Identification of Novel Benzopyridonyl Cyanovinylpyrimidines as Potential Broad-Spectrum Antibacterial Members

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.