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

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.