..….…………27 INTRODUCTION………………………………………………………………………………………….27 From closed lactam ring to modification into the open β-lactam analogues………….….27 v RESEARCH OBJECTIVES………………………………………………………………………………29 Covalent inhibition of MBLs with strained 3-membered ring open lactam analogues ..…29 Proposed mechanism of action of covalent 3-membered ring open lactam analogues....31 RESULTS AND DISCUSSION..…………………………………………………………………………34 Synthesis of Vinylglycine methyl ester hydrochloride (23) ………………………...……….34 Attempted synthesis of (2S)-(2-amino-2-phenylacetamido)-3-oxo-(3-sulfanylpropyl)amino- (oxiran-2-yl)acetic acid (12) ………………………………………………………….……….35 Attempted synthesis of (2S)-(2-phenylacetamido)-3-oxo-(3-sulfanylpropyl)amino-(oxiran- 2-yl) acetic acid (13)..…………………………………………………………..…………….…40 Attempted synthesis of (2S)-2-({[9H-fluoren-9-yl)methoxy]carbonyl]amino)-4-oxo-(1- methoxy-1-oxobut-3-en-2-yl)amino)-1-oxo-1-[(prop-2-en-yl)oxy]butanoate (14)……...…45 CONCLUSIONS…….………………………………………………………………………………….…53 CHAPTER III. CAPTOPRIL-INSPIRED COMPOUNDS AS COVALENT INHIBITORS OF METALLO- β-LACTAMASES……………………………………………………………………….…55 IINTRODUCTION…………………………………………………………………………………………55 Development of captopril and applications to enzyme inhibition ……………..……….….55 RESEARCH OBJECTIVES………………………………………………………………………62 Covalent inhibition of MBLs using new captopril derivatives containing a thiirane or epoxide functional group………….………………………………………...……..62 Proposed mechanism of action for the captopril derivatives containing a strained 3-membered ring for covalent inhibition……….………………………………..…...64 RESULTS AND DISCUSSION…………………..……………………………………….……………..66 vi Synthesis of 1-(2-methyloxirane-2-carbonyl)pyrrolidine-2-carboxylic acid (82) and 1-(2- methylthiirane-2-carbonyl)pyrrolidine-2-carboxylic acid (83) ……….………………...……66 Synthesis of 1-[2-(oxiran-2yl)propanoyl] pyrrolidine-2-carboylic acid (84) and 1-[2- (thiirane-2yl)propanoyl] pyrrolidine-2-carboylic acid (85)………………………..……….…72 CONCLUSION…………………………………………………………………………………………….74 CHAPTER IV. EXPERIMENTAL……………………………………...…………………………...….76 GENERAL PROCEDURES..…………………………………………………………………….………76 Solvents……………………………………..………………………………….………….…….76 Reagents and reaction conditions………………..…………………………………….……..76 Purification techniques………………………………..………………………………....……..77 Instrumentation for compound characterization………………………………..……….……77 DETAILED EXPERIMENTAL SECTION CHAPTER II……………………………..…..…….………79 Cbz-L-methionine methyl ester hydrochloride (19b)……………………...……..….….……79 Cbz- L-Methionine methyl ester sulfoxide (20b)………………………………….…………..79 Synthesis of Cbz-L-Vinylglycine methyl ester (21b)…………………………..…………..…80 Synthesis of L-vinylglycine hydrochloride(22b)…………………………………..……...…..81 Synthesis of L-vinylglycine methyl ester(23b)…………………………………..……………81 Synthesis of prop-2-enyl- (2S)-2-amino-3(tert-butyl(dimethylsilyl)oxypropanoate (34) …82 Synthesis of 3-(prop-2-en-1-yl)-2-[(2S)-2-N-tert-butoxycarbonylamino-2- phenylacetamido]-1-tert-butyl(dimethylsilyl)oxypropanoate (35) .…………………………83 Synthesis of 3-(prop-2-en-1-yl)-2-[(2S)-2-N-tert-butoxycarbonylamino-2- phenylacetamido]-1-hydroxypropanoate (36)………………………………………..………84 vii Synthesis of 3-(prop-2-en-1-yl)-(2-phenylacetamido)-1-tert- butyl(dimethylsilyl)oxypropanoate (41)…………………………………..……………..…….85 Synthesis of 3-(prop-2-en-1-yl)-(2-phenylacetamido)-1-hydroxypropanoate (42)………..86 Synthesis of 3-(prop-2-en-1-yl)-(2S)-2-phenylacetamido-1-bromopropanoate (43)…..…86 Synthesis of prop-2-en-1-yl-(2S)-[(tert-butoxycarbonyl)amino]-3-hydroxy propanoate (46)……………………………………………………………………………………………….87 Synthesis of prop-2-en-1-yl-(2S)-[(tert-butoxycarbonyl)amino]-3-oxopropanoate (47)….88 Synthesis of (2S)-2-({[9H-fluoren-9-yl)methoxy]carbonyl]amino)-4-oxo-(1-methoxy-1- oxobut-3-en-2-yl)amino)-1-oxo-1-[(prop-2-en-yl)oxy]butanoate (51)………………………88 Synthesis of 1-tert-butyl 4-methyl (2S)-(2-phenylacetamido)butanedioate (58) …………89 Synthesis of 4-tert-butoxy-4-oxo- (3S)-(2-phenylacetamido)butanoic acid (59) …………90 Synthesis of 1-tert-butyl -4-[(2S)-(1-methoxy-1-oxobut-3-en-2-yl)amino]-4-oxo-(2S)-(2- phenylacetamido)butanedioate (60)…………………………………………………………..91 Synthesis of 4-[(1-methoxy-1-oxobut-3-en-2-yl)amino]-4-oxo-(2S)-(2- phenylacetamido)butanoic acid (61)………………..…………………………………………92 Synthesis of 4-{[2-methoxy-2-oxo-1-(oxiran-2-yl)-2-oxoethyl]amino}-4-oxo-2-(2- phenylacetamido)butaneoic acid (62)…………………………………………..…………….93 Synthesis of 4-{[2-methoxy-2-oxo-1-(oxiran-2-yl)-2-oxoethyl]amino}-4-oxo-2-(2- phenulacetamido)butaneoic acid (63)…………………………………………..…………….93 DETAILED EXPERIMENTAL SECTION CHAPTER III……………………………………………....94 Synthesis of ethyl-1-(2-methylprop-2-enoyl)pyrrolidine-2-carboxylate (92)……………....94 Synthesis of ethyl-1-(2-methyloxirane-2carbonyl)pyrrolidine-2-carboxylate (93)………...95 Synthesis of 1-(2-Methyloxirane-2-carbonyl)pyrrolidine-2-carboxylic acid (82)…………..96 viii Synthesis of ethyl-1-(2-methylthiirane-2-carbonyl)pyrrolidine-2-carboxylate (94)…..…...96 Synthesis of 1-(2-methylthiirane-2-carbonyl)pyrrolidine-2-carboxylic acid (83)……..……97 Synthesis of ethyl-1-(2-methylbut-3-enoyl)pyrrolidine-2-carboxylate (98)………..……….98 Synthesis of ethyl-1-[2-(oxiran-2-yl)propanoyl]pyrrolidine-2-carboxylate
Load more

Recommended publications
  • Structure, Genetics and Worldwide Spread of New Delhi Metallo-Β-Lactamase (NDM): a Threat to Public Health Asad U
    Khan et al. BMC Microbiology (2017) 17:101 DOI 10.1186/s12866-017-1012-8 REVIEW Open Access Structure, Genetics and Worldwide Spread of New Delhi Metallo-β-lactamase (NDM): a threat to public health Asad U. Khan1*, Lubna Maryam1 and Raffaele Zarrilli2,3* Abstract Background: The emergence of carbapenemase producing bacteria, especially New Delhi metallo-β-lactamase (NDM-1) and its variants, worldwide, has raised amajor public health concern. NDM-1 hydrolyzes a wide range of β-lactam antibiotics, including carbapenems, which are the last resort of antibiotics for the treatment of infections caused by resistant strain of bacteria. Main body: In this review, we have discussed blaNDM-1variants, its genetic analysis including type of specific mutation, origin of country and spread among several type of bacterial species. Wide members of enterobacteriaceae, most commonly Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and gram-negative non-fermenters Pseudomonas spp. and Acinetobacter baumannii were found to carry these markers. Moreover, at least seventeen variants of blaNDM-type gene differing into one or two residues of amino acids at distinct positions have been reported so far among different species of bacteria from different countries. The genetic and structural studies of these variants are important to understand the mechanism of antibiotic hydrolysis as well as to design new molecules with inhibitory activity against antibiotics. Conclusion: This review provides a comprehensive view of structural differences among NDM-1 variants, which are a driving force behind their spread across the globe. Keywords: Enterobacteriaceae, New Delhi-Metallo-Beta-Lactamases, Carbapenemases, Antibiotic resistance Background bacteria allowing the resistant bacteria to bloom and Although antibiotics were developed to fight infections, the susceptible bacteria to pass away.
    [Show full text]
  • Chemoenzymatic Asymmetric Synthesis of the Metallo- Β
    University of Groningen Chemoenzymatic asymmetric synthesis of the metallo-β-lactamase inhibitor aspergillomarasmine A and related aminocarboxylic acids Fu, Haigen; Zhang, Jielin; Saifuddin, Mohammad; Cruiming, Gea; Tepper, Pieter G.; Poelarends, Gerrit J. Published in: Nature Catalysis DOI: 10.1038/s41929-018-0029-1 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2018 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Fu, H., Zhang, J., Saifuddin, M., Cruiming, G., Tepper, P. G., & Poelarends, G. J. (2018). Chemoenzymatic asymmetric synthesis of the metallo-β-lactamase inhibitor aspergillomarasmine A and related aminocarboxylic acids. Nature Catalysis, 1(3), 186-191. https://doi.org/10.1038/s41929-018-0029-1 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 25-09-2021 ARTICLES https://doi.org/10.1038/s41929-018-0029-1 Chemoenzymatic asymmetric synthesis of the metallo-β-lactamase inhibitor aspergillomarasmine A and related aminocarboxylic acids Haigen Fu1,2, Jielin Zhang1,2, Mohammad Saifuddin1,2, Gea Cruiming1, Pieter G.
    [Show full text]
  • University of California San Diego
    UNIVERSITY OF CALIFORNIA SAN DIEGO Conversion of Metal Chelators to Selective and Potent Inhibitors of New Delhi Metallo-beta-lactamase A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Chemistry by Allie Yingyao Chen Committee in charge: Professor Seth M. Cohen, Chair Professor Michael D. Burkart, Co-Chair Professor Bradley S. Moore Professor Joseph M. O’Connor Professor Faik Akif Tezcan 2020 The Dissertation of Allie Yingyao Chen is approved, and it is acceptable in quality and form for publication on microfilm and electronically: _____________________________________________________________ _____________________________________________________________ _____________________________________________________________ _____________________________________________________________ Co-Chair _____________________________________________________________ Chair University of California San Diego 2020 iii DEDICATION To my family - thank you & I love you. iv TABLE OF CONTENTS Signature Page………………………………………………………………………………….iii Dedication……………………………………………………………………………………….iv Table of Contents…………………………………………………………………………..v List of Symbols and Abbreviations……………………………………….……………..ix List of Figures……………………………………………………………….……………..xiii List of Schemes………………………………………………………………..…………...xvi List of Tables…………………………………………………..…………………………..xviii Acknowledgements………………………………………..……………..……….…………xx Vita…………………………………………………..…………………………………………xxiii Abstract of the Dissertation………………………………………………………..…..xxiv Chapter
    [Show full text]
  • Full-Text PDF (Final Published Version)
    Tooke, C. , Hinchliffe, P., Bragginton, E., Colenso, C. K., Hirvonen, V., Takebayashi, Y., & Spencer, J. (2019). β-Lactamases and β- Lactamase Inhibitors in the 21st Century. Journal of Molecular Biology. https://doi.org/10.1016/j.jmb.2019.04.002 Publisher's PDF, also known as Version of record License (if available): CC BY Link to published version (if available): 10.1016/j.jmb.2019.04.002 Link to publication record in Explore Bristol Research PDF-document This is the final published version of the article (version of record). It first appeared online via Elsevier at https://www.sciencedirect.com/science/article/pii/S0022283619301822?via%3Dihub#!. Please refer to any applicable terms of use of the publisher. University of Bristol - Explore Bristol Research General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/ Review KDC YJMBI-66067; No. of pages: 29; 4C: β-Lactamases and β-Lactamase Inhibitors in the 21st Century Catherine L. Tooke †, Philip Hinchliffe †, Eilis C. Bragginton, Charlotte K. Colenso, Viivi H.A. Hirvonen, Yuiko Takebayashi and James Spencer School of Cellular and Molecular Medicine, University of Bristol Biomedical Sciences Building, University Walk, Bristol BS8 1TD, United Kingdom Correspondence to James Spencer: [email protected]. https://doi.org/10.1016/j.jmb.2019.04.002 Edited by G. Dowson Christopher Abstract The β-lactams retain a central place in the antibacterial armamentarium. In Gram-negative bacteria, β-lactamase enzymes that hydrolyze the amide bond of the four-membered β-lactam ring are the primary resistance mechanism, with multiple enzymes disseminating on mobile genetic elements across opportunistic pathogens such as Enterobacteriaceae (e.g., Escherichia coli) and non-fermenting organisms (e.g., Pseudomonas aeruginosa).
    [Show full text]