Date of Award
Summer 2020
Document Type
Thesis
Degree Name
Master of Science (MS)
Department
Chemistry
First Advisor
Donaldson, William
Second Advisor
St. Maurice, Martin
Third Advisor
Dockendorff, Chris
Abstract
Through structure-based drug design (SBDD), a series of small molecules have been synthesized and evaluated for inhibitory activity against the pyruvate carboxylase (PC) enzyme via two biological assays. The -hydroxycinnamic acid scaffold was identified as the most privileged scaffold for inhibition of PC. Analogues of phenylpyruvic acid were generated and evaluated, leading to the discovery of inhibitors with single digit micromolar (M) IC50 values. The most potent inhibitors identified were evaluated for inhibitory activity against other metalloproteins, and 2-hydroxy-3-(quinolone-2-yl)propenoic acid did not significantly inhibit human carbonic anhydrase II, matrix metalloproteinase-2, malate dehydrogenase, or lactate dehydrogenase. The small molecules presented in this work represent the most potent inhibitors of the pyruvate carboxylase enzyme to date.