Design, synthesis and antibacterial evaluation of oxazolidinone derivatives containing N-methylglycyl or quaternary ammonium salts

The continuous evolution of multidrug-resistant (MDR) bacteria to existing Antibiotic treatment regimens poses a serious threat to human health, so the discovery of new and potent antimicrobial drugs that are less likely to develop resistance is of great clinical significance. As a result, Oxazolidinone antibiotics have emerged as a significant class of Bacterial protein synthesis inhibitors, with particular success in the treatment of MDR Gram-positive infections. Herein, a series of novel C-ring modified Oxazolidinone derivatives with the introduction of N-methylglycyl groups or quaternary ammonium salts were synthesized and evaluated for their Antibacterial efficacy, among which most of the N-methylglycyl derivatives showed significant activity against E. faecalis. Notably, compounds 11g-11i showed good activity against E. faecalis and S. aureus with MICs of 2-8 μg/mL. The selected compound 11g exhibited rapid bactericidal properties, good biofilm disruption capacity, low tendency to induce Bacterial resistance, and low cytotoxicity against mammalian cells (HeLa). Furthermore, compound 11g showed relatively good stability in mammalian body fluids and exhibited a longer post-antibiotic effect (PAE). Mechanistic studies showed that compound 11g exerted its Antibacterial effect by inhibiting glutathione (GSH) activity and inducing Reactive Oxygen Species (ROS) accumulation, leading to Bacterial death. These findings suggest that 11g is a promising candidate for the exploitation of N-methylglycyl oxazolidinones as novel Antibacterial agents.

Antibacterial activity; Gram-positive bacteria; Oxazolidinones derivatives; Structure-activity relationship.