Date of Award

Spring 2021

Project Type

Dissertation

Program or Major

Chemistry

Degree Name

Doctor of Philosophy

First Advisor

Marc Boudreau

Second Advisor

Arthur Greenberg

Third Advisor

Richard P. Johnson

Abstract

ABSTRACT DEVELOPMENT OF OPEN LACTAM AND CAPTOPRIL ANALOGUES FOR THE COVALENT INHIBITION OF METALLO-β-LACTAMASES

ByMARIE-JOSIANE OHOUEU University of New Hampshire, May 2021 The synthesis of a series of compounds designed to act as inhibitors of metallo-β-lactamase enzymes (MBLs), a sub-class of β-lactamases found in several clinically difficult to treat bacteria that are responsible for the widespread β-lactam antibiotic resistance, are described. The strategy involves the introduction of a functional group, such as an epoxide or thiirane, in the designed inhibitors capable of covalently binding the MBL targets and shutting them down irreversibly. This would prevent the enzymes from hydrolyzing the antibiotic drugs which would maintain their efficacy as a form of treatment. This was first attempted through the development of a convergent synthesis which involved the formation of L- and D-vinylglycine methyl ester, serving for the incorporation of the strained member ring, in a five-step synthetic pathway. This was subsequently introduced using coupling chemistry to a dipeptide. The intermediate dipeptide precursor synthesized through amino acid coupling was phenylglycine-serine (Phe-Ser) followed by a phenylacetic acid-serine (PAA-Ser), which both mimic an open lactam structure. They were subjected to halogenation to convert the serine alcohol functional group to a bromide for the alkylation reaction with the amino group contained in the protected vinylglycine. However, the bromination of Phe-Ser proved to be difficult while the formation of the desired tripeptide with the brominated PAA-Ser was not observed. Evidence of an alkene product was observed which was attributed to the acidic proton at the α-position favoring the elimination of the bromine. Those limitations led to the modification of the serine core to aspartic acid which was thought to circumvent the elimination issue by introducing the vinylglycine by amide bond formation rather than alkylation. Investigation with the phenylacetic-acid-aspartic acid dipeptide led to a promising route in which the coupling of the vinylglycine was achieved efficiently. The subsequent last steps of epoxidation of the alkene and deprotection seemed to be successful although optimization of these is still required. Another strategy for the development of covalent inhibitors was the synthesis of compounds inspired from L-captopril, an inhibitor of angiotensin converting enzyme (ACE inhibitors) which plays a role in heart attack. Here, the strategy involves the synthesis of an alkene-containing intermediate with 2-methylprop-2-enoic acid or 2-methyl-3-butenoic acid through acylation of proline ethyl ester with the corresponding acyl chlorides. The intermediates were successfully obtained enabling the formation of the epoxide and thiirane compounds. Subsequently, the ethyl ester hydrolysis was done to get the final derivatives 1-(2-methyloxirane-2-carbonyl) pyrrolidine-2-carboxylic acid (82) and 1-(2-methylthiirane-2-carbonyl) pyrrolidine-2-carboxylic acid (83) with evidence of the formation of the desired 82 and 83. In the case of the longer chain analogues, 1-[2-(oxirane-2yl)propanoyl] pyrrolidine-2-carboylic acid (84) and 1-[2-(thiirane-2yl)propanoyl] pyrrolidine-2-carboylic acid (85), the deprotection led to the isolation of the final thiirane compound 85 in an overall 5% yield while this last deprotection step remains to be optimized to obtain 84. The synthetic pathway of the open lactam derivatives was overall successful with only the last two steps requiring further optimization which would provide a new class of β-lactamase inhibitors. The pathway for the development of the proline derivatives afforded efficiently one of the desired captopril derivatives while the purification of last step to isolate the remaining compounds needs to be improved. The strategy presented could be used in the future to provide further library compounds for MBL inhibition for further studies.

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