Discovery of antibacterial and synergistic acylhydrazone functionalized α-mangostin derivatives against drug-resistant pathogens.

By strategically combining the acylhydrazone scaffold with α-mangostin (α-MG)'s membrane-targeting properties, we designed 48 novel conjugates to enhance antibacterial potential and biofilm penetration while reducing toxicity. The candidate compound 7-8 demonstrated exceptional anti-Methicillin-Resistant Staphylococcus aureus (MRSA) activity (MIC = 1 μg/mL) with in vivo efficacy (5 mg/kg, s.c.) comparable to vancomycin. 7-8 exhibited superior safety profiles versus α-MG, including minimal cytotoxicity (IC50 > 100 μg/mL in A549/LO-2 cells), negligible hemolysis (HC50 > 400 μg/mL), excellent in vivo tolerance, and no genotoxicity. Mechanistic studies revealed a dual antibacterial action: i) membrane disruption causing cellular content leakage, and ii) ROS-mediated oxidative stress. 7-8 also showed remarkable biofilm inhibition/eradication capacity through downregulation of key biofilm genes (ica, agr). Pharmacokinetic evaluation revealed favorable metabolic stability, moderate plasma protein binding, and optimal lipophilicity. These results established 7-8 as a promising multi-target therapeutic candidate against drug-resistant infections, combining enhanced biofilm penetration with improved safety.