Hagen, Timothy J.
M.S. (Master of Science)
Department of Chemistry and Biochemistry
Invasive fungal species provide a challenge to the current drug landscape, only partiallymet by approved drugs. The Acetyl Coenzyme Synthetase (ACS) enzymes are an attractive target for antifungal compounds because normal mammalian cells do not rely on ACS for energy metabolism while fungal cells do rely on ACS. This work focuses on the design and synthesis of inhibitors of various fungal ACS enzymes. The first class of inhibitors is based on the 2-aminothiazole scaffold originating from a saturation transfer difference (STD) nuclear magnetic resonance (NMR) study and previous whole-organism assays. Ultimately, the 2-aminothiazole core compounds were found to not be potent inhibitors of fungal ACS enzymes. The second class of inhibitors were the diacylhydrazides. This series was based on selected compounds from the Medicines for Malaria Venture (MMV), which were studied against Plasmodium falciparum ACS enzyme. A homology study indicated that the same compounds could potentially inhibit fungal ACS in a similar manner, which was later found to not be the case. The synthesized compounds were tested against P, falciparum ACS and found to have some inhibitory activity. The third class of compounds were based on a Celecoxib derivative, AR-12, which was previously found to have antifungal, antibacterial, and antiviral activity. This compound was found to inhibit the ACS1 enzymes of various fungal species, and several analogs of AR-12 were synthesized in an effort to increase this activity.
Heene, Michael Emmett, "Design, Synthesis, and Evaluation of Acetyl CoA Synthetase Inhibitors" (2023). Graduate Research Theses & Dissertations. 7148.
Northern Illinois University
Rights Statement 2
NIU theses are protected by copyright. They may be viewed from Huskie Commons for any purpose, but reproduction or distribution in any format is prohibited without the written permission of the authors.
Available for download on Monday, June 16, 2025