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

Bioorg Med Chem Lett

Authors	Chao Fang Katie Lee Raymond Nietupski Robert Bates Raquel Fernandez-Menendez Eva Lopez-Roman Laura Guijarro-Lopez Yunxing Yin Zuozhong Peng James Gomez Stewart Fisher David Barros-Aguirre Brian Hubbard Michael Serrano-Wu Deborah Hung
Keywords	Animals Mice Disease Models, Animal Bacterial Proteins Microbial Sensitivity Tests Structure-Activity Relationship Drug Evaluation, Preclinical Quinolines Antitubercular Agents Mycobacterium tuberculosis Tuberculosis Coumarins
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.
Year of Publication	2018
Journal	Bioorg Med Chem Lett
Volume	28
Issue	22
Pages	3529-3533
Date Published	2018 Dec 01
ISSN	1464-3405
DOI	10.1016/j.bmcl.2018.09.037
PubMed ID	30316633
PubMed Central ID	PMC6233306
Links
Grant list	R01 AI132300 / AI / NIAID NIH HHS / United States

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