Design, synthesis, and biological evaluation of pyrazole-ciprofloxacin hybrids as antibacterial and antibiofilm agents against .

In our continued efforts to tackle antibiotic resistance, a new series of pyrazole-ciprofloxacin hybrids were designed, synthesized, and evaluated for their antibacterial activity against (), (), and (). Most of the compounds exhibited good to excellent activities against , and six compounds (7a, 7b, 7d, 7g, 7k, and 7p) exhibited higher or comparable activity (MIC = 0.125-0.5 μg mL) to ciprofloxacin (0.125 μg mL). Further, these selected compounds were non-toxic (CC ≥ 1000 μg mL) when evaluated for cell viability test against the Hep-G2 cell line. Three compounds (7a, 7d, and 7g) demonstrated excellent activity against ciprofloxacin-resistant with MIC values ranging from 0.125-0.5 μg mL and good antibiofilm activity. Among them, 7g displayed remarkable antibiofilm activity with an MBIC value of 0.02 μg mL, which is 50 times lower than ciprofloxacin (MBIC = 1.06 μg mL). A time-kill kinetics study indicated that 7g showed both concentration and time-dependent bactericidal properties. In addition, 7g effectively inhibited DNA-gyrase supercoiling activity at 1 μg mL (8× MIC). Two compounds 7b and 7d exhibited the highest activity against with a MIC of 0.5 μg mL, while 7c showed the highest activity against with a MIC value of 2 μg mL. Molecular docking studies revealed that 7g formed stable interactions at the DNA active site.