Synthesis and Characterization of Pyrazine-Based Prodrugs: A Novel Approach to Combat Multi-Drug Resistant Tuberculosis
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2024-01-10Author
Chambers, Charles
0009-0000-0466-1226
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**Please note that the full text is embargoed until 02/01/2026** Synthesis and Characterization of Pyrazine-Based Prodrugs: A Novel Approach to
Combat Multi-Drug Resistant Tuberculosis
Charles Cole Chambers
The University of Texas – Arlington, 2023
Supervising Professor: Dr. Joseph Buonomo.
The work described in this thesis investigates the development and characterization
of a novel prodrug designed to combat multi-drug resistant tuberculosis (MDR-TB), a
significant and growing global health challenge. Central to this study is the synthesis of a
pyrazine-based prodrug, which innovatively utilizes bicyclic orthoester (BOE) moieties to
improve the therapeutic efficacy and safety profile of this tuberculosis treatment.
At the core of this research project is the strategic design of a prodrug to exploit the
acidic microenvironment within macrophages infected by Mtb. This unique approach
enables the selective acid-catalyzed hydrolysis of the prodrug, releasing pyrazinoic acid
(POA), the active pharmacological agent at the site of action. The specificity of this
mechanism likely minimizes systemic toxicity, potentially paving the way for higher
dosage administrations and addressing the limitations of current TB medications,
particularly in the context of drug resistance and adverse side effects.
The research methodically explores the synthesis, chemical properties, and
potential therapeutic implications of various orthoester structures. This includes an
extensive investigation of symmetrical bicyclic orthoesters and asymmetrical orthoesters.
The study employs advanced synthetic techniques, such as the Steglich esterification, along
with a series of epoxidation reactions to generate key epoxide-alcohol intermediates. These
intermediates are vital for the subsequent cyclization processes, ultimately leading to the
formation of the targeted bicyclic orthoester structures.
Moreover, the thesis discusses the prodrug's mechanism of action, delving into the
biological interactions and metabolic pathways within the M. tuberculosis infected
macrophages. The research also touches upon the challenges of drug resistance in TB
treatment, examining how the prodrug's design could potentially circumvent these issues.
The findings of this research demonstrate the promising potential of the synthesized
prodrug in overcoming the pervasive challenges of drug resistance and toxicity in TB
treatment. The tailored drug delivery mechanism of the prodrug, coupled with its selective
activation in the desired biological environment, underscores its potential application in
more effective TB therapy. This study not only contributes significant insights into the
treatment of MDR-TB but also lays a solid foundation for future in-vitro and in-vivo
evaluations, which could revolutionize the approach to TB therapy and have far-reaching
implications in the field of medicinal chemistry as well as specifically for any other ailment
that resides in an acidic environment within the body