Development of Small-Molecule Inhibitors for Bacteroides, Naegleria, and Toxoplasma Microorganisms and Synthesis of N-Heterocycles From Thiolated ENE-YNES and Azodicarboxylates

Author

Samuel Kwain, Clemson UniversityFollow

Date of Award

5-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Committee Chair/Advisor

Dr. Daniel C. Whitehead

Committee Member

Dr. Brian N. Dominy

Committee Member

Dr. Byoungmoo Kim

Committee Member

Dr. Kristi J. Whitehead

Abstract

Humans and microorganisms are intricately interconnected, with microbes constituting an essential component of human biology and ecology. This interdependence necessitates a delicate balance between leveraging beneficial microbes and mitigating the impact of harmful ones. The human gut microbiome, home to trillions of microorganisms, predominantly comprises commensal species that support health. However, dysbiosis within this ecosystem has been linked to serious diseases. For instance, an overrepresentation of Bacteroides species is associated with Type I diabetes mellitus (T1D) and various chronic gut disorders, including ulcerative colitis, inflammatory bowel disease, celiac disease, and colorectal cancer. Similarly, Naegleria fowleri, a free-living amoeba, causes the highly fatal primary amebic meningoencephalitis, while Toxoplasma gondii, a pervasive parasite, infects approximately one-third of the global population.

This dissertation presents efforts to develop targeted therapeutic strategies against Bacteroides spp., Naegleria fowleri, and Toxoplasma gondii. Chapter one describes our group’s continual effort towards a non-microbicidal approach to gut microbiota modulation. This strategy leverages molecular modeling in the design of small molecules targeting the Bacteroides starch utilization system (Sus), offering a novel strategy for selective microbial control. Chapter two introduces a structure-based drug design strategy to inhibit Naegleria fowleri enolase (NfENO), an enzyme critical for glucose metabolism in the trophozoite life-cycle stage, thus impeding infection establishment. Chapter three highlights the development of potent antiparasitic compounds targeting protoporphyrinogen oxidase (PPO), a key enzyme in Toxoplasma gondii heme biosynthesis.

In addition to microbial therapeutics, the dissertation explores innovative organic synthesis methodologies. Chapter four presents a regio- and stereoselective debenzylative cycloetherification reaction for synthesizing stereochemically rich tetrahydrofuran compounds under mild conditions. Chapter five details a cascade cyclization approach for generating richly functionalized tetrahydroindoles and fused pyrroles, compounds with significant potential in medicinal chemistry. Collectively, this work advances both therapeutic interventions for pathogenic microorganisms and synthetic strategies for bioactive molecule development.

Recommended Citation

Kwain, Samuel, "Development of Small-Molecule Inhibitors for Bacteroides, Naegleria, and Toxoplasma Microorganisms and Synthesis of N-Heterocycles From Thiolated ENE-YNES and Azodicarboxylates" (2025). All Dissertations. 3891.
https://open.clemson.edu/all_dissertations/3891