Synthesis and in vitro antibacterial activity of N-acylarylhydrazone-ciprofloxacin hybrids as novel fluoroquinolone derivatives

Authors：Yang, Ping; Luo, Jia-Bao; Wang, Zi-Zhou; Zhang, Li-Lei; Xie, Xiao-Bao^*; Shi, Qing-Shan; Zhang, Xin-Guo

Source：Journal of Molecular Structure, 2022, 1262: 133007.

DOI：10.1016/j.molstruc.2022.133007

• Fluoroquinolone
• N-acylarylhydrazone
• Pharmacophore
• Antibacterial
• Ciprofloxacin

Twelve novel fluoroquinolone derivatives were rationally designed and synthesized by introducing N- acylarylhydrazone to the C-7 position of ciprofloxacin. Antibacterial evaluation revealed that compound 3k was over 4-folds more potent than ciprofloxacin against S. aureus, with a MIC value <= 0.125 mu g/mL. Compound 3g showed activity against methicillin-resistant S. aureus (MRSA) with a MIC value of 32 mu g/mL. Time-killing assays showed that compound 3g eradicated S. aureus in 4 h and E. coli in 2 h. Compound 3g had a high affinity towards DNA topoisomerase IV, with a least binding energy of -9.9 kcal/mol, which was better than ciprofloxacin ( -8.0 kcal/mol). The binding modes of compound 3g to DNA topoisomerase IV differed from that of ciprofloxacin. Molecular dynamics simulation results support that the interaction between the receptor 3rae and the compound 3g is stable. Besides, cytotoxicity and hemolysis assays demonstrated that compound 3g and 3k have negligible risks of toxic effects.

• Institution
  广州大学; 南方医科大学