ORCID Identifier(s)

0009-0000-0466-1226

Graduation Semester and Year

2023

Language

English

Document Type

Thesis

Degree Name

Master of Science in Chemistry

Department

Chemistry and Biochemistry

First Advisor

Joseph Buonomo

Second Advisor

Junha Jeon

Abstract

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

Keywords

Mycobacterium tuberculosis, TB, PZA, POA, Prodrug, Bicyclic orthoester, Medchem, Medicinal chemistry, Tuberculosis, MDR-TB, Pharmacokinetics, Drug design, Antitubercular, Synthesis, Chemistry

Disciplines

Chemistry | Physical Sciences and Mathematics

Comments

Degree granted by The University of Texas at Arlington

Available for download on Sunday, February 01, 2026

Included in

Chemistry Commons

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