Design and Synthesis of Novel Analogs as Potential Antitubercular Agents

Author

Peggy McCluggageFollow

Date of Award

Spring 5-8-2020

Document Type

Undergraduate Thesis

Department

Chemistry and Biochemistry

First Advisor

Sudeshna Roy

Second Advisor

Susan Pedigo

Third Advisor

Randy Wadkins

Relational Format

Dissertation/Thesis

Abstract

Tuberculosis (TB) is an infectious, airborne disease which primarily infects the lungs. One-third of the world’s population is currently estimated to be infected with Mycobacterium tuberculosis (Mtb), the causative agent for TB [1]. Current treatment for this disease requires at least six months of taking multiple antibiotics with undesirable side effects [2]. Difficulty in complying to this regimen as well as the prevalence of HIV/AIDS has led to antimicrobial resistance seen in Mtb. In order to combat the Multi-Drug Resistant and Extensively-Drug Resistant strains of the disease-causing bacteria, preventative care and novel antibiotics are urgently needed [3]. The purpose for this research is to design and synthesize novel and improved analogs as potential antitubercular agents. One promising new target explored was the protein phosphoMurNAc-pentapeptide translocase (MraY) responsible for the biosynthesis of peptidoglycan in the cell wall of Mtb [4]. Two narrow-spectrum analogs were designed and synthesized with the collaboration of other lab members, and initial testing showed that neither was active against Mtb. While the MraY project was being pursued, other members of Roy lab were developing regioselective synthetic methods for 4-fluoro-1,5- disubstituted-1,2,3- triazoles. A paper by Patpi et al showed that 1,2,3-triazoles combined with dibenzothiophene through a molecular hybridization approach led to the synthesis of analogs with promising antitubercular activity. Because of the potential increased pharmacokinetic properties fluorine can provide, the second part of this project sought to create fluorinated versions of these analogs. To create the fluorinated analogs, an αfluoronitroalkene would be reacted with an azide to cyclize to the final product. While v the azide was synthesized, the α-fluoronitroalkene moiety was not synthesized as a result of time restrictions caused by the COVID-19 pandemic. After the synthesis of these analogs is completed, they can be tested for antitubercular activity and, hopefully, contribute to the fight to slow antimicrobial resistance.

Recommended Citation

McCluggage, Peggy, "Design and Synthesis of Novel Analogs as Potential Antitubercular Agents" (2020). Honors Theses. 1572.
https://egrove.olemiss.edu/hon_thesis/1572

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