Synthesis and SAR studies of 1,4-benzoxazine MenB inhibitors: Novel antibacterial agents against Mycobacterium tuberculosis

Xiaokai Li; Nina Liu; Huaning Zhang; Susan E. Knudson; Richard A. Slayden; Peter J. Tonge

doi:10.1016/j.bmcl.2010.08.076

Synthesis and SAR studies of 1,4-benzoxazine MenB inhibitors: Novel antibacterial agents against Mycobacterium tuberculosis

Xiaokai Li, Nina Liu, Huaning Zhang, Susan E. Knudson, Richard A. Slayden, Peter J. Tonge

Research output: Contribution to journal › Article › peer-review

93 Scopus citations

Abstract

Menaquinone is an essential component of the electron transport chain in many pathogens and consequently enzymes in the menaquinone biosynthesis pathway are potential drug targets for the development of novel antibacterial agents. In order to identify leads that target MenB, the 1,4-dihydroxy-2-naphthoyl-CoA synthase from Mycobacterium tuberculosis, a high-throughput screen was performed. Several 1,4-benzoxazines were identified in this screen and subsequent SAR studies resulted in the discovery of compounds with excellent antibacterial activity against M. tuberculosis H37Rv with MIC values as low as 0.6 μg/ml. The 1,4-benzoxazine scaffold is thus a promising foundation for the development of antitubercular agents.

Original language	English (US)
Pages (from-to)	6306-6309
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	21
DOIs	https://doi.org/10.1016/j.bmcl.2010.08.076
State	Published - Nov 1 2010
Externally published	Yes

Keywords

1,4-Benzoxazine
1,4-Dihydroxy-2-naphthoyl-CoA synthase
MenB
Menaquinone
Mycobacterium 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.2010.08.076

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title = "Synthesis and SAR studies of 1,4-benzoxazine MenB inhibitors: Novel antibacterial agents against Mycobacterium tuberculosis",

abstract = "Menaquinone is an essential component of the electron transport chain in many pathogens and consequently enzymes in the menaquinone biosynthesis pathway are potential drug targets for the development of novel antibacterial agents. In order to identify leads that target MenB, the 1,4-dihydroxy-2-naphthoyl-CoA synthase from Mycobacterium tuberculosis, a high-throughput screen was performed. Several 1,4-benzoxazines were identified in this screen and subsequent SAR studies resulted in the discovery of compounds with excellent antibacterial activity against M. tuberculosis H37Rv with MIC values as low as 0.6 μg/ml. The 1,4-benzoxazine scaffold is thus a promising foundation for the development of antitubercular agents.",

keywords = "1,4-Benzoxazine, 1,4-Dihydroxy-2-naphthoyl-CoA synthase, MenB, Menaquinone, Mycobacterium tuberculosis",

author = "Xiaokai Li and Nina Liu and Huaning Zhang and Knudson, {Susan E.} and Slayden, {Richard A.} and Tonge, {Peter J.}",

note = "Funding Information: This work was supported in part by National Institutes of Health Grants AI044639 , AI070383 , and AI058785 to P.J.T. High throughput screening was performed at The National Screening Laboratory for the Regional Centers of Excellence in Biodefense and Emerging Infectious Diseases (NSRB) with the support of National Institutes of Health Grant U54AI057159 . We thank members of the NSRB and ICCB-Longwood for their help with compound screening. ",

year = "2010",

month = nov,

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doi = "10.1016/j.bmcl.2010.08.076",

language = "English (US)",

volume = "20",

pages = "6306--6309",

journal = "Bioorganic and Medicinal Chemistry Letters",

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T2 - Novel antibacterial agents against Mycobacterium tuberculosis

AU - Li, Xiaokai

AU - Liu, Nina

AU - Zhang, Huaning

AU - Knudson, Susan E.

AU - Slayden, Richard A.

AU - Tonge, Peter J.

N1 - Funding Information: This work was supported in part by National Institutes of Health Grants AI044639 , AI070383 , and AI058785 to P.J.T. High throughput screening was performed at The National Screening Laboratory for the Regional Centers of Excellence in Biodefense and Emerging Infectious Diseases (NSRB) with the support of National Institutes of Health Grant U54AI057159 . We thank members of the NSRB and ICCB-Longwood for their help with compound screening.

PY - 2010/11/1

Y1 - 2010/11/1

N2 - Menaquinone is an essential component of the electron transport chain in many pathogens and consequently enzymes in the menaquinone biosynthesis pathway are potential drug targets for the development of novel antibacterial agents. In order to identify leads that target MenB, the 1,4-dihydroxy-2-naphthoyl-CoA synthase from Mycobacterium tuberculosis, a high-throughput screen was performed. Several 1,4-benzoxazines were identified in this screen and subsequent SAR studies resulted in the discovery of compounds with excellent antibacterial activity against M. tuberculosis H37Rv with MIC values as low as 0.6 μg/ml. The 1,4-benzoxazine scaffold is thus a promising foundation for the development of antitubercular agents.

AB - Menaquinone is an essential component of the electron transport chain in many pathogens and consequently enzymes in the menaquinone biosynthesis pathway are potential drug targets for the development of novel antibacterial agents. In order to identify leads that target MenB, the 1,4-dihydroxy-2-naphthoyl-CoA synthase from Mycobacterium tuberculosis, a high-throughput screen was performed. Several 1,4-benzoxazines were identified in this screen and subsequent SAR studies resulted in the discovery of compounds with excellent antibacterial activity against M. tuberculosis H37Rv with MIC values as low as 0.6 μg/ml. The 1,4-benzoxazine scaffold is thus a promising foundation for the development of antitubercular agents.

KW - 1,4-Benzoxazine

KW - 1,4-Dihydroxy-2-naphthoyl-CoA synthase

KW - MenB

KW - Menaquinone

KW - Mycobacterium tuberculosis

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Synthesis and SAR studies of 1,4-benzoxazine MenB inhibitors: Novel antibacterial agents against Mycobacterium tuberculosis

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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