Year of Award
2025
Document Type
Dissertation
Degree Type
Doctor of Philosophy (PhD)
Degree Name
Chemistry (Organic Option)
Department or School/College
Department of Chemistry and Biochemistry
Committee Chair
Nigel Preistley
Commitee Members
Orion B. Berryman, Christopher P. Palmer, Aaron Thomas, Andrea Stierle
Keywords
antibiotics, natural products
Abstract
Antibacterial drug discovery is an important necessity across all medical practices in both treatment and prevention of antimicrobial resistance. Infections with antimicrobial resistant pathogens are likely to increase over the years, and new classes of antibiotics can address this issue directly. Traditional screening of natural product libraries unfortunately has exhausted these resourceful compounds so that few easily accessible medical drug candidates remain. Natural products have often been recognized for their unique and complex structures that are attributed to their biological activity. This esteemed trait also is linked to cytotoxic activity and difficult synthetic modifications. A fragment of the natural product instead will provide controlled synthetic handles for synthesis while retaining some of the original unique structure.
Diversity oriented synthesis with the natural product fragments can improve refinement of antimicrobial benefits, and discovery of new antimicrobial scaffolds. The synthetic handles of the nonactin fragment scaffold can be exchanged for different branches as seen with the antibacterial candidate 31G12 (3) and analogs (4-6). The antibacterial candidates do contain four chiral centers, and often chirality plays an important role when binding to potential biological targets. A structural activity relationship study was completed, investigating the stereoisomeric effects of the nonactin scaffold on bioactivity. The 31G12 candidate also contains an amide bond which is a common metabolized target. The amide bond was exchanged for an amine and a triazole, to potentially increase the drug lifespan without compromising the antibacterial activity. The nonactin fragment was also combined with a salinomycin fragment to create a new hybrid natural product scaffold. The natural product fragments were synthetically modified into unnatural amino acids for peptide coupling to form the new scaffold. This scaffold was investigated for potential bioactivity with the introduction of a new library based on these unnatural amino acids transformed from natural product fragments.
Recommended Citation
Schwartz, Evelyn Amelia, "NONACTIN AND SALINOMYCIN FRAGMENT SCAFFOLD DERIVED SYNTHESIS FOR ANTIBIOTIC DRUG DISCOVERY" (2025). Graduate Student Theses, Dissertations, & Professional Papers. 12544.
https://scholarworks.umt.edu/etd/12544
© Copyright 2025 Evelyn Amelia Schwartz