Synthesis, anti-biofilm and molecular docking of amino-substituted chalcones targeting <i>Staphylococcus aureus</i> sortase A

Antibiotic resistance is an urgent global health challenge that requires the development of new antibacterial agents. In this study, 14 aminochalcones bearing electron-withdrawing groups were synthesized and evaluated for antibacterial activity. Chalcone <b>C5</b>, with an <i>ortho</i>-chlorine on ring B, demonstrated the most potent effect, notably against methicillin-susceptible and methicillin-resistant <i>Staphylococcus aureus</i> (MICs of 1.9 and 3.9 µg/mL, respectively), comparable to vancomycin. <b>C5</b> showed synergistic interaction with vancomycin, reducing its MIC tenfold. Time-kill assays confirmed C5’s bactericidal action within 8 h, with no bacterial regrowth up to 12 h. <b>C5</b> also significantly inhibited bacterial adhesion to keratinocytes (HaCaT) and reduced biofilm formation and survival at both MIC and 10× MIC, showing effects comparable to vancomycin. <i>In silico,</i> ADMET predictions indicated favorable pharmacokinetic and safety profiles, including high intestinal absorption and lack of hERG inhibition or cytotoxicity. Molecular docking against <i>S. aureus</i> sortase A (SrtA) suggests strong interactions with key residues (Arg197, Glu105, Asn114), supporting the anti-adhesion activity. Furthermore, <i>in vivo</i> toxicity assessment using <i>Galleria mellonella</i> larvae showed minimal toxicity at 100× MIC. These findings support chalcone <b>C5</b> as a promising lead compound for the development of new antibacterial agents, particularly for combating <i>S. aureus</i> infections and biofilm-associated pathologies.