Enhanced Substituted Resorcinol Hydrophobicity Augments Tyrosinase Inhibition Potency

Abstract

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 IC(50) values, providing good correlations. The observed IC(50) of the isopropyl ester was 0.07 microM, 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.

Inhibition of Mushroom Tyrosinase Activity by Orsellinates

“…Introducing a methyl group into position 5 of resorcinol to yield orcinol led to a slight decrease in inhibition (50.79%). Khatib et al 10) reported that tyrosinase inhibitors containing a resorcinol subunit are typically highly active, and 2,4-resorcinol derivatives are significantly more potent than 3,5-substituted counterparts. Introduction of a carboxyl into position 4 of orcinol to produce orsellinic acid slightly diminished diphenolase inhibition to 63.35% an inhibitory level still higher than that of 82.69% observed for lecanoric acid.…”

“…Khatib et al 10) suggested that the increasing inhibitory potency exhibited by 3-(2,4-dihydroxyphenyl) propionic esters does not necessarily correlate with longer alkyl chains, but may be related to the increasing volume of ester groups. Similar results were obtained by Kubo et al 4) for esters of gallic acid.…”

“…7) Tyrosinase inhibitors are often structurally analogous to phenolic substrates, which generally show competitive inhibition. A number of naturally occurring tyrosinase inhibitors have been described, mostly phenols and polyphenols, 8) resorcinol derivatives, [9][10][11] benzoic acid and pyridine derivatives, 12,13) gallate derivatives, 14) and vanillin derivatives. 15) However, only a few compounds are known to serve as effective tyrosinase inhibitors, owing to high toxicity, low activity, or economic factors.…”

Rational Design and Synthesis of 4-O-Substituted Phenylmethylenethiosemicarbazones as Novel Tyrosinase Inhibitors

“…3) However, recently studies showed that the abnormal accumulation of pigmentation causes the quality loss of vegetables and fruits and various dermatological disorders, such as hyperpigmentation, freckles, melasma, ephelide, and senile lentigines. 4) Furthermore, the melanin pigments are also found in the mammalian brain where tyrosinase plays a key role in the synthesis of neuromelanin and is linked to Parkinson's and other neurodegenerative diseases. 4,5) Therefore, tyrosinase inhibitors should be clinically useful for the treatment of some dermatological disorders associated with melanin hyperpigmentation and also important in cosmetics and food industry.…”

“…4) Furthermore, the melanin pigments are also found in the mammalian brain where tyrosinase plays a key role in the synthesis of neuromelanin and is linked to Parkinson's and other neurodegenerative diseases. 4,5) Therefore, tyrosinase inhibitors should be clinically useful for the treatment of some dermatological disorders associated with melanin hyperpigmentation and also important in cosmetics and food industry. [6][7][8] So far, a large number of potential tyrosinase inhibitors have been described from natural source, such as kojic acid (Fig.…”