Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 18, Issue 10, Pages 3029-3033Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2008.04.038
Keywords
tuberculosis; diaryl ether; enoyl reductase; mycolic acids; InhA; isoniazid; antitubercular drug; diphenyl ether; FabI; lipinski parameter; bioavailability
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Funding
- NIAID NIH HHS [R01 AI044639-07, U01 AI070383-01, R01 AI044639-08, U01 AI070383, U01 AI070383-02, R21 AI044639, AI70383, R01 AI044639] Funding Source: Medline
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Previous structure-based design studies resulted in the discovery of alkyl substituted diphenyl ether inhibitors of InhA, the enoyl reductase from Mycobacterium tuberculosis. Compounds such as 5-hexyl-2-phenoxyphenol 19 are nM inhibitors of InhA and inhibit the growth of both sensitive and isoniazid-resistant strains of Mycobacterium tuberculosis with MIC(90) values of 1-2 mu g/mL. However, despite their promising in vitro activity, these compounds have ClogP values of over 5. In efforts to reduce the lipophilicity of the compounds, and potentially enhance compound bioavailability, a series of B ring analogues of 19 were synthesized that contained either heterocylic nitrogen rings or phenyl rings having amino, nitro, amide, or piperazine functionalities. Compounds 3c, 3e, and 14a show comparable MIC(90) values to that of 19, but have improved ClogP values. (c) 2008 Elsevier Ltd. All rights reserved.
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