Discovery of heterocyclic replacements for the coumarin core of anti-tubercular FadD32 inhibitors.
Fang C, Lee KK, Nietupski R, Bates RH, Fernandez-Menendez R, Lopez-Roman EM, Guijarro-Lopez L, Yin Y, Peng Z, Gomez JE, Fisher S, Barros-Aguirre D, Hubbard BK, Serrano-Wu MH, Hung DT.
Previous work established a coumarin scaffold as a starting point for inhibition of Mycobacterium tuberculosis (Mtb) FadD32 enzymatic activity. After further profiling of the coumarin inhibitor 4 revealed chemical instability, we discovered that a quinoline ring circumvented this instability and had the advantage of offering additional substitution vectors to further optimize. Ensuing SAR studies gave rise to quinoline-2-carboxamides with potent anti-tubercular activity. Further optimization of ADME/PK properties culminated in 21b that exhibited compelling in vivo efficacy in a mouse model of Mtb infection.