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

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

doi:10.1016/j.bmcl.2018.09.037

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. Epub 2018 Sep 29.

Authors

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antitubercular Agents / chemistry*
Antitubercular Agents / metabolism
Antitubercular Agents / pharmacology
Antitubercular Agents / therapeutic use
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / metabolism
Coumarins / chemistry*
Disease Models, Animal
Drug Evaluation, Preclinical
Mice
Microbial Sensitivity Tests
Mycobacterium tuberculosis / drug effects
Mycobacterium tuberculosis / metabolism
Quinolines / chemistry
Structure-Activity Relationship
Tuberculosis / drug therapy
Tuberculosis / microbiology

Substances

Antitubercular Agents
Bacterial Proteins
Coumarins
Quinolines
coumarin
quinoline

Grants and funding

R01 AI132300/AI/NIAID NIH HHS/United States