Enhanced substituted resorcinol hydrophobicity augments tyrosinase inhibition potency

The objective of the present study was to investigate to what extent the addition of hydrophobic residues to a 2,4-resorcinol derivative would contribute to their tyrosinase inhibitory potency. Hence, 3-(2,4-dihydroxyphenyl)propionic acid, isolated from Ficus carica, was transformed into esters, and the relationship between the structure of these esters to their mushroom tyrosinase inhibition activity was explored. The enzyme crystallographic structure, published recently (Matoba, Y. et al. J. Biol. Chem. 2006, 281, 8981-8990) was docked with the new esters, and their calculated free energy (FE) and docking energy (DE) were compared with the experimental IC50 values, providing good correlations. The observed IC50 of the isopropyl ester was 0.07 mu M, and its interaction with the enzyme binding site appears to be composed of four hydrogen bonds and two hydrophobic interactions. It may be concluded that the addition of a hydrophobic moiety to 2,4-resorcinol derivatives augments tyrosinase inhibitory potency as was predicted from the modeling study.