Synthesis of natural and nature-inspired ferulic acid derivatives as antimicrobial agents

Plant secondary metabolites play a pivotal role in defense mechanisms both as antimicrobial compounds and as substrates for cell wall reinforcement. Their accumulation is often observed after pathogen infections and wounding. Cinnamoylamides are phytoalexins containing a cinnamic acid unit coupled with biogenic amines1 and are involved in dimerization reactions under biotic or abiotic stress conditions triggered by oxygen radical species. Dimers are often endowed with higher antimicrobial activity, as reported for the ferulic acid dimer poacic acid and for hordatines2. To deepen the investigation of their biological activity, high amounts of the compounds are needed, but their recovery from the natural matrices is often laborious and low yielding. The development of efficient synthetic strategies could overcome this limitation, finally opening the possibility to enrich this collection of compounds with new analogues. A small library of feruloyl-amides was obtained by chemical condensations and enzymatic amidations using the lipase B from Candida antartica (CaLB) in the green solvent tert-amyl alcohol. In parallel, to obtain ferulic acid dimers, radical reactions were performed employing the horse radish peroxidase (HRP) in presence of H2O2. Starting from the carboxylic intermediates shown in Figure 1, a series of natural and nature-derived analogues was synthesized. Preliminary results about their antibacterial and antifungal activities suggest the possible application of new synthetized natural compounds for a wide range of different sectors.