New potent ciprofloxacin-uracil conjugates as DNA gyrase and topoisomerase IV inhibitors against methicillin-resistant Staphylococcus aureus

[Display omitted] •New ciprofloxacin-uracil conjugates were prepared and characterized.•Promising activity against S. aureus ATCC 6538 better than the Gram-negative strains.•5b and 5g exhibited potent activities against MRSA AUMC 261 with MICs, 0.031 and 0.046 µM.•5b and 5g showed potent inhibitory activities against DNA gyrase and topoisomerase IV.•5b and 5g formed stable complexes with the active sites of DNA gyrase and topoisomerase IV. A series of ciprofloxacin-uracil conjugates 5a-t were synthesized and identified by 1H NMR, 13C NMR, mass spectroscopy and elemental analyses. The antibacterial results revealed that the new derivatives exhibited better activity against Gram-positive than the Gram-negative strains; most of the target compounds exhibited good activities against S. aureus ATCC 6538. Compounds 5b and 5g possess the highest activities with MICs of 1.25 and 2.37 µM, respectively, which are more potent than the parent drug ciprofloxacin, MIC, 7.58 µM. In addition, they also exhibited potent activities against MRSA AUMC 261 with MICs, 0.031 and 0.046 µM respectively, higher than ciprofloxacin with MIC, 0.57 µM. Moreover, compounds 5b and 5g showed potent inhibitory activities against DNA gyrase (IC50 = 1.72 and 5.72 µM) and topoisomerase IV (4.36 and 7.77 µM) compared to ciprofloxacin with IC50 values 0.66 and 8.16 µM, respectively. The molecular docking study revealed that compounds 5b and 5g may formed stable interaction with the active sites of DNA gyrase and topoisomerase IV similar to ciprofloxacin. Hence, 5b and 5g are considered promising antibacterial candidated against MRSA AUMC 261 strains that requires further optimization.