44a(Southwest University)

The diversity of chemically synthesized scaffolds provides the channel for discovering antibacterial agents with novel structures or targets to conquer microbial resistance. This work developed a unique type of novel benzopyridonyl cyanovinylpyrimidines (BCPs). Most of BCPs gave high and broad-spectrum antibacterial activity; especially, amino BCP 31f and methylthio BCP 44a exhibited higher bacteriostatic potency (MICs = 0.25-1 μg/mL) against Staphylococcus aureus strains than ciprofloxacin. Low hemolysis, cytotoxicity, drug resistance, good plasma stability, and rapid bactericidal effects revealed their development potential. Mechanism research showed that active BCPs could intercalate into DNA to form a DNA-BCP supramolecular complex that might block DNA replication, inhibit the production of staphyloxanthin, and be effectively transported by human serum albumin. Moreover, amino BCP 31f displayed superior anti-MRSA efficacy to vancomycin in vivo. This series of medicinal chemobiological evaluation implied the great potential of novel benzopyridonyl cyanovinylpyrimidines as broad-spectrum antibacterial members to combat drug resistance.