2. Academic Validation
  3. Discovery of heterocyclic replacements for the coumarin core of anti-tubercular FadD32 inhibitors

Discovery of heterocyclic replacements for the coumarin core of anti-tubercular FadD32 inhibitors

  • Bioorg Med Chem Lett. 2018 Dec 1;28(22):3529-3533. doi: 10.1016/j.bmcl.2018.09.037.
Chao Fang 1,  Katie K Lee 2,  Raymond Nietupski 1,  Robert H Bates 3,  Raquel Fernandez-Menendez 3,  Eva Maria Lopez-Roman 3,  Laura Guijarro-Lopez 3,  Yunxing Yin 4,  Zuozhong Peng 5,  James E Gomez 2,  Stewart Fisher 1,  David Barros-Aguirre 3,  Brian K Hubbard 1,  Michael H Serrano-Wu 1,  Deborah T Hung 6
Affiliations

Affiliations

  • 1 The Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA 02142, USA.
  • 2 The Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA 02142, USA; Department of Molecular Biology and Center for Integrative and Computational Biology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114, USA.
  • 3 Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain.
  • 4 WuXi AppTec, 168 Nanhai Rd, Tianjin Economic-Technological Development Area (TEDA), Tianjin 300457, China.
  • 5 WuXi AppTec, 288 Fute Zhong Rd, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 6 The Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA 02142, USA; Department of Molecular Biology and Center for Integrative and Computational Biology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: hung@molbio.mgh.harvard.edu.
PMID: 30316633 DOI: 10.1016/j.bmcl.2018.09.037
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

FadD32 inhibitor; In vivo efficacy; Mycobacterium tuberculosis; Quinoline-2-carboxamide; Structure-activity relationship.

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