Dissertation/Thesis Abstract

Design, Synthesis and Biological Evaluation of Small Molecules to Target Mycobacterium tuberculosis Dxr: Exploration of Modified Carbon Chain Lengths and Extended Acyl Substituents
by Jackson, Emily R., Ph.D., The George Washington University, 2013, 222; 3592919
Abstract (Summary)

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the deadliest infectious diseases. Emergence of drug resistant strains of Mtb and co-infection with HIV has made TB both difficult and expensive to treat. New TB therapies are needed to shorten treatment and be effective against all strains and metabolic states of the organism. Development of inhibitors of 1-deoxy-D-xylulose-5-phosphate reducto-isomerase (Dxr), an essential enzyme for Mtb, is a novel approach toward the development of a new TB chemotherapy. Natural product fosmidomycin inhibits Dxr and kills other organisms (Plasmodium falciparum, Escherichia coli) reliant on this enzyme. Interestingly, fosmidomycin is not effective against Mtb. The goals of this work are to rationally design inhibitors that will specifically inhibit Mtb Dxr and enhance cellular uptake. Two series of compounds were designed and synthesized. Compounds from both series inhibit Mtb Dxr and demonstrate enhanced whole cell activity. The synthetic and biological results of this work will be presented.

Indexing (document details)
Advisor: Dowd, Cynthia S.
Commitee: Cahill, Christopher L., King, Michael M., Seley-Radtke, Katherine, Voutchkova-Kostal, Adelina
School: The George Washington University
Department: Chemistry
School Location: United States -- District of Columbia
Source: DAI-B 74/12(E), Dissertation Abstracts International
Subjects: Chemistry, Organic chemistry
Keywords: Acyl substituents, Carbon chain lengths, Dxr, Mycobacterium tuberculosis
Publication Number: 3592919
ISBN: 978-1-303-34745-0
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