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Design, Synthesis, and Biological Evaluation of Atypical Novel Bacterial Topoisomerase Inhibitors (NBTIs)

Powell, Joshua
http://orcid.org/0000-0001-8912-471X
http://rave.ohiolink.edu/etdc/view?acc_num=osu1713530415014774

Abstract Details

2024, Doctor of Philosophy, Ohio State University, Pharmacy.
Antimicrobial resistance (AMR) is a major complication in treatment of bacterial infections. While many of the antibiotics developed in the twentieth century maintain efficacy in the clinical setting, there has been a great reduction in the number of compounds with comprehensive, broad-spectrum antibacterial activity. The focus of the Mitton-Fry lab is to overcome the resistance seen with common drugs (such as the fluoroquinolones) through the development of Novel Bacterial Topoisomerase Inhibitors (NBTIs). Similar to the fluoroquinolones, NBTIs inhibit the function of type II topoisomerases in bacteria, specifically DNA gyrase and topoisomerase IV (topoIV). These are important targets, as the human equivalent is distinct from that of the bacterial enzymes – allowing for specific targeting in bacteria. The work presented in this document includes, three sets of atypical NBTIs were synthesized. The first set was prepared with the assistance of a computational model, conducted in collaboration with the Lindert Lab of The Ohio State University. These compounds test the limits of what is required for NBTI pharmacophores in order to retain potency against bacterial pathogens. The second set of NBTIs was generated based on the idea of using isosteric replacement to develop new compounds with similar structures to known moieties. These compounds were designed to replace the amide moiety of the enzyme-binding region of the NBTI. The last set of compounds presented in this thesis was synthesized to determine the structure activity relationships (SAR) of NBTIs with a novel enzyme-binding motif, an aromatic, 5-membered heterocyclic system. These compounds synthesized are used to determine the relative placement of heteroatoms (nitrogen and oxygens, specifically) along this ring system and how these placements may affect overall antibacterial activity.
Mark Mitton-Fry (Advisor)
Liva Rakatondraibe (Committee Member)
Karl Werbovetz (Committee Member)
James Fuchs (Committee Member)
377 p.
Chemistry; Pharmacy Sciences

Recommended Citations

Citations

  • Powell, J. (2024). Design, Synthesis, and Biological Evaluation of Atypical Novel Bacterial Topoisomerase Inhibitors (NBTIs) [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1713530415014774

    APA Style (7th edition)

  • Powell, Joshua. Design, Synthesis, and Biological Evaluation of Atypical Novel Bacterial Topoisomerase Inhibitors (NBTIs). 2024. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1713530415014774.

    MLA Style (8th edition)

  • Powell, Joshua. "Design, Synthesis, and Biological Evaluation of Atypical Novel Bacterial Topoisomerase Inhibitors (NBTIs)." Doctoral dissertation, Ohio State University, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=osu1713530415014774

    Chicago Manual of Style (17th edition)

osu1713530415014774
188
© 2024, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.
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