Investigating the Antibacterial Activity of Drimane Natural Products and Semi-synthetic Derivatives

The increasing societal impact of antimicrobial resistance motivates the search for new hit compounds to populate the antibiotic development pipeline. Given the structural complexity and promising bioactivities of plant-derived natural products, the current study explored the antibacterial potential of the sesquiterpenes polygodial (1), paxidal (2) and isopaxidal (3) isolated from Drimys winteri. Furthermore, compounds 1 and 2 were used as starting points for the synthesis of analogues. Whilst 1, its analogues, and 3 were largely inactive, compound 2 demonstrated promising activity against Gram-positive bacteria. Structure activity studies of 2 showed that both the dialdehyde and cinnamate ester motifs were essential for antibacterial activity. Given the amenability of paxidal towards semisynthesis, it represents an interesting starting point for further optimization.