Design, synthesis, and evaluation of novel C-6-amino-substituted naphthalimide derivatives for activity against gram-positive bacteria.

The growing crisis of antibiotic resistance demands innovative antimicrobial agents that combine high potency with low toxicity. In this study, we designed and synthesized a series of novel C-6-amino-substituted naphthalimide derivatives to target drug-resistant Gram-positive bacteria. A total of 28 compounds were prepared and evaluated for antibacterial activity, revealing that most exhibited moderate to excellent efficacy against pathogens including S. aureus. Among them, compound W-2-4 demonstrated the strongest antibacterial effect, with minimum inhibitory concentration (MIC) ranging from 0.5 to 4 μg/mL, and exhibited low hemolytic and cytotoxic properties. Additionally, W-2-4 exhibits potent bactericidal properties, extremely low resistance rates, and effectively disrupts bacterial biofilms. Notably, in a mouse infection model with S. aureus, the high-dose group (30 mg/kg) demonstrated superior in vivo antibacterial efficacy and wound healing capacity compared to the vancomycin control group (20 mg/kg). Therefore, W-2-4 represents a valuable lead compound for further structural optimization and mechanistic investigation as a potential naphthalimide-based antibacterial agent against resistant Gram-positive infections.