Nature-Inspired Biphenyls and Diphenyl Ethers: Design, Synthesis, and Biological Evaluation

Phlorotannins are polyphenolic compounds made of phloroglucinol units mainly found in brown algae, exhibiting diverse structural features and bioactive properties. Notably, dimeric phlorotannins, i.e., fucols and phloroethols, share the biphenyl and diphenyl ether motifs characteristic of several antimicrobial phytoalexins, typically produced by plants under biotic and abiotic stress conditions. Considering the difficult supply from their biological matrices, natural difucol, hexaacetyl-difucol, and diphloroethol have been synthesized; moreover, a small collection of analogues has been prepared by versatile synthetic approaches consisting in a partial or complete methylation (or acetylation) of the monomers. Finally, oxidative dimerization or Ullmann condensation provided the desired compounds. The resulting derivatives have been evaluated as inhibitors of mycelium growth, spore germination, and appressorium formation of Pyricularia oryzae (PO-2107 Qol-resistant strain and PO-A252 Qol-sensitive strain), Botrytis cinerea (BC-2A10), and Fusarium culmorum (FC-UK). None of the biphenyl derivatives significantly affected the tested fungal strains; however, polymethylated diphenyl ethers 10, 11, and 14 at 500 μM concentration showed inhibition of mycelium growth between 20 and 45% against all the tested strains, highlighting that the methylation pattern, as well as the connection between the two aromatic rings, could have a role in the interaction with the biological target. Antibacterial assays against one Gram-positive (Staphylococcus aureus) and three Gram-negative bacteria (Escherichia coli, Salmonella enterica Enteritidis, and Pseudomonas aeruginosa) showed minimum inhibitory concentrations (MICs) equal or higher than 128 μg/mL for all the tested compounds.