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Background: Infection is a global threat to human health, and there is an urgent need to develop new effective antibacterial drugs to treat bacterial infections. Objective: To study the antibacterial activity of piperazine substituted chalcone sulphonamides. Materials and Methods: A series of novel piperazine substituted chalcone sulphonamides have been prepared, and in vitro antibacterial activity against Staphylococcus aureus, Bacillus subtilis and Escherichia coli strains were evaluated. Results: The results showed that derivatives 6a, 6c and 6h displayed good antibacterial activity against Bacillus subtilis with MIC values of 4.0-8.0 mg/mL. Conclusion: Piperazine substituted chalcone sulphonamides may be used as potential antibacterial agents.