Design, synthesis, and antibacterial activity study of novel β - aminoketone compounds based on the symmetrical twin-drugs design method.

The overuse of antibiotics has led to widespread bacterial resistance, and developing antibiotics with novel structural scaffolds is a crucial strategy to address this challenge. Based on the antibacterial potential of local anesthetics, this study selected dyclonine - the one with the highest antibacterial activity - as the parent scaffold, and designed and synthesized two series of β-aminoketone-based twin-drugs using a symmetrical twin-drug design. Their analgesic and antibacterial activities were evaluated. Structure-activity relationship (SAR) analysis revealed that the linker chain length is a critical determinant of antibacterial activity. In vitro assays showed that compound I-9 exhibited potent antibacterial activity (MIC = 2 μg/mL against S. aureus), low hemolytic activity (HC50 > 1280 μg/mL), and a rapid bactericidal effect, which was associated with membrane depolarization. Furthermore, in vivo evaluation in a mouse abscess model demonstrated that compound I-9 had stronger antibacterial activity than vancomycin. In conclusion, compound I-9 is a promising novel antibiotic candidate worthy of further research, and this study provides a new structural scaffold for the design of new antibiotics.