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

•In this study we design, new possible scaffolds acting as antibacterial agents.•We synthesized and characterized new linezolid-like compounds.•We test their antibacterial activity and their cytotoxicity.

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) 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.

Graphical abstractThe synthesis and the in vitro antibacterial activity of novel linezolid-like oxadiazoles are reported. Molecular modeling performed using two different approaches shows that the 1,2,4-oxadiazole moiety of the newly synthesized compounds seems to perfectly mimic the function of the linezolid morpholinic ring.Figure optionsDownload full-size imageDownload as PowerPoint slide