Design and synthesis of amphiphilic cannabichromene derivatives with antimicrobial potential

Antimicrobial resistance (AMR) has emerged as a critical global health threat, prompting the urgent need for new antimicrobial agents. This study presents the design and synthesis of a series of amphiphilic derivatives that mimic antimicrobial peptides (AMPs) by incorporating quaternary ammonium cations into the lipophilic cannabichromene (CBC) scaffold. Through AI-driven predictive modeling, we assessed the antimicrobial efficacy of these novel compounds and validated their activity with experimental testing. The results show that incorporating cationic moieties into the CBC framework significantly enhances its antibacterial activity, especially against Gram-positive bacteria such as S. aureus and MRSA. Among the derivatives, compound 5D demonstrated broad-spectrum antibacterial activity, high salt stability, and showed no apparent resistance development after 20 consecutive passages induced with 1/2 MIC of compound 5D. Mechanistic studies suggested that compound 5D interacts electrostatically with the negatively charged bacterial membrane components, such as phosphatidylglycerol (PG), leading to membrane loosening and structural disruption. Overall, this study represents an initial effort to combine natural product modification with AI-assisted prediction as a potential strategy to support antibacterial drug discovery.