Potent anti-melanogenic activity and favorable toxicity profile of selected 4-phenyl hydroxycoumarins in the zebrafish model and the computational molecular modeling studies

Bioorg Med Chem. 2017 Dec 15;25(24):6286-6296. doi: 10.1016/j.bmc.2017.09.021. Epub 2017 Sep 18.

Abstract

7-Hydroxy-4-phenylcoumarin (7C) and 5,7-dihydroxy-4-phenylcoumarin (5,7C) have been evaluated as potential anti-melanogenic agents in the zebrafish (Danio rerio) model in comparison to commercially utilized depigmenting agents hydroquinone and kojic acid. 7C and 5,7C decreased the body pigmentation at 5 µg/mL, while did not affect the embryos development and survival at doses ≤50 µg/mL and ≤25 µg/mL. Unlike hydroquinone and kojic acid, 4-phenyl hydroxycoumarins were no melanocytotoxic, showed no cardiotoxic side effects, neither caused neutropenia in zebrafish embryos, suggesting these compounds may present novel skin-whitening agents with improved pharmacological properties. Inhibition of tyrosinase was identified as the possible mode of anti-melanogenic action. Molecular docking studies using the homology model of human tyrosinase as well as adenylate cyclase revealed excellent correlation with experimentally obtained results.

Keywords: 4-Phenyl hydroxycoumarins; Melanogenesis; Molecular docking; Tyrosinase inhibitors; Zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Coumarins / chemistry
  • Coumarins / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Melanocytes
  • Models, Animal*
  • Models, Molecular
  • Molecular Structure
  • Monophenol Monooxygenase / antagonists & inhibitors
  • Monophenol Monooxygenase / metabolism
  • Structure-Activity Relationship
  • Zebrafish

Substances

  • Coumarins
  • Enzyme Inhibitors
  • Monophenol Monooxygenase