Structure–Activity Relationships of Cannabigerol and Cannabigerolic Acid Derivatives as Antibacterial Agents against Gram-Positive Bacteria

Antimicrobial resistance has emerged as a critical global health challenge, necessitating the discovery of new antibiotics. Cannabigerol (CBG) and cannabigerolic acid (CBGA) from Cannabis sativa have shown promising activity as antibacterial agents. In this work, a total of 26 CBG and CBGA derivatives (13 of each) featuring varied terpene chain lengths and substitution patterns were synthesized and characterized; of these, 20 are novel analogs. To determine their structure–activity relationships (SAR), we tested their antibacterial activity against Gram-positive bacterial strains, including Bacillus subtilis, Staphylococcus epidermidis, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and vancomycin-resistant Enterococcus faecalis (VRE). Our results reveal that terpene chain lengths between 6 and 13 carbons show potent antibacterial activity with no detectable cytotoxicity toward mammalian cells. In addition, several CBG analogs exhibited minimum inhibitory concentrations (MICs) similar to the FDA-approved drug, daptomycin, against multiple Gram-positive strains. Comparing the antibacterial activities of different CBG and CBGA derivatives establishes the terpene moiety as a critical structural determinant for antibacterial potency in CBG and CBGA scaffolds and provides strong evidence that rational modification of this moiety can significantly enhance bioactivity.