Inspired by the potent tyrosinase inhibitory activity of phenolic compounds with a 2-phenylbenzo[d]thiazole scaffold, we explored phenolic compounds 1–15 with 2-phenylbenzo[d]oxazole, which is isosterically related to 2-phenylbenzo[d]thiazole, as novel tyrosinase inhibitors. Among these, compounds 3, 8, and 13, featuring a resorcinol structure, exhibited significantly stronger mushroom tyrosinase inhibition than kojic acid, with compound 3 showing a nanomolar IC50 value of 0.51 μM. These results suggest that resorcinol plays an important role in tyrosinase inhibition. Kinetic studies using Lineweaver–Burk plots demonstrated the inhibition mechanisms of compounds 3, 8, and 13, while docking simulation results indicated that the resorcinol structure contributed to tyrosinase binding through hydrophobic and hydrogen bonding interactions. Additionally, these compounds effectively inhibited tyrosinase activity and melanin production in B16F10 cells and inhibited B16F10 tyrosinase activity in situ in a concentration-dependent manner. As these compounds showed no cytotoxicity to epidermal cells, melanocytes, or keratinocytes, they are appropriate for skin applications. Compounds 8 and 13 demonstrated substantially higher depigmentation effects on zebrafish larvae than kojic acid, even at 800- and 400-times lower concentrations than kojic acid, respectively. These findings suggest that 2-phenylbenzo[d]oxazole is a promising candidate for tyrosinase inhibition.

中文翻译：

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通过抑制黑色素生物合成和酪氨酸酶活性探索具有 2-苯基苯并[d]恶唑支架的化合物作为潜在的亮肤剂


受具有 2-苯基苯并[d]噻唑支架的酚类化合物的有效酪氨酸酶抑制活性的启发，我们探索了具有 2-苯基苯并[d]恶唑的酚类化合物 1-15，其与 2-苯基苯并[d]噻唑具有电子等排关系，作为新型酪氨酸酶抑制剂。其中，化合物3、8和13具有间苯二酚结构，对蘑菇酪氨酸酶的抑制作用明显强于曲酸，其中化合物3的纳摩尔IC50值为0.51 μM。这些结果表明间苯二酚在酪氨酸酶抑制中发挥重要作用。使用 Lineweaver-Burk 图进行的动力学研究证明了化合物 3、8 和 13 的抑制机制，而对接模拟结果表明间苯二酚结构通过疏水和氢键相互作用有助于酪氨酸酶的结合。此外，这些化合物有效抑制B16F10细胞中的酪氨酸酶活性和黑色素产生，并以浓度依赖性方式原位抑制B16F10酪氨酸酶活性。由于这些化合物对表皮细胞、黑素细胞或角质形成细胞没有细胞毒性，因此它们适合皮肤应用。化合物 8 和 13 对斑马鱼幼虫的脱色效果明显高于曲酸，即使浓度分别比曲酸低 800 倍和 400 倍。这些发现表明 2-苯基苯并[d]恶唑是酪氨酸酶抑制的有希望的候选者。