Synthesis, Antibacterial Evaluation and Molecular Modeling of Novel Chalcone Derivatives Incorporating the Diphenyl Ether Moiety.

Twenty-one novel chalcone derivatives, 5a-5u, incorporating a diphenyl ether moiety, were designed, prepared, and subsequently characterized using NMR and HR-MS and FR-IR techniques. Antibacterial evaluation of the target compounds was carried out against Staphylococcus aureus, Escherichia coli, Salmonella, and Pseudomonas aeruginosa. The in vitro results demonstrated that most compounds exhibited considerable potency in inhibiting bacterial growth, with MIC values ranging from 25.23 to 83.50 μM for S. aureus, 27.53 to 76.25 μM for E. coli, 29.73 to 71.73 μM for Salmonella, and 27.53 to 71.73 μM for P. aeruginosa. Notably, all synthesized compounds exhibited superior antibacterial activity compared to the lead chalcone. In particular, compound 5u, which features two diphenyl ether moieties, displayed outstanding antibacterial performance, with MIC values of 25.23 μM for S. aureus and 33.63 μM for E. coli, Salmonella, and P. aeruginosa. Moreover, compound 5u outperformed both ciprofloxacin and gentamicin against Salmonella and P. aeruginosa, and time-kill curve assays further revealed that concentrations of compound 5u at or above 33.63 μM provided potent and sustained inhibition of both Salmonella and P. aeruginosa. Additionally, molecular modeling of the P. aeruginosa LpxC-compound 5u complex suggested that compound 5u could strongly bind to and interact with the binding site of the LpxC. Based on these findings, compound 5u represents a promising lead for future antimicrobial development.