Resorcinol-based hemiindigoid derivatives as human tyrosinase inhibitors and melanogenesis suppressors in human melanoma cells

Human tyrosinase (hsTYR) catalyzes the key steps of melanogenesis, making it a privileged target for reducing melanin production in vivo. However, very few hsTYR inhibitors have been reported so far in the literature, whereas thousands of mushroom tyrosinase (abTYR) inhibitors are known. Yet, as these enzymes are actually very different, including at their active sites, there is an urgent need for new true hsTYR inhibitors in order to enable human-directed pharmacological and dermocosmetic applications without encountering the inefficiency and toxicity issues currently triggered by kojic acid or hydroquinone. Starting from the two most active com-pounds reported to date, i.e. a 2-hydroxypyridine-embedded aurone and thiamidol, we combined herein key structural elements and developed new nanomolar hsTYR inhibitors with cell-based activity. From a complete series of thirty-eight synthesized derivatives, excellent inhibition values were obtained for two compounds in both human melanoma cell lysates and purified hsTYR assays, and a promising improvement was observed in whole cell experiments.

Automated summary

Considering the crucial role of human tyrosinase (hsTYR) in melanogenesis, finding new hsTYR inhibitors is essential for targeted pharmacological and dermocosmetic applications. Despite the abundance of mushroom tyrosinase (abTYR) inhibitors, the structural differences between these enzymes necessitate the development of true hsTYR inhibitors. In this study, researchers synthesized 38 derivatives and found two compounds that showed excellent inhibition values in hsTYR assays and demonstrated promising improvement in whole cell experiments.