Discovery of heterocyclic replacements for the coumarin core of anti-tubercular FadD32 inhibitors.
Bioorg Med Chem Lett
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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
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Journal | Bioorg Med Chem Lett
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Volume | 28
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Issue | 22
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Pages | 3529-3533
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Date Published | 2018 Dec 01
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ISSN | 1464-3405
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DOI | 10.1016/j.bmcl.2018.09.037
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PubMed ID | 30316633
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PubMed Central ID | PMC6233306
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Grant list | R01 AI132300 / AI / NIAID NIH HHS / United States
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