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.