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 compounds 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.

人酪氨酸酶 ( hs TYR) 催化黑色素生成的关键步骤，使其成为减少体内黑色素生成的优先目标。然而，迄今为止在文献中报道的hs TYR 抑制剂非常少，而已知的蘑菇酪氨酸酶 ( ab TYR) 抑制剂有数千种。然而，由于这些酶实际上非常不同，包括在它们的活性位点上，因此迫切需要新的真正的hs TYR 抑制剂，以实现针对人类的药理学和皮肤美容应用，而不会遇到目前由曲酸引发的低效和毒性问题或对苯二酚。从迄今为止报道的两种最活跃的化合物开始，即作为 2-羟基吡啶包埋的金酮和噻虫胺，我们在此结合了关键结构元素，并开发了具有细胞活性的新型纳摩尔hs TYR 抑制剂。从完整系列的 38 种合成衍生物中，两种化合物在人黑色素瘤细胞裂解物和纯化的hs TYR 测定中均获得了优异的抑制值，并且在全细胞实验中观察到了有希望的改进。