New Linezolid-like 1,2,4-oxadiazoles active against Gram-positive multiresistant pathogens

The synthesis and the in vitro antibacterial activity of novel Linezolid-like oxadiazoles is reported. Replacement of the Linezolid morpholine C-ring with 1,2,4-oxadiazole results in a bacterial 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) side-chain 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.