Design, synthesis, and inhibitory activity of hydroquinone ester derivatives against mushroom tyrosinase

• Published in: RSC advances Vol. 14; no. 9; pp. 685 - 695
• Main Authors: Xie, Dong, Han, Kangjia, Jiang, Qian, Xie, Sida, Zhou, Jielong, Zhang, Yingjun, Xu, Junming, He, Yuanping, Zhao, Ping, Yang, Xiaoqin
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 14.02.2024
• Subjects: Amino acids; Analogs; Catalytic activity; Copper; Enzymes; Hydroquinone; Molecular docking; Molecular dynamics; Mushrooms; Substrates; Synthesis; Toxicity; Tyrosinase
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/d4ra00007b

Tyrosinase is a widely distributed copper-containing enzyme found in various organisms, playing a crucial role in the process of melanin production. Inhibiting its activity can reduce skin pigmentation. Hydroquinone is an efficient inhibitor of tyrosinase, but its safety has been a subject of debate. In this research, a scaffold hybridization strategy was employed to synthesize a series of hydroquinone-benzoyl ester analogs ( 3a-3g ). The synthesized compounds were evaluated for their inhibitory activity against mushroom tyrosinase (mTyr). The results revealed that these hydroquinone-benzoyl ester analogs exhibited inhibitory activity against mTyr, with compounds 3a-3e displaying higher activity, with compound 3b demonstrating the highest potency (IC 50 = 0.18 ± 0.06 μM). Kinetic studies demonstrated that the inhibition of mTyr by compounds 3a-3e was reversible, although their inhibition mechanisms varied. Compounds 3a and 3c exhibited non-competitive inhibition, while 3b displayed mixed inhibition, and 3d and 3e showed competitive inhibition. UV spectroscopy analysis indicated that none of these compounds chelated with copper ions in the active center of the enzyme. Molecular docking simulations and molecular dynamics studies revealed that compounds 3a-3e could access the active pocket of mTyr and interact with amino acid residues in the active site. These interactions influenced the conformational flexibility of the receptor protein, subsequently affecting substrate-enzyme binding and reducing enzyme catalytic activity, in line with experimental findings. Furthermore, in vitro melanoma cytotoxicity assay of compound 3b demonstrated its higher toxicity to A375 cells, while displaying low toxicity to HaCaT cells, with a dose-dependent effect. These results provide a theoretical foundation and practical basis for the development of novel tyrosinase inhibitors. Tyrosinase is a widely distributed copper-containing enzyme found in various organisms, playing a crucial role in the process of melanin production.