Design, synthesis and evaluation of cinnamic acid ester derivatives as mushroom tyrosinase inhibitors

Abstract

Tyrosinase is a key enzyme in melanin biosynthesis, and is also involved in the enzymatic browning of plant-derived foods. Tyrosinase inhibitors are very important in medicine, cosmetics and agriculture. In order to develop more active and safer tyrosinase inhibitors, an efficient approach is to modify natural product scaffolds. In this work, two series of novel tyrosinase inhibitors were designed and synthesized by the esterification of cinnamic acid derivatives with paeonol or thymol. Their inhibitory effects on mushroom tyrosinase were evaluated. Most of these compounds (IC₅₀: 2.0 to 163.8 μM) are found to be better inhibitors than their parent compounds (IC₅₀: 121.4 to 5925.0 μM). Among them, (<i>E</i>)-2-acetyl-5-methoxyphenyl-3-(4-hydroxyphenyl)acrylate (<b>5a</b>), (<i>E</i>)-2-acetyl-5-methoxyphenyl-3-(4-methoxyphenyl)acrylate (<b>5g</b>) and (<i>E</i>)-2-isopropyl-5-methylphenyl-3-(4-hydroxyphenyl)acrylate (<b>6a</b>) showed strong inhibitory activities; the IC₅₀ values were 2.0 μM, 8.3 μM and 10.6 μM, respectively, compared to the positive control, kojic acid (IC₅₀: 32.2 μM). Analysis of the inhibition mechanism of <b>5a</b>, <b>5g</b> and <b>6a</b> demonstrated that their inhibitory effects on tyrosinase are reversible. The inhibition kinetics, analyzed by Lineweaver-Burk plots, revealed that <b>5a</b> acts as a non-competitive inhibitor while <b>5g</b> and <b>6a</b> are mixed-type inhibitors. Furthermore, docking experiments were carried out to study the interactions between <b>6a</b> and mushroom tyrosinase.