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 journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)533-545
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume65
DOIs
Publication statusPublished - 2013

Keywords

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

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

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