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A series of novel hybrids possessing chalcone and thiazole moieties were synthesized and evaluated for their antibacterial activities. In general this class of hybrids exhibited potency against Staphylococcus aureus, and in particular, compound 27 exhibited potent inhibitory activity with respect to other synthesized hybrids. Furthermore, the hemolytic and toxicity data demonstrated that the compound 27 was nonhemolytic and nontoxic to mammalian cells. The in vivo studies utilizing a S. aureus septicemia model demonstrated that compound 27 was as potent as vancomycin. The results of antibacterial activities underscore the potential of this scaffold that can be utilized for developing a new class of novel antibiotics.