Synthesis of KasA Enzyme Inhibitors to Induce Tuberculosis Cell Death

By Carrie Garvey

Faculty Mentor: Dr. Davis Oldham


The World Health Organization names TB the 13th leading cause of death and the second leading infectious killer in the world, with current drugs becoming less effective as the cells grow more resistant. The KasA protein in Mycobacterium Tuberculosis (TB) catalyzes a four-step fatty acid elongation that enables the strengthening of the TB cell wall. Creating an organic molecule to inhibit the KasA enzyme would then cause cell lysis, resulting in TB cell death. Previous computer simulations identified possible drug candidates, one of which was shown to inhibit the growth of TB cells. A series of analogs were prepared by varying the two aromatic substituents on the piperidine ring. Four commercially available arylpiperidinols were alkylated with three alkyl chlorides catalyzed by potassium iodide, which were prepared by reacting alcohols with thionyl chloride. To increase the number of analogs on the piperidinol ring, several methods for synthesizing Grignard reagents were attempted but products were not obtained in satisfactory yield. To test the effect of the oxygen on the piperidinol ring, a model analog was dehydrated, and further hydrogenation was proven successful. The future of this project is to test the synthesized alkylation products on their lethality in TB cells, continue to synthesize more dehydrated products for testing, and optimize the Grignard reaction so that the inhibitors can be made through all four reactions in an efficient, low-cost manner.


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