From local anesthetics to antibacterial agents: design, synthesis, and activity evaluation of dyclonine quaternary ammonium salt derivatives.

The discovery of antibiotics with novel structures is a crucial strategy to combat antibiotic resistance. This study was motivated by the reported antibacterial activity of local anesthetics. Dyclonine hydrochloride, which shows the highest antibacterial activity among local anesthetics, was selected as the structural scaffold. Based on the structural characteristics of quaternary ammonium salt antibiotics, a series of dyclonine quaternary ammonium salt derivatives were designed and synthesized, and their analgesic and antibacterial activities were evaluated. The target compounds exhibited almost no analgesic effect but generally showed varying degrees of antibacterial effects against Gram-positive bacteria. Compound 17, the most potent derivative, had a minimum inhibitory concentration (MIC) of 0.5 μg/mL against S. aureus (MIC of amoxicillin against S. aureus: 2 μg/mL; MIC of dyclonine hydrochloride against S. aureus: 64 μg/mL). Further animal experiments demonstrated that compound 17 displayed excellent in vivo antibacterial activity. In addition, the preliminary action mechanism of compound 17 was studied using membrane depolarization assays, confirming that compound 17 exerted antibacterial effects by acting on bacterial cell membranes. In summary, this study identifies the β-aminoketone quaternary ammonium salt as a promising core structure for further antibiotic development.