New linezolid-like 1,2,4-oxadiazolesactive against Gram-positive multiresistant pathogens

Cosimo G. Fortuna, Carmela Bonaccorso, Alessandra Bulbarelli, Gianluigi Caltabiano, Laura Rizzi, Laura Goracci, Giuseppe Musumarra, Andrea Pace, Antonio Palumbo Piccionello, Annalisa Guarcello, Paola Pierro, Clementina E.A. Cocuzza, Rosario Musumeci

Research output: Contribution to journalArticleResearchpeer-review

36 Citations (Scopus)

Abstract

The synthesis and the in vitro antibacterial activity of novel linezolid-like oxadiazoles are reported. Replacement of the linezolid morpholine C-ring with 1,2,4-oxadiazole results in an antibacterial activity against Staphylococcus aureus both methicillin-susceptible and methicillin-resistant comparable or even superior to that of linezolid. While acetamidomethyl or thioacetoamidomethyl moieties in the C(5) sidechain are required, fluorination of the phenyl B ring exhibits a slight effect on an antibacterial activity but its presence seems to reduce the compounds cytotoxicity. Molecular modeling performed using two different approaches - FLAP and Amber software - shows that in the binding pose of the newly synthesized compounds as compared with the crystallographic pose of linezolid, the 1,2,4-oxadiazole moiety seems to perfectly mimic the function of the morpholinic ring, since the H-bond interaction with U2585 is retained. © 2013 Elsevier Masson SAS. All rights reserved.
Original languageEnglish
Pages (from-to)533-545
JournalEuropean Journal of Medicinal Chemistry
Volume65
DOIs
Publication statusPublished - 1 Jan 2013

Keywords

  • Antimicrobial activity
  • Cell viability
  • Drug design
  • Linezolid
  • Oxazolidinones
  • Staphylococcus aureus

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