Identification of CH2-linker modified desfluoroquinolone-aminopyrimidine hybrids to combat antibiotic-resistant gram-positive bacteria

The increasing prevalence of antibiotic-resistant bacterial infections has emerged as a major public health crisis, necessitating an urgent need for the development of new antimicrobial agents. In this manuscript, structural modifications were conducted on the CH₂ linker of the antibacterial desfluoroquinolone-aminopyrimidine hybrids that we had previously obtained, resulting in compounds A7, B1, and D6. These three compounds exhibited potent activity against a panel of antibiotic-resistant Gram-positive bacteria, including fluoroquinolone-resistant Staphylococcus aureus, linezolid-resistant Staphylococcus aureus, vancomycin-intermediate Staphylococcus aureus (VISA), and vancomycin-resistant Enterococcus faecium. Particularly, despite their structural similarity to classical quinolones, compounds A7, B1, and D6 exhibited no cross-resistance with ciprofloxacin. Additionally, the difluorinated CH₂-linker modified compound demonstrated enhanced metabolic stability. These promising results encourage us to move forward to the next phase of structural optimization, with a specific focus on reducing mammalian cytotoxicity.