Design, synthesis, in-silico and in-vitro evaluation of Novel Complex Naphthalimide-Ciprofloxacin Hybrids as next-generation antimicrobial agents

Abstract

A series of ciprofloxacin-naphthalimide hybrid drugs as novel antibacterial agents were synthesized and screened for their antibacterial property against gram-positive and gram-negative bacterial strains, including drug-resistant clinical isolates. Minimum inhibitory concentration (MIC) analysis revealed that hybrids exhibited varying antibacterial activity comparable to ciprofloxacin. Among them, hybrids 20b and 20e demonstrated the most potent efficacy against Gram-positive strains, inhibiting Staphylococcus aureus (MIC 4 µg/mL) and Enterococcus faecalis (MIC 1 µg/mL). Notably, hybrid 20e also showed significant activity against Gram-negative bacteria, including Escherichia coli (MIC 5 µg/mL) and Klebsiella pneumoniae (MIC 4 µg/mL). Hybrids containing shorter linkers (20b–20e) generally displayed enhanced antibacterial potency compared to those with longer linkers, with 18b as an exception. Evaluation against ciprofloxacin-resistant clinical isolates demonstrated the variable but improved sensitivity relative to ciprofloxacin, while activity against ciprofloxacin-sensitive isolates remained comparable to the ciprofloxacin. Checkerboard assays indicated additive interactions between ciprofloxacin and the active hybrids, with no evidence of antagonism. Further, in-vitro cytotoxicity assessment demonstrated that hybrids 20b and 20e were less toxic and exhibited a more favorable safety profile than ciprofloxacin. Overall, hybrids 20b and 20e with potent antibacterial activity, effective against resistant strains, additive interaction with ciprofloxacin, and low cytotoxicity, highlighting their promise as potential candidates for further antibacterial drug development.