Design, synthesis, and biological evaluation of membrane-active cannabichromene derivatives as potent antibacterial agents

Bin Long; Na Wang; Zhangqun Hou; Hefei Shi; Yufei Che; Yuchi Wang; Ting Peng; Yuqi Mao; Tong Luo; Ling Mei; Hongbo Dong

doi:10.1016/j.ejmech.2025.117888

Design, synthesis, and biological evaluation of membrane-active cannabichromene derivatives as potent antibacterial agents

Eur J Med Chem. 2025 Jun 24:296:117888. doi: 10.1016/j.ejmech.2025.117888. Online ahead of print.

Authors

Bin Long¹, Na Wang¹, Zhangqun Hou², Hefei Shi¹, Yufei Che¹, Yuchi Wang¹, Ting Peng², Yuqi Mao¹, Tong Luo², Ling Mei¹, Hongbo Dong³

Affiliations

¹ Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, School of Pharmacy, Chengdu University, Chengdu, 610106, China.
² Anti-infective Agent Creation Engineering Research Centre of Sichuan Province, School of Pharmacy, Chengdu University, Chengdu, 610106, China.
³ Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, School of Pharmacy, Chengdu University, Chengdu, 610106, China. Electronic address: donghongbo@cdu.edu.cn.

PMID: 40580638
DOI: 10.1016/j.ejmech.2025.117888

Abstract

The increasing prevalence of multidrug-resistant (MDR) bacterial infections underscores the urgent need for novel antimicrobial agents with distinct mechanisms. In this study, we present the rational design and synthesis of cationic amphiphilic cannabichromene (CBC, 1) derivatives that mimic antimicrobial peptides (AMPs). Structural optimization of CBC through the incorporation of quaternary ammonium cations improved hydrophilicity and expanded the antibacterial spectrum. Among the 35 derivatives, compound 11F emerged as the lead candidate, exhibiting potent activity against Gram-positive (MIC = 0.25-0.5 μg/mL) and Gram-negative pathogens (MIC = 0.5-8 μg/mL), surpassing vancomycin and ceftazidime in efficacy. Mechanistic studies revealed that 11F disrupts bacterial membranes through high-affinity binding to phosphatidylglycerol (PG), resulting in membrane permeabilization and cytoplasmic leakage. Molecular dynamics simulations supported its membrane-targeting mechanism, driven by amphiphilic insertion into lipid bilayers. The synergistic accumulation of reactive oxygen species (ROS) further amplified the bactericidal effects. Compound 11F demonstrated low hemolysis and cytotoxicity, showing in vivo efficacy in a murine MRSA sepsis model (98.8 % bacterial reduction at 10 mg/kg) and displaying excellent safety. This study establishes compound 11F as a promising membrane-active antibacterial agent with potential for translation into clinical use against MDR infections.