Structure-Activity Relationship (SAR) Analysis of Newly Synthesized Antimicrobial Agents

The increasing threat of antimicrobial resistance (AMR) necessitates the development of new antimicrobial agents with improved potency and safety. Although heterocyclic scaffolds have shown promise, limitations in efficacy and selectivity remain. In this study, we designed, synthesized, and characterized 24 novel antimicrobial compounds based on thiazole, quinoxaline, and ultrashort lipopeptide scaffolds using one-pot cyclization and solid-phase peptide synthesis. These compounds were evaluated against a panel of multidrug-resistant Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. Cytotoxicity tests on human HEK 293 cells confirmed low toxicity and favorable selectivity indices. A quantitative structure-activity relationship (QSAR) model identified moderate lipophilicity (cLogP 3–5), limited hydrogen bond donors, and para electronegative substituents as key positive predictors of antibacterial activity, while high polar surface area and basicity reduced potency. The lead compound, 4f, exhibited potent sub-micromolar activity (MIC 0.25 µg/mL) against resistant S. aureus with an SI >100. Molecular docking suggested strong binding to DNA gyrase, corroborating activity data. Time-kill and post-antibiotic effect assays demonstrated rapid and sustained bactericidal effects. These findings provide valuable insights for developing next-generation antimicrobials against AMR.