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).