Synthesis, Antimicrobial Activity, and Tyrosinase Inhibition by Multifunctional 3,4-Dihydroxy-Phenyl Peptidomimetics

National Science Center, Poland project OPUS No. 2023/49/B/NZ7/02469; COST Action EURESTOP, CA21145.

The purpose of the present study was to evaluate the synergistic effect of two important pharmacophores, 3,4-dihydroxyphenyl and peptidomimetic moieties, as mushroom tyrosinase inhibitors and antimicrobial agents targeting specific strains of pathogenic bacteria. The 3,4-dihydroxybenzaldehyde (protocatechuic aldehyde) was found to be an effective inhibitor of tyrosinase activity, and due to the fact that it is a safe natural substance with such a scaffolded structure, it is likely that dihydroxyl-substituted phenolic derivatives can exhibit potent tyrosinase inhibitory activity. Series of peptidomimetics with an incorporated 3,4-dihydroxyphenyl scaffold was synthesized and characterized. The inhibitory effects of peptidomimetics on a mushroom tyrosinase were studied. The results showed that among the compounds, five of them showed higher inhibitory activity than the parent 3,4-dihydroxybenzyl aldehyde. In silico docking studies with mushroom tyrosinase (PDB ID 2Y9X) predicted possible binding modes in the enzymatic pocket for these compounds. Furthermore, the antimicrobial activities of peptidomimetics against selected Gram-positive and Gram-negative bacterial strains (E. coli, A. baumannii, P. aeruginosa, E. cloacae, and S. aureus) were investigated. The results showed that all tested peptidomimetics have antimicrobial activities (MIC values from 0.25 to 4.0 μM) comparable with those observed for the commonly used antibiotics (ciprofloxacin, bleomycin, and cloxacillin). Notably, all evaluated compounds demonstrated significant activity against E. coli and S. aureus strains, which are primary sources of infections resulting in numerous fatalities. Additionally, the cytotoxicity of sixteen derivatives was assessed using the MTT assay on BALB/c3T3 mouse fibroblast cell lines. Cytotoxicity analyses indicated that the tested substances have a similar or reduced impact on cell proliferation compared to commonly utilized antibiotics within the range of therapeutic doses. This study presents the potential of peptidomimetics with 3,4-dihydroxyphenyl scaffolds could be beneficial for developing novel tyrosinase inhibitors and new potent food preservatives or cosmetic additives.