Design, Synthesis, and Studies of New Norfloxacin Analogues with Broad Spectrum Antibacterial Activity Topoisomerase II Inhibition.

: Novel norfloxacin derivatives were synthesized, characterized, and screened for their antibacterial activity against Gram-positive strain and Gram-negative strains; , , and using the agar cup diffusion method. : The results revealed that compounds - exhibited more potent activity towards with MIC values of 0.21-3.61 µM than norfloxacin with a MIC of 7.83 µM. The most potent compound, , showed 37-fold more potency than norfloxacin. More importantly, compound exhibited more potent activity against than norfloxacin, with MIC values of 0.80 and 1.96 µM, respectively. Meanwhile, compounds and have potent activity towards the Gram-negative strains with MIC values of 0.20-0.79 µM compared with norfloxacin with a MIC of 0.24 µM. Moreover, the potent compounds showed higher activity towards topoisomerase II enzymes, especially against topoisomerase IV, which confirms the docking study with the gyrase enzyme active binding site (PDB ID: 2XCT). In addition, cytotoxicity assays of the most potent compounds showed that compounds , , , and have negligible risks of toxic effects when evaluated against the normal cell line WI 38. : The docking study of the most potent compounds , , , and on the gyrase enzyme active site (PDB: 2XCT) aligns their antibacterial activity and topoisomerase inhibition. The physicochemical and pharmacokinetic characteristics of the target derivatives were forecasted via SwissADME. Hence, these compounds are considered promising antibacterial candidates that require further optimization.