Synthesis and molecular docking of new N4-piperazinyl ciprofloxacin hybrids as antimicrobial DNA gyrase inhibitors

Abstract

A series of N -4 piperazinyl ciprofloxacin derivatives as urea-tethered ciprofloxacin-chalcone hybrids 2a-j and thioacetyl-linked ciprofloxacin-pyrimidine hybrids 5a-i were synthesized. The target compounds were investigated for their antibacterial activity against S. aureus , P. aeruginosa, E. coli, and C. albicans strains, respectively. Ciprofloxacin derivatives 2a-j and 5a-i revealed broad antibacterial activity against either Gram positive or Gram negative strains, with MIC range of 0.06–42.23 µg/mL compared to ciprofloxacin with an MIC range of 0.15–3.25 µg/mL. Among the tested compounds, hybrids 2b , 2c , 5a, 5b , 5h, and 5i exhibited remarkable antibacterial activity with MIC range of 0.06–1.53 µg/mL against the tested bacterial strains. On the other hand, compounds 2c , 2e , 5c, and 5e showed comparable antifungal activity to ketoconazole against candida albicans with MIC range of 2.03–3.89 µg/mL and 2.6 µg/mL, respectively. Further investigations showed that some ciprofloxacin hybrids have inhibitory activity against DNA gyrase as potential molecular target compared to ciprofloxacin with IC 50 range of 0.231 ± 0.01–7.592 ± 0.40 µM and 0.323 ± 0.02 µM, respectively. Docking studies of compounds 2b, 2c, 5b, 5c, 5e, 5h, and 5i on the active site of DNA gyrase (PDB: 2XCT) confirmed their ability to form stable complex with the target enzyme like that of ciprofloxacin. Graphical abstract

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