Ashton Drake / Chemistry & Biochemistry / Faculty Mentor: Joseph Buonomo
Mycobacterium tuberculosis (Mtb) is the causative agent of the transmissible disease tuberculosis. The complex structure of the mycobacterial cell wall contributes to its successful virulence. Of particular interest is the Mycobacterial membrane protein Large 3 (MmpL3), a mycolic acid and lipid transporter that has been widely viewed as a potential drug target. MmpL3 is required for the transport of trehalose monomycolates (TMMs) across the cell membrane for cell wall synthesis. A set of TMM analogs was prepared via the addition of N-methylhydroxylamine and N-hydroxylamine at the 6-position. Various synthetic routes were explored and subsequently analyzed. Three synthetic routes, including tosylated SN2, reductive amination, and a modified Appel, were chosen and judged based on selectivity, scalability, and yield. Based upon these parameters the tosylated SN2 route was found to be most favorable, with greater scalability, yield, and control over selectivity. All routes were effective in preparing both analogues and have exhibited effectiveness in Msmeg which has permitted the imaging and mapping of the TMM population.
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