Tyrosinase is a key player in ultraviolet-induced melanogenesis. Because excessive melanin accumulation in the skin can induce hyperpigmentation, the development of tyrosinase inhibitors has attracted attention in cosmetic-related fields. However, side effects including toxicity and low selectivity have limited the use of many tyrosinase inhibitors in cosmetics. We synthesized 12 novel 2-(substituted benzylidene)malononitrile derivatives and investigated their anti-melanogenic activities. Of these 12 compounds, 2-(3, 4-dihydroxy benzylidene)malononitrile (BMN11) exhibited the strongest inhibitory activity against tyrosinase (IC50 = 17.05 μM). In parallel with this, BMN11 treatment notably decreased alpha-melanocyte-stimulating hormone-induced melanin accumulation in B16F10, cells without toxicity and also decreased melanin accumulation in a human skin model. As a mechanism underlying the BMN11-mediated anti-melanogenic effect, docking simulation showed that BMN11 can directly bind to tyrosinase by forming two hydrogen bonds with GLY281 and ASN260 residues, and via three hydrophobic interactions with VAL283, PHE264, and ALA286 residues in the tyrosinase binding pocket, and this likely contributes to its inhibitory effect on tyrosinase. Consistently, Lineweaver-Burk and Cornish-Bowden plots showed that BMN11 is a competitive inhibitor of tyrosinase. We concluded that BMN11 may be a novel tyrosinase inhibitor that could be used in cosmetics.

中文翻译：

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2-（3,4-二羟基亚苄基）丙二腈作为新型抗黑色素生成化合物。

酪氨酸酶是紫外线诱导的黑色素生成的关键因素。由于皮肤中过多的黑色素积聚会导致色素沉着过度，因此酪氨酸酶抑制剂的开发引起了化妆品相关领域的关注。然而，包括毒性和低选择性的副作用限制了化妆品中许多酪氨酸酶抑制剂的使用。我们合成了12种新型的2-（取代的亚苄基）丙二腈衍生物，并研究了它们的抗黑色素生成活性。在这12种化合物中，2-（3,4-二羟基亚苄基）丙二腈（BMN11）对酪氨酸酶的抑制作用最强（IC50 = 17.05μM）。与此同时，BMN11处理显着降低了刺激B16F10的α-黑素细胞刺激激素诱导的黑色素蓄积，在人类皮肤模型中没有毒性的黑色素细胞也减少了黑色素的积累。作为BMN11介导的抗黑色素生成作用的潜在机制，对接模拟显示BMN11可以通过与GLY281和ASN260残基形成两个氢键，以及与酪氨酸酶中的VAL283，PHE264和ALA286残基进行三个疏水相互作用而直接与酪氨酸酶结合。结合口袋，这可能有助于抑制酪氨酸酶。一致地，Lineweaver-Burk和Cornish-Bowden图显示BMN11是酪氨酸酶的竞争性抑制剂。我们得出的结论是BMN11可能是一种可用于化妆品的新型酪氨酸酶抑制剂。对接模拟表明，BMN11可以通过与GLY281和ASN260残基形成两个氢键，并通过与酪氨酸酶结合口袋中的VAL283，PHE264和ALA286残基的三个疏水相互作用而直接与酪氨酸酶结合，这可能有助于抑制酪氨酸酶。 。一致地，Lineweaver-Burk和Cornish-Bowden图显示BMN11是酪氨酸酶的竞争性抑制剂。我们得出的结论是BMN11可能是一种可用于化妆品的新型酪氨酸酶抑制剂。对接模拟表明，BMN11可以通过与GLY281和ASN260残基形成两个氢键，并通过与酪氨酸酶结合口袋中的VAL283，PHE264和ALA286残基的三个疏水相互作用而直接结合至酪氨酸酶，这可能有助于抑制酪氨酸酶。 。一致地，Lineweaver-Burk和Cornish-Bowden图显示BMN11是酪氨酸酶的竞争性抑制剂。我们得出的结论是BMN11可能是一种可用于化妆品的新型酪氨酸酶抑制剂。