Identification of 4-substituted 1,2,3-triazoles as novel oxazolidinone antibacterial agents with reduced activity against monoamine oxidase A

F Reck, F Zhou, M Girardot, G Kern, C J Eyermann, N J Hales, R R Ramsay, M B Gravestock

Research output: Contribution to journalArticlepeer-review

246 Citations (Scopus)

Abstract

Oxazolidinones represent a new and promising class of antibacterial agents. Current, research in this area is mainly concentrated on improving the safety profile and the antibacterial spectrum. Many oxazolidinones, including linezolid (marketed as 2 Zyvox), are inhibitors of monoamine oxidase A (MAO-A), which presents an undesired side effect. Recently, it was found that the 1,2,3-triazole is a good replacement for the conventional acetamide functionality found in oxazolidinones. We now disclose the finding that 1,2.3-triazoles bearing, a substituent like methyl, small substituted methyl, bromo, or a linear (sp-hybridized) group at the 4 position (compounds such as 5, 16, 19, and 21) are good antibacterials with reduced or no activity.. within the detection limit of the assay, against MAO-A. The results are especially promising for the development of oxazolidinones with an improved safety profile. The MAO-A SAR can be rationalized on the basis of docking studies to a MAO-A/MAO-B homolog; model.

Original languageEnglish
Pages (from-to)499-506
Number of pages8
JournalJournal of Medicinal Chemistry
Volume48
Issue number2
DOIs
Publication statusPublished - 27 Jan 2005

Keywords

  • RESISTANT ENTEROCOCCUS-FAECIUM
  • GRAM-POSITIVE INFECTIONS
  • LINEZOLID-RESISTANT
  • STAPHYLOCOCCUS-AUREUS
  • TERMINAL ALKYNES
  • SITE
  • ANTIBIOTICS
  • DERIVATIVES
  • MANAGEMENT
  • INHIBITORS

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