New Ciprofloxacin-Pyrazolopyrimidine Hybrids as Topoisomerase IV and Gyrase Inhibitors against MRSA AUMC 261

Eleven novel ciprofloxacin-pyrazolopyrimidine hybrids 4 a-k were synthesized and structurally elucidated using NMR, elemental analysis, and mass spectrometry. The antibacterial screening showed that the newly synthesized compounds revealed a remarkable shifting of antibacterial activity from Gram-negative toward Gram-positive bacteria. Most of the synthesized hybrids displayed good to excellent activity against Staph aureus ATCC 6538 especially hybrids 4 a and 4 g which revealed MICs of 12.5 and 6.25 mu g/ml, respectively, compared to the ciprofloxacin MIC, 25 mu g/ml as a reference drug. In addition, both hybrids displayed potent activity toward MRSA AUMC 261 with MICs, 71 and 36 mu g/ml respectively, compared to the ciprofloxacin MIC, 190 mu g/ml as a reference drug. Additionally, hybrids, 4 a and 4 g exhibited effective inhibitory activity against DNA gyrase and topoisomerase IV enzymes with IC50 values, 0.404, 1.626 mu M and 3.647 and 3.791 mu M, respectively, compared to ciprofloxacin IC50 values 0.661 and 8.159. A molecular modeling investigation showed a high fitting affinity of hybrids 4 a and 4 g toward gyrase and topoisomerase IV active sites compared to ciprofloxacin.