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

Abstract

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 (CC₅₀ ≥ 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 MBIC₅₀ value of 0.02 μg mL^-1, which is 50 times lower than ciprofloxacin (MBIC₅₀ = 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.