Publication Date

2016

Document Type

Dissertation/Thesis

First Advisor

Hagen, Timothy J.

Degree Name

M.S. (Master of Science)

Department

Department of Chemistry and Biochemistry

LCSH

Enzyme inhibitors||Enzymes--Synthesis||Antibacterial agents

Abstract

This thesis explores the inhibition of the IspE enzyme, found within the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway, using a variety of molecular scaffolds for the development of potential antibacterial agents. This research involved two distinct projects: First, the design of an improved synthetic route for MEP. MEP is the substrate utilized in the IspD reaction and can be converted enzymatically to produce CDP-ME, the substrate for IspE. Therefore, MEP is a valuable compound that is necessary for our IspD and IspE inhibition assays. Second, the design and synthesis of two different scaffold series was implemented for the purpose of developing IspE inhibitors. The first series contained the 2-indolinone scaffold and was screened for its antibacterial properties against 9 bacterial strains. Two compounds had large zones of inhibition at 1 mM against all tested organisms indicating moderate antibacterial activity. The second series incorporated an oxadiazole ring with either an indole or a benzothiazole ring attached. These compounds were screened against Burkholderia thailandensis and Escherichia coli IspE utilizing a thermal shift assay and an enzyme inhibition assay. The compounds were also tested against 9 bacterial strains. Three compounds had low micromolar IC50 values against E. coli IspE. There was a range of activity between the 15 compounds in this series permitting the determination of a structure-activity relationship (SAR).

Comments

Advisors: Timothy J. Hagen.||Committee members: James R. Horn; Lee S. Sunderlin.||Includes bibliographical references.||Includes illustrations.

Extent

ix, 128 pages

Language

eng

Publisher

Northern Illinois University

Rights Statement

In Copyright

Rights Statement 2

NIU theses are protected by copyright. They may be viewed from Huskie Commons for any purpose, but reproduction or distribution in any format is prohibited without the written permission of the authors.

Media Type

Text

Share

COinS