This study aims to evaluate, in vitro, antibacterial activity of four novel sulfonamide derivatives (1a-d) against Staphylococcus aureus: reference strain ATCC 25923 and 40 clinical isolates. Inhibition zones were performed with the disk diffusion method. The MIC values were determined by the dilution broth method. A 48 hours MIC-Kinetic curve was performed for the tested compounds. All compounds showed significant antibacterial activity. The mean values of the inhibition zones diameter for compounds 1a-d were 22.15 ± 6.22, 16.39 ± 1.17, 15.42 ± 0.66 and 15.83 ± 1.28 mm, respectively (p value = 0.001). The MIC values were ranged between 64 and 512 g/ml. The compound 1b showed better activity. The 48 hours MIC-kinetic curve showed an inhibiting bacterial growth. The studied compounds 1a-d showed a promising antibacterial effect to response to the urgent need for innovative drugs that could be more effective against resistant pathogens.