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The Development of Novel Heteroatom-Activated Acylating Agents: Potential Beta-Lactam Mimics

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posted on 2014-09-08, 00:00 authored by Nicole M. Windmon

The research in this dissertation focuses on the synthesis and in vitro testing of structurally novel potential β-lactam antibiotic mimics utilizing a heteroatom-activation strategy. It had been previously demonstrated that isoxazolidines appended with a phenyl acetyl side chain exhibited antibacterial activity when tested against a strain of bacteria sensitive to β-lactam antibiotics such as E. coli X580. It was then hypothesized that the activity seen with this compound was due to the Weinreb amide moiety present in the molecule and a carefully positioned ionizable group. This moiety was believed to activate the Weinreb amide carbonyl towards acylation in the same way that monobactams such as oxamazin and aztreonam are activated by adjacent heteroatoms. If isoxazolidines are in fact mimicking β-lactam antibiotics by exploiting a heteroatom-activation strategy, then appropriate elaboration of these molecules may provide a more potent antibiotic. The overall hypothesis of the present work is that heteroatom-activated acylating agents are a potential new class of antibiotic, that mimic β-lactam antibiotics.

In order to test this hypothesis, three specific aims were executed. First, side chain variation of the lead compound was explored in order to increase the potency and broad- spectrum antibacterial activity. Additional isoxazolidines were synthesized which incorporated side chains analogous to side chains that many effective β-lactam antibiotics utilized. These side chains included phenylglycine and 2-(2-aminothiazol-4-yl)-2- methoxyiminoacetic acid (ATMO).

Secondly, it was imperative that the minimum essential features of a heteroatom- activated β-lactam mimic were established. The hypothesis was accomplished by synthesizing three different core structures such as an acyclic, monocyclic and bicyclic core. All of which utilized heteroatom-activation strategy and contained side chains analogous to those used in known β-lactam antibiotics. In addition, the current progress towards a diketopiperzine derived from an isoxazolidine is presented which could also exhibit antibacterial activity.

Lastly, each compound synthesized was evaluated for antibacterial activity by conducting zone of inhibition assays against a broad range of bacterial isolates, determining MIC values for active compounds, and submitting all the compounds for β- lactamase inhibition assays.

History

Date Modified

2017-06-02

Defense Date

2014-09-04

Research Director(s)

Marvin Miller

Committee Members

Marvin Miller

Degree

  • Doctor of Philosophy

Degree Level

  • Doctoral Dissertation

Language

  • English

Alternate Identifier

etd-09082014-124018

Publisher

University of Notre Dame

Program Name

  • Chemistry and Biochemistry

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