Novel antimicrobial ciprofloxacin-pyridinium quaternary ammonium salts with improved physicochemical properties and DNA gyrase inhibitory activity

New ciprofloxacin/ quaternary ammonium salts 3a–e were designed and synthesized as potential antimicrobial agents. Most of the prepared derivatives showed promising dual antibacterial/antifungal activities. Compound 3e was the most potent and afforded vast spectrum antibacterial activity against S. aureus and most of the tested Gram-negative bacterial strains with MIC values ranging from 1.53–9.54 µg/mL. Moreover, ciprofloxacin and compound 3e induced DNA cleavage in S. aureus DNA gyrase and S. aureus TOPO IV DNA by 1 and 10 µM, respectively. In addition, docking study results agreed with results of DNA cleavage assays where all the tested compounds showed no additional significant interactions over the parent ciprofloxacin. On the other side, compounds 3e and 3f exhibited outstanding antifungal activity better than the reference itraconazole with MICs of 1.87, 4.67, and 11.22 µg/mL, respectively, against Candida. albicans. These data suggest the prevalence of another mechanism in addition to DNA gyrase circumvention, like metal chelation, antibiofilm, and/or improvement of lipophilicity and subsequent penetration.