Here in, we report the design, synthesis, and antibacterial activity of series of bulky arenesulfonamido derivatives using ciprofloxacin and norfloxacin as scaffolds. All the synthesized compounds were investigated in vitro for their antibacterial activities against two Gram-positive and two Gram-negative organisms using dilution broth method. Among the tested compounds examined, compounds 3-7 showed significance difference from the standard drug ciprofloxacin. 2D-QSAR study provides details on the fine relationship linking structure and activity and offers clues for structural modifications that can improve the activity. Docking study of the compound 3b into the active site of the topoisomerase II DNA-gyrase enzymes revealed a similar binding mode to ciprofloxacin with additional classical and nonclassical hydrogen bonds.