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

Twenty-one novel chalcone derivatives, <b>5a</b>-<b>5u</b>, 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 <i>Staphylococcus aureus</i>, <i>Escherichia coli</i>, <i>Salmonella</i>, and <i>Pseudomonas aeruginosa</i>. 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 <i>S. aureus</i>, 27.53 to 76.25 μM for <i>E. coli</i>, 29.73 to 71.73 μM for <i>Salmonella</i>, and 27.53 to 71.73 μM for <i>P. aeruginosa</i>. Notably, all synthesized compounds exhibited superior antibacterial activity compared to the lead chalcone. In particular, compound <b>5u</b>, which features two diphenyl ether moieties, displayed outstanding antibacterial performance, with MIC values of 25.23 μM for <i>S. aureus</i> and 33.63 μM for <i>E. coli</i>, <i>Salmonella</i>, and <i>P. aeruginosa</i>. Moreover, compound <b>5u</b> outperformed both ciprofloxacin and gentamicin against <i>Salmonella</i> and <i>P. aeruginosa</i>, and time-kill curve assays further revealed that concentrations of compound <b>5u</b> at or above 33.63 μM provided potent and sustained inhibition of both <i>Salmonella</i> and <i>P. aeruginosa</i>. Additionally, molecular modeling of the <i>P. aeruginosa</i> LpxC-compound <b>5u</b> complex suggested that compound <b>5u</b> could strongly bind to and interact with the binding site of the LpxC. Based on these findings, compound <b>5u</b> represents a promising lead for future antimicrobial development.