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

  • Bioorg Chem. 2025 Nov:166:109108. doi: 10.1016/j.bioorg.2025.109108.
Qun Tang  1 ,  Haiyang Zhang  2 ,  Zirui Jiao  1 ,  Han Bai  3 ,  Xiangan Han  1 ,  Xiaoyang Wang  1 ,  Keyu Zhang  1 ,  Chunmei Wang  4 ,  Wen Zhou  5
Affiliations
  • 1. Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China; Key laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China.
  • 2. Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China.
  • 3. Department of Clinical Pharmacy, College of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541199, PR China.
  • 4. Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China; Key laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China. Electronic address: [email protected].
  • 5. Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China; Key laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China. Electronic address: [email protected].
PMID: 41109067 DOI: 10.1016/j.bioorg.2025.109108
Abstract

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.

Keywords
MRSA; acylhydrazone; antibacterial; synergistic effect; α-Mangostin.
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