Synthesis, anti-biofilm and molecular docking of amino-substituted chalcones targeting Staphylococcus aureus sortase A.

Abstract

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 C5, with an ortho-chlorine on ring B, demonstrated the most potent effect, notably against methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MICs of 1.9 and 3.9 µg/mL, respectively), comparable to vancomycin. C5 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. C5 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. In silico, ADMET predictions indicated favorable pharmacokinetic and safety profiles, including high intestinal absorption and lack of hERG inhibition or cytotoxicity. Molecular docking against S. aureus sortase A (SrtA) suggests strong interactions with key residues (Arg197, Glu105, Asn114), supporting the anti-adhesion activity. Furthermore, in vivo toxicity assessment using Galleria mellonella larvae showed minimal toxicity at 100× MIC. These findings support chalcone C5 as a promising lead compound for the development of new antibacterial agents, particularly for combating S. aureus infections and biofilm-associated pathologies.