Novel chalcone-conjugated, multi-flexible end-group coumarin thiazole hybrids as potential antibacterial repressors against methicillin-resistant Staphylococcus aureus

The increasing resistance of methicillin-resistant Staphylococcus aureus (MRSA) to antibiotics has led to a growing effort to design and synthesize novel structural candidates of chalcone-conjugated, multi-flexible end-group coumarin thiazole hybrids with outstanding bacteriostatic potential. Bioactivity screening showed that hybrid 5i, which was modified with methoxybenzene, exerted a significant inhibitory activity against MRSA (MIC = 0.004 mM), which was 6 times better than the anti-MRSA activity of the reference drug norfloxacin (MIC = 0.025 mM). Compound 5i neither conferred apparent resistance onto MRSA strains even after multiple passages nor triggered evident toxicity to human hepatocyte LO2 cells and normal mammalian cells (RAW 264.7). Molecular docking showed that highly active molecule 5i might bind to DNA gyrase by forming stable hydrogen bonds. In addition, molecular electrostatic potential surfaces were developed to explain the high antibacterial activity of the target compounds. Furthermore, preliminary mechanism studies suggested that hybrid 5i could disrupt the bacterial membrane of MRSA and insert itself into MRSA DNA to impede its replication, thus possibly becoming a potential antibacterial repressor against MRSA. [Display omitted] •Coumarin hybrids were developed by a convenient and efficient method.•Hybrid 5i showed good anti-MRSA activity and low cytotoxicity.•Hybrid 5i could efficiently bind with gyraseDNA.•Hybrid 5i could rupture the bacterial membrane of MRSA.•Hybrid 5i might insert into MRSA DNA to form compound-DNA complex.