Design, synthesis, and biological evaluation of pyrazole-ciprofloxacin hybrids as antibacterial and antibiofilm agents against <i>Staphylococcus aureus</i>

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 Staphylococcus aureus ( S. aureus ), Pseudomonas aeruginosa ( P. aeruginosa ), and Mycobacterium tuberculosis ( Mtb ). Most of the compounds exhibited good to excellent activities against S. aureus , and six compounds (7a, 7b, 7d, 7g, 7k, and 7p) exhibited higher or comparable activity (MIC = 0.125-0.5 μg mL -1 ) to ciprofloxacin (0.125 μg mL -1 ). Further, these selected compounds were non-toxic (CC 50 ≥ 1000 μg mL -1 ) when evaluated for cell viability test against the Hep-G2 cell line. Three compounds (7a, 7d, and 7g) demonstrated excellent activity against ciprofloxacin-resistant S. aureus with MIC values ranging from 0.125-0.5 μg mL -1 and good antibiofilm activity. Among them, 7g displayed remarkable antibiofilm activity with an MBIC 50 value of 0.02 μg mL -1 , which is 50 times lower than ciprofloxacin (MBIC 50 = 1.06 μg mL -1 ). 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 -1 (8× MIC). Two compounds 7b and 7d exhibited the highest activity against Mtb with a MIC of 0.5 μg mL -1 , while 7c showed the highest activity against P. aeruginosa with a MIC value of 2 μg mL -1 . Molecular docking studies revealed that 7g formed stable interactions at the DNA active site.