Cannabichromene-based imidazolium salts as antibacterial agents: microwave-assisted synthesis and biological evaluation

The increasing prevalence of antimicrobial resistance highlights the urgent need for new antimicrobial agents with improved efficacy and safety profiles. Cannabichromene (CBC) is a non-psychoactive phytocannabinoid with reported antibacterial activity, but its limited chemical stability restricts broader therapeutic applications. In this study, we designed and synthesized a novel series of hybrid cannabichromene-based imidazolium salts (CBC-IMSs) that combine a cannabinoid scaffold with a membrane-active imidazolium moiety. The resulting CBC-IMSs exhibited enhanced chemical stability compared to the parent CBC. The target compounds were synthesized via an efficient five-step route, four stages of which were performed under microwave irradiation, reducing reaction times from hours to minutes and improving overall yields. The structures of all derivatives were confirmed by NMR, FTIR, HRMS, and elemental analysis. Antibacterial activity was evaluated using an ATP-based luminescence assay against Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa. All derivatives showed potent activity against S. epidermidis, with IC₅₀ values in the range of 1.0-5.2 µM, while limited activity was observed against Gram-negative strains. Structure-activity analysis indicated that the length of the N-alkyl side chain plays a key role in modulating antibacterial potency, with the butyl-substituted derivative (CBC-C₄) identified as the most active compound. In silico ADMET predictions suggest favorable drug-like properties and low toxicity risk for the synthesized compounds. Overall, these findings demonstrate that CBC-IMS hybrids represent a promising starting point for developing stable cannabinoid-based antimicrobial agents targeting Gram-positive bacteria.