Date of Award
Chemistry and Biochemistry
Bryan J. Cowen, Ph.D.
Novel carbocycles, Medicinal chemistry, Quinones
Tuberculosis is a pulmonary disease that has ravaged the world throughout history. Even today, many developed and developing countries are experiencing this plight, made worse by the scourge of antibiotic-resistant bacteria.
Mycobacterium tuberculosis's class II fructose-1,6-bisphosphate aldolase presents an interesting target in the design of new therapies against this disease. Previous attempts to construct an inhibitor to this enzyme fell short due to poor selectivity or poor cellular uptake. However a new class of noncompetitive inhibitor based on 8-hydoxyquinoline-2-carboxylic acid presents a fresh approach. Preliminary studies indicate various modifications to this scaffold could be beneficial to its inhibitory efficacy.
Modifications made to the phenol ring of the quinoline included small hydrophobic moieties such as methyl groups and fluorine. Additionally various carboxylic acid derivatives were installed next to the nitrogen of the heteroring. These derivatives included esters, amides, carbamates and ureas, and heterocycles. Biochemical testing of these compounds is ongoing but is already showing promising results.
Many methods exist for the construction of quinoline rings systems, which can be utilized based on the pattern of substitution desired. Synthesis of heteroring-unsubstituted quinolines, however, has historically presented more of a challenge. Herein is described a novel method of cyclizing anilines with acrolein diethyl acetal to form these desired structures. This method produces quinolines with various substitutions on the phenyl ring in moderate to high yields without the use of harsh oxidants, extended reaction times, or organic solvents.
The Lewis base-catalyzed annulation of allenoates with alkene acceptors in [3+2] cycloadditions is a new but burgeoning field. Many acceptors have been used in these reactions, but the use of quinones is unprecedented. Due to the highly reactive nature of quinones, it became necessary to screen various Lewis bases that would catalyze the reaction without being oxidized by the quinone. This is an ongoing investigation but is promising in the production of novel carbocycles that have potential benefits in medicinal chemistry.
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Ramann, Ginelle A., "Quinolines: Novel Synthesis and Derivatives of Heterocyclic Bioactive Agents" (2016). Electronic Theses and Dissertations. 1116.
Received from ProQuest
Chemistry, Organic Chemistry