A novel strategy for nephritis-associated infections: dual-antibacterial/anti-inflammatory effects of Schiff base

To address the antimicrobial treatment needs for lupus nephritis and pyelonephritis, this study designed and synthesized ten Schiff base derivatives using 4-(diethylamino)salicylaldehyde as the core scaffold <i>via</i> aldehyde-amine condensation reactions. Activity screening identified compound D5 as exhibiting potent antibacterial activity against <i>Staphylococcus aureus</i> ATCC 29213 with an MIC of 8 μg mL^-1, demonstrating low cytotoxicity toward mammalian cells (HK-2, LO2) and no hemolysis at 256 μg mL^-1. Mechanistic studies revealed that D5 disrupts bacterial membrane integrity, causing leakage of intracellular proteins and DNA. Furthermore, it completely eradicated bacteria within 10 hours at 8 × MIC concentration with a low propensity for resistance induction, and possessed both inhibitory and eradicative effects against biofilms. In an LPS-induced RAW 264.7 macrophage model, D5 significantly downregulated the levels of inflammatory factors including TNF-α, IL-6, IL-1β, and NO. Preliminary druggability assessment confirmed its compliance with Lipinski's rule of five. In summary, D5 combines potent antibacterial, anti-biofilm, and anti-inflammatory activities with an excellent safety profile, positioning it as a promising candidate compound for further development.