Publication Date

2015

Document Type

Dissertation/Thesis

First Advisor

Hagen, Timothy J.

Degree Name

M.S. (Master of Science)

Legacy Department

Department of Chemistry and Biochemistry

LCSH

Organic chemistry; Isopentenoids; Lipids--Synthesis--Inhibitors; Enzyme inhibitors; Pharmaceutical chemistry

Abstract

The 2-C-methyl-D-erythritol-4-phosphate pathway, or MEP pathway, has recently gained attention as being a prime target for inhibition of many pathogenic species due to the lack of analogous enzymes in humans and many higher eukaryotes that use the mevalonic acid pathway. Either the MEP pathway or mevalonic acid pathway are utilized by all living organisms to generate the molecules isopentenyl diphosphate, IPP, and dimethyallyl diphosphate, DMAPP, which in turn can be used to create a wide variety of necessary cellular components called isoprenoids, such as cholesterol, some vitamins, pigments, etc. The MEP pathway involves seven different enzymes, which are unique in the cellular machinery. Each is a potential target for inhibition by small molecules that could prove to be fatal to the organism.;In an NMR based screening of the Fragments of Life library, the fragment FOL7082 was one of thirty-seven compounds that bound to both IspD of Mycobacterium paratuburculosis and IspE of Mycobacterium abscessus. The fragment hit FOL7082 was optimized using a Topliss Tree approach to generate a small library of analogs that were tested in a variety of biological assays. Synthesis of this library was performed using a reaction scheme that allowed for a high number of analogs to be made from the same starting material with only variation of the carboxylic acid used. Further changes to FOL7082 were made by incorporating different heterocycles in place of indole, such as benzothiazole and benzimidazole, to test if there was an increased activity against enzymatic targets IspD and IspE.;Overall, analogs of the original fragment hit, FOL7082 were synthesized that resulted in a greater than 20-fold increase in activity against enzyme target IspD. Analogs showed some antibacterial activity as well as herbicidal activity through inhibition of germination. While the project was successful in taking a fragment hit with no measurable activity to a compound with 50 muM activity against IspD, further analogs need to be developed to enhance activity further.

Comments

Advisors: Timothy Hagen.||Committee members: Jim Horn; Douglas Klumpp.

Extent

177 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

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