There is a considerable attention for the development of inhibitors of tyrosinase (TYR) as therapeutic strategy for the treatment of hyperpigmentation disorders in humans. Continuing in our efforts to identify TYR inhibitors, we describe the design, synthesis and pharmacophore exploration of new small molecules structurally characterized by the presence of the 4-fluorobenzylpiperazine moiety as key pharmacophoric feature for the inhibition of TYR from Agaricus bisporus (AbTYR). Our investigations resulted in the discovery of the competitive inhibitor [4-(4-fluorobenzyl)piperazin-1-yl]-(3-chloro-2-nitro-phenyl)methanone 26 (IC₅₀=0.18 μM) that proved to be ∼100-fold more active than reference compound kojic acid (IC₅₀=17.76 μM). Notably, compound 26 exerted antimelanogenic effect on B16F10 cells in absence of cytotoxicity. Docking analysis suggested its binding mode into AbTYR and into modelled human TYR.

中文翻译：

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4-(4-氟苄基)哌嗪-1-基]-基化合物作为具有抗黑色素生成作用的竞争性酪氨酸酶抑制剂的评价

酪氨酸酶抑制剂 (TYR) 的开发作为治疗人类色素沉着过度症的治疗策略受到了相当大的关注。在我们继续努力识别 TYR 抑制剂的过程中，我们描述了新的小分子的设计、合成和药效团探索，其结构特征在于 4-氟苄基哌嗪部分的存在作为抑制双孢蘑菇(AbTYR) 中 TYR 的关键药效​​团特征。我们的研究发现了竞争性抑制剂 [4-(4-fluorobenzyl)piperazin-1-yl]-(3-chloro-2-nitro-phenyl)methanone 26 (IC ₅₀ =0.18 μM)，证明是～比参比化合物曲酸活性高 100 倍（IC ₅₀=17.76 微米）。值得注意的是，化合物26在没有细胞毒性的情况下对 B16F10 细胞发挥抗黑色素生成作用。对接分析表明其与 AbTYR 和模型化的人类 TYR 的结合模式。