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

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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
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