Coumaric acid derivatives as tyrosinase inhibitors: Efficacy studies through in silico, in vitro and ex vivo approaches

• Published in: Bioorganic chemistry 2020-10, Vol.103, p.104108, Article 104108
• Main Authors: Varela, Marina Themoteo, Ferrarini, Márcio, Mercaldi, Vitória Gallo, Sufi, Bianca da Silva, Padovani, Giovana, Nazato, Lucas Idacir Sbrugnera, Fernandes, João Paulo S.
• Format: Article
• Language: English
• Subjects: Antimelanogenic agent; Coumaric acid ester; Coumaric Acids - chemical synthesis; Coumaric Acids - chemistry; Coumaric Acids - pharmacology; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Melanin synthesis inhibitor; Melanins - analysis; Molecular docking; Molecular Docking Simulation; Molecular Structure; Monophenol Monooxygenase - antagonists & inhibitors; Monophenol Monooxygenase - metabolism; Structure-Activity Relationship; Tyrosinase inhibitor
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104108

[Display omitted] •The p-coumaric acid esters are inhibitors of tyrosinase.•The antimelanogenic activity is independent of radical scavenging effect.•The compounds are effective antimelanogenic agents in human skin.•Molecular modelling studies reinforces the activity of the intact esters. p-Coumaric acid is a known inhibitor of tyrosinase, an enzyme involved in the initial steps of the melanin synthesis in human and other species. However, its low lipophilicity impairs its penetration through skin and efficacy as antimelanogenic agent indeed. Accordingly, this paper reports the assessment of several coumaric acid derivatives as tyrosinase inhibitors and antimelanogenic agents in in vitro, in silico and ex vivo assays. The compounds were designed with modifications in the aromatic and acid moieties of p-coumaric acid, being the coumarate esters the most promising derivatives. The compounds showed higher tyrosinase inhibitory activity (pIC50 3.7–4.2) than the parent acid, being compounds 1d, 1e and 1f the most potent inhibitors. Docking analysis showed that these esters are competitive inhibitors per se, and act independently of a redox mechanism as suggested by DPPH assays. Moreover, the esters showed efficacy in reducing the melanin deposition in human skin fragments at 0.1% concentration, especially compound 1e. In summary, there is an important equilibria between tyrosinase affinity and lipophilicity that must be considered to get effective antimelanogenic agents with adequate permeability in the skin.