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Discovery of heterocyclic replacements for the coumarin core of anti-tubercular FadD32 inhibitors |
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| Authors: | Chao Fang Katie K Lee Raymond Nietupski Robert H Bates Raquel Fernandez-Menendez Eva Maria Lopez-Roman Laura Guijarro-Lopez Yunxing Yin Zuozhong Peng James E Gomez Stewart Fisher David Barros-Aguirre Brian K Hubbard Michael H Serrano-Wu Deborah T Hung |
| Institution: | 1. The Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA 02142, USA;2. Department of Molecular Biology and Center for Integrative and Computational Biology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114, USA;3. Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA;4. Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain;5. WuXi AppTec, 168 Nanhai Rd, Tianjin Economic-Technological Development Area (TEDA), Tianjin 300457, China;6. WuXi AppTec, 288 Fute Zhong Rd, Waigaoqiao Free Trade Zone, Shanghai 200131, China |
| Abstract: | 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. |
| Keywords: | (minimum inhibitory concentration for 90%) (Mycobacterium tuberculosis) CFU (colony-forming unit) (effective dose for 99% CFU count reduction) mLM (mouse liver microsome) hLM (human liver microsome) 95% CI (95% confidence interval) Mycobacterium tuberculosis FadD32 inhibitor Structure-activity relationship Quinoline-2-carboxamide In vivo efficacy |
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