Design, synthesis, and antibacterial assessment of a new series of ciprofloxacin-based compounds as possible dual DNA gyrase/topoisomerase IV inhibitors

Abstract Simultaneous inhibition of DNA gyrase and topoisomerase IV (Topo IV) is a primary pharmacological strategy to enhance antibacterial efficacy and markedly reduce the emergence of antibiotic resistance. In this regard, a new set of twelve ciprofloxacin-based derivatives was rationally developed, synthesized, and structurally verified. The DNA gyrase and Topo IV inhibitory actions of the developed Compounds 6a-l were investigated. Compound 6 g showed the most promising results, with IC50 values of 1.75 ± 0.05 and 03.47 ± 0.14 µM against DNA gyrase and Topo IV, respectively, compared to ciprofloxacin at 02.13 ± 0.06 and 25.22 ± 1.27 µM, respectively. Compound 6 g demonstrated the highest antibacterial activity, with MIC values of 0.025, 0.025, and 0.125 µg/mL against E. coli, P. aeruginosa, and S. aureus, respectively. It exhibits comparable efficacy to ciprofloxacin against E. coli, a gram-negative bacterium, although it possesses only half the potency against P. aeruginosa and the gram-positive S. aureus. Compound 6 g exhibits a significant antibiofilm action; at the MIC level, the biofilm inhibition percentage was 96%. Docking analyses revealed that Compound 6 g displays enhanced binding affinity for E. coli DNA gyrase B and Topo IV compared to ciprofloxacin. Molecular dynamics simulations validated the exceptional stability of the 6 g–DNA gyrase B complex. In silico ADMET studies demonstrated satisfactory lipophilicity and metabolic characteristics. These findings collectively underscore 6 g as a viable antibacterial candidate.