Multi-Step Synthesis of Small Molecules as Potential Inhibitors for MurG

Anna Schroeder

Name: Anna Schroeder
Major: Chemistry
Minor: French and Francophone Studies
Advisor: Dr. Sara Martin
The threat of antibiotic resistance demands a response in the form of new antibiotics that inhibit essential bacterial enzymes. A further requirement is methods for the synthesis of these inhibitors. MurG is an ideal target enzyme for this research as it is an essential enzyme in the synthesis pathway of peptidoglycan and no effective methods for inhibition have been found for this enzyme. Past computational models have found a potential inhibitor for MurG in coumarin-3-carboxamide analogues and previous work using Knoevenagel condensation reactions to synthesize these coumarins has produced contaminated product mixtures. The goal of this project is to develop a modified Knoevenagel condensation method in order to increase yield and product formation and make a small library of possible MurG inhibitors by synthesizing the analogues with a Q6S group. By heating the first part of the Knoevenagel condensation, three of the derivatives (1, 2, 3) were synthesized with increased yield and product formation while condensations to form three others (4, 5, 6) result in no product formation. Analogues 1, 2, and 3 were purified using column chromatography and then reacted with 2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride (Q6S-Cl) to synthesize, via a nucleophilic reaction, a full inhibitor candidate (7, 8, or 9). 7 was successfully synthesized and purified while synthesis of 8 resulted in a contaminated product mixture due to the presence of an impurity, and 9 did not form. Future work on this project should include further purification to isolate 8 and further synthesis to form 9 and other compounds for the library, as well as testing full inhibitor candidates for inhibition of MurG.

Anna will be online to field comments on April 16:
10am-noon EDT (Asia: late evening, PST: 6-8am, Africa/Europe: late afternoon)

Posted in I.S. Symposium 2021, Independent Study.