Graduation Semester and Year

2008

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry

Department

Chemistry and Biochemistry

First Advisor

Carl Lovely

Abstract

This dissertation discusses the synthetic methods towards and the preliminary biological studies of an unnamed, imidazole-containing alkaloid, derived from the marine species Oceanapia. This alkaloid was first discovered in 1996 by researchers at the NIH as a possible inhibitor of the key enzyme in the detoxification cycle of Mycobacterium tuberculosis. Chapter 1 provides an overview of tuberculosis, which is currently the second highest cause of death worldwide, with one third of the world's population infected. In recent years, the emergence of multi-drug resistant strains has created new interest and funding for tuberculosis research. New treatments like the alkaloid described above are of special interest because they attack unique enzymatic pathways of the bacterium species that are not found in the human host. Chapter 2 of this dissertation describes a potential synthetic route to this marine alkaloid which is predicated on the assemble and union of three key fragments: a spiro-isoxazoline, an imidazole, and a quiniolone. The spiro-isoxazoline fragment was synthesized using a minor modification of a previously described synthetic route involving an oxidative dearomatization. The imidazole fragment began with the oxidation of L-histidine into 4-cyanomethylimidazole, which was further elaborated into highly functionalized ester and amine intermediates suitable for use in cross-coupling chemistry. The quinolone fragments were synthesized by rearrangement of Meldrum's acid or cyanoacetate adducts. In the course of this chemistry an interesting chemoselectivity issue was uncovered relating to the selective N- vs O- protection. The key cross-coupling of the imidazole-quinolone fragment was attempted by several methods, but unfortuently this proved to be inefficient, these studies are described in detail. A disk diffusion method was used to evaluate the activity of the main anti-tuberculosis drugs in a non-virulent model system, Mycobacterium smegmatis. Pre-loaded disks were purchased from VWR and placed onto petri dishes with the model bacteria. Plates were incubated for 24-48 hrs and the zones of inhibition were recorded. Several advanced intermediates were also screened for activity against the growth of the bacterial model system. Several of the intermediates tested had zone of inhibition ranges similar to the antimycobacterial agents isonazid and rifampin.

Disciplines

Chemistry | Physical Sciences and Mathematics

Comments

Degree granted by The University of Texas at Arlington

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