Development and antibacterial evaluation of oxazolidinone derivatives with a substituted N-methylglycyl C-ring moiety

Multidrug-resistant bacterial infections have now become a serious problem in anti-infective therapy and continue to pose a major threat to public health with high morbidity and mortality, necessitating the need for the development new type antibacterial agents with high efficacy and low tendency to induce drug-resistance. In this study, a series of novel oxazolidinone compounds containing substituted N-methylglycyl C-ring units were designed and synthesized using a scaffold hopping strategy with ranbezolid as the core structure. Compounds 10c, 10d, and 10e were identified as potent compounds with MICs of 2–8 μg/mL against E. faecalis and S. aureus. Selected compounds 10c and 10e demonstrated low cytotoxic activity, high stability in mammalian bodily fluids, and a longer post-antibiotic effect (PAE). Furthermore, these compounds exhibited good bacterial biofilm disruption capabilities, minimal resistance frequency, and rapid bactericidal effects. Mechanistic studies revealed that compounds 10c and 10e exerted their inhibitory effects by disrupting glutathione (GSH)/reactive oxygen species (ROS) homeostasis, thereby increasing oxidative stress through ROS accumulation, leading to bacterial membrane damage, resulting in nucleic acid leakage and bacterial death. These results provide valuable insights into the functions of oxazolidinone antibiotics by the exploitation of substituted N-methylglycyl C-ring moiety for the development of novel oxazolidinone antibacterial agents.