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

doi:10.1016/j.bmcl.2008.04.038

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 journal › Article › peer-review

78 Scopus citations

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 language	English (US)
Pages (from-to)	3029-3033
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	10
DOIs	https://doi.org/10.1016/j.bmcl.2008.04.038
State	Published - May 15 2008
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2008.04.038

Cite this

am Ende, C. W., Knudson, S. E., Liu, N., Childs, J., Sullivan, T. J., Boyne, M., Xu, H., Gegina, Y., Knudson, D. L., Johnson, F., Peloquin, C. A., Slayden, R. A., & 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

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

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title = "Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors",

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.",

keywords = "Antitubercular drug, Bioavailability, Diaryl ether, Diphenyl ether, Enoyl reductase, FabI, InhA, Isoniazid, Lipinski parameter, Mycolic acids, Tuberculosis",

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

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doi = "10.1016/j.bmcl.2008.04.038",

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AU - am Ende, Christopher W.

AU - Knudson, Susan E.

AU - Liu, Nina

AU - Childs, James

AU - Sullivan, Todd J.

AU - Boyne, Melissa

AU - Xu, Hua

AU - Gegina, Yelizaveta

AU - Knudson, Dennis L.

AU - Johnson, Francis

AU - Peloquin, Charles A.

AU - Slayden, Richard A.

AU - Tonge, Peter J.

N1 - Funding Information: This work was supported by NIH Grant AI70383.

PY - 2008/5/15

Y1 - 2008/5/15

N2 - 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.

AB - 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.

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KW - Diphenyl ether

KW - Enoyl reductase

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KW - InhA

KW - Isoniazid

KW - Lipinski parameter

KW - Mycolic acids

KW - Tuberculosis

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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