We report the design, synthesis, and antimicrobial evaluation of a series of ciprofloxacin (CP) conjugates coupled with nitrogen-containing heterocycles. In vitro screening of these new hybrid compounds (1–13) against a panel of planktonic bacterial strains highlighted thiazolyl homologs 6 and 7 as the most promising candidates for further investigation. These derivatives demonstrated potent growth-inhibitory activity against various standard and clinical isolates, with minimum inhibitory concentrations (MICs) ranging from 0.05 to 0.4 µg/ml, which are higher or comparable to the reference fluoroquinolone. Both compounds effectively inhibited biofilm formation by selected staphylococci across all tested concentrations (1–8 x MIC), displaying greater efficacy at higher doses compared to CP alone. Notably, conjugate 7 also significantly eradicated existing biofilms formed by S. aureus of various origin. Molecular docking studies revealed that conjugate 7 engages in a broader range of interactions with DNA gyrase and DNA topoisomerase IV than CP, suggesting stronger binding affinity and enhanced flexibility. This may contribute to its potential in overcoming bacterial resistance mechanisms. The above findings indicate compound 7 as a promising candidate for clinical development.
