Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:18

Article; Proceedings Paper

Ende, Christopher W. am²  Liu, Nina²  Childs, James³  Sullivan, Todd J.²  Boyne, Melissa¹  Xu, Hua²  Gegina, Yelizaveta²  Johnson, Francis²  Peloquin, Charles A.³  Slayden, Richard A.¹  Tonge, Peter J.² 

[1] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA

[2] SUNY Stony Brook, Dept Chem, Inst Chem Biol & Drug Discovery, Stony Brook, NY 11794 USA

[3] Natl Jewish Med & Res Ctr, Infect Dis Pharmacokinet Lab, Denver, CO 80206 USA

关键词: tuberculosis;    diaryl ether;    enoyl reductase;    mycolic acids;    InhA;    isoniazid;    antitubercular drug;    diphenyl ether;    FabI;    lipinski parameter;    bioavailability;   

DOI  :  10.1016/j.bmcl.2008.04.038

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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