Graduation Semester and Year

2016

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry

Department

Chemistry and Biochemistry

First Advisor

Frank W Foss

Abstract

Current bacterial chemotherapy faces an overwhelming reduction in efficacy due to an increase in bacterial resistance; resulting in a higher clinical demand for novel therapeutics and the investigation for their respective targets. Vitamin pathways exogenous to the human body represent an attractive target for drug development since the enzymatic machinery is solely and ubiquitously to many infectious agents. HMP kinase [E.C 2.7.1.49] is a key enzyme in the thiamine metabolism. It catalyzes two subsequent phosphorylations of 4-amino-5-hydroxymethyl-2-methylpyrimidine (HMP), making it indispensable for microbial survival. Our efforts aimed for a substrate-based approach, where over 50 HMP analogs were synthesized and assayed towards substrate scope and enzyme inhibition. Development of in vitro and in silico analyses were imperative in our search for the needle in a haystack; furthermore, they have aided in the formulation of a structure-activity relationship (SAR) and paved the way for future synthesis. The catalytic activity of HMP was confirmed via a multitude of analytical tools such as UV-Vis, chemiluminescence, liquid chromatography, and mass spectrometry; resulting in the first generation of inhibitors and giving light to a whole new realm of compounds with pro-drug characteristics.

Keywords

Antibiotics, Enzyme assay

Disciplines

Chemistry | Physical Sciences and Mathematics

Comments

Degree granted by The University of Texas at Arlington

Included in

Chemistry Commons

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