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

## TL;DR

This paper explores the synthesis and biological evaluation of biphenyl and diphenyl ether compounds inspired by natural phlorotannins found in brown algae.

## Contribution

The study introduces a new set of synthesized biphenyl and diphenyl ether analogs and evaluates their antimicrobial potential.

## Key findings

- Polymethylated diphenyl ethers showed 20-45% inhibition of fungal mycelium growth at 500 μM.
- Antibacterial activity against Gram-positive and Gram-negative bacteria was weak, with MICs ≥128 μg/mL.
- Methylation patterns and aromatic ring connections influenced biological activity.

## Abstract

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.