Semisynthesis, characterisation, and antibacterial evaluation of a novel lecanoric acid-derived amide library

The known lichen depside, lecanoric acid (1), was identified as a scaffold of interest for the generation of a unique semisynthetic biodiscovery screening library. Large-scale extraction and isolation on the Australian-sourced lichen Parmotrema tinctorum resulted in the purification of ≈1 g of the desired scaffold 1, along with other known lichen metabolites that included divaricatic acid (2), orcinol (3), orsellinic acid (4), and methyl orsellinate (5). Parallel solution-phase synthesis using amidation chemistry on the abundant scaffold 1 afforded a series of novel amide derivatives 6-13 in high purity (>95%) and low to moderate yields (12-53%). All new semisynthetic compounds were fully characterised following 1D/2D NMR, MS and UV data analysis. Crystalline lecanoric acid was obtained during the chemical investigations of the lichen extract, enabling the first X-ray crystallographic analysis to be undertaken on this depside. Compounds 1-13 were evaluated for antibacterial activity against the human pathogen Pseudomonas aeruginosa using a biofilm inhibition assay. Of the new semisynthetics, amide analogue 12 showed the greatest planktonic cell growth inhibition (13% at 50 µM), whilst amide analogue 11 was the most active at inhibiting the formation of biofilm (21% at 50 µM).