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

Christopher W. am Ende, Susan E. Knudson, Nina Liu, James Childs, Todd J. Sullivan, Melissa Boyne, Hua Xu, Yelizaveta Gegina, Dennis L. Knudson, Francis Johnson, Charles A. Peloquin, Richard A. Slayden, Peter J. Tonge

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

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 MIC90 values of 1-2 μg/mL. However, despite their promising in vitro activity, these compounds have Clog P 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 MIC90 values to that of 19, but have improved Clog P values.

Original languageEnglish (US)
Pages (from-to)3029-3033
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number10
DOIs
StatePublished - May 15 2008
Externally publishedYes

Fingerprint

Isoniazid
Mycobacterium tuberculosis
Amides
Ether
Oxidoreductases
Nitrogen
Biological Availability
Growth
piperazine
phenyl ether
In Vitro Techniques

Keywords

  • Antitubercular drug
  • Bioavailability
  • Diaryl ether
  • Diphenyl ether
  • Enoyl reductase
  • FabI
  • InhA
  • Isoniazid
  • Lipinski parameter
  • Mycolic acids
  • Tuberculosis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

am Ende, C. W., Knudson, S. E., Liu, N., Childs, J., Sullivan, T. J., Boyne, M., ... Tonge, P. J. (2008). Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors. Bioorganic and Medicinal Chemistry Letters, 18(10), 3029-3033. https://doi.org/10.1016/j.bmcl.2008.04.038

Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors. / am Ende, Christopher W.; Knudson, Susan E.; Liu, Nina; Childs, James; Sullivan, Todd J.; Boyne, Melissa; Xu, Hua; Gegina, Yelizaveta; Knudson, Dennis L.; Johnson, Francis; Peloquin, Charles A.; Slayden, Richard A.; Tonge, Peter J.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 18, No. 10, 15.05.2008, p. 3029-3033.

Research output: Contribution to journalArticle

am Ende, CW, Knudson, SE, Liu, N, Childs, J, Sullivan, TJ, Boyne, M, Xu, H, Gegina, Y, Knudson, DL, Johnson, F, Peloquin, CA, Slayden, RA & Tonge, PJ 2008, 'Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 10, pp. 3029-3033. https://doi.org/10.1016/j.bmcl.2008.04.038
am Ende, Christopher W. ; Knudson, Susan E. ; Liu, Nina ; Childs, James ; Sullivan, Todd J. ; Boyne, Melissa ; Xu, Hua ; Gegina, Yelizaveta ; Knudson, Dennis L. ; Johnson, Francis ; Peloquin, Charles A. ; Slayden, Richard A. ; Tonge, Peter J. / Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2008 ; Vol. 18, No. 10. pp. 3029-3033.
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