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 journalArticle

57 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)6306-6309
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number21
DOIs
StatePublished - Nov 1 2010
Externally publishedYes

Fingerprint

Benzoxazines
Vitamin K 2
Mycobacterium tuberculosis
Antitubercular Agents
Anti-Bacterial Agents
Biosynthesis
Pathogens
Coenzyme A
Electron Transport
Scaffolds
Throughput
Enzymes
Pharmaceutical Preparations

Keywords

  • 1,4-Benzoxazine
  • 1,4-Dihydroxy-2-naphthoyl-CoA synthase
  • Menaquinone
  • MenB
  • Mycobacterium tuberculosis

ASJC Scopus subject areas

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

Cite this

Synthesis and SAR studies of 1,4-benzoxazine MenB inhibitors : Novel antibacterial agents against Mycobacterium tuberculosis. / Li, Xiaokai; Liu, Nina; Zhang, Huaning; Knudson, Susan E.; Slayden, Richard A.; Tonge, Peter J.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 20, No. 21, 01.11.2010, p. 6306-6309.

Research output: Contribution to journalArticle

Li, Xiaokai ; Liu, Nina ; Zhang, Huaning ; Knudson, Susan E. ; Slayden, Richard A. ; Tonge, Peter J. / Synthesis and SAR studies of 1,4-benzoxazine MenB inhibitors : Novel antibacterial agents against Mycobacterium tuberculosis. In: Bioorganic and Medicinal Chemistry Letters. 2010 ; Vol. 20, No. 21. pp. 6306-6309.
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