CoA adducts of 4-oxo-4-phenylbut-2-enoates: Inhibitors of MenB from the M. tuberculosis menaquinone biosynthesis pathway

Xiaokai Li, Nina Liu, Huaning Zhang, Susan E. Knudson, Huei Jiun Li, Cheng Tsung Lai, Carlos Simmerling, Richard A. Slayden, Peter J. Tonge

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

A high-throughput screen led to the discovery of 2-amino-4-oxo-4- phenylbutanoate inhibitors of the 1,4-dihydroxy-2-naphthoyl-CoA synthase (MenB) from the menaquinone biosynthesis pathway in Mycobacterium tuberculosis. However, these compounds are unstable in solution and eliminate to form the corresponding 4-oxo-4-phenylbut-2-enoates that then react with CoA in situ to form nanomolar inhibitors of MenB. The potency of these compounds results from interaction of the CoA adduct carboxylate with the MenB oxyanion hole, a conserved structural motif in the crotonase superfamily. 4-Oxo-4- chlorophenylbutenoyl methyl ester has minimum inhibitory concentrations of 0.6 and 1.5 μg/mL against replicating and nonreplicating M. tuberculosis, respectively, and it is proposed that the methyl ester penetrates the cell where it is hydrolyzed and reacts with CoA to generate the active antibacterial. The CoA adducts thus represent an important foundation for the development of novel MenB inhibitors and suggest a general approach to the development of potent inhibitors of acyl-CoA binding enzymes.

Original languageEnglish (US)
Pages (from-to)818-823
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume2
Issue number11
DOIs
StatePublished - Nov 10 2011

Keywords

  • 1,4-dihydroxy-2-naphthoyl-CoA synthase
  • CoA
  • HTS
  • MenB
  • Menaquinone
  • o-succinylbenzoic acid

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Li, X., Liu, N., Zhang, H., Knudson, S. E., Li, H. J., Lai, C. T., Simmerling, C., Slayden, R. A., & Tonge, P. J. (2011). CoA adducts of 4-oxo-4-phenylbut-2-enoates: Inhibitors of MenB from the M. tuberculosis menaquinone biosynthesis pathway. ACS Medicinal Chemistry Letters, 2(11), 818-823. https://doi.org/10.1021/ml200141e