Discovery of Axially Halogenated Chiral BINOL Derivatives as Multitarget Antibacterial Agents.

Antibiotic resistance has become one of the most pressing global public health concerns. Therefore, the development of effective chiral antibacterial agents capable of simultaneously inhibiting multiple enzymes and specifically interacting with biological targets is a critical and urgent priority. In this study, halogenated chiral BINOL derivatives were designed, synthesized, and characterized, followed by evaluation of their antibacterial activities. Results showed that (S)-6,6'-dibromo-BINOL (S4) exhibited the strongest antibacterial activity against Staphylococcus aureus ATCC 6538 with a minimum inhibitory concentration (MIC) of 2.0 μg/mL and against methicillin-resistant S. aureus (MRSA) ATCC 43,300 with a MIC of 8 μg/mL. Biofilm adhesion of both S. aureus and MRSA was significantly reduced after S4 treatment compared to the parent chiral BINOL (S0). Furthermore, complete bacterial killing of S. aureus and MRSA bacteria was achieved within 12 h at 2MIC of S4. The results also indicated that S-configured BINOL derivatives possess superior antibacterial potency compared to their R-configured counterparts. Multitarget docking analysis further revealed that S4 can strongly bind to key virulence-related targets, including thymidylate kinase (TMK), Pseudomonas aeruginosa quorum-sensing receptor (PqsR), and penicillin-binding protein 2a (PBP2a). These findings confirm that both the stereochemistry and the presence of halogen atoms in these chiral molecules play crucial roles in modulating their antibacterial activities.