Evaluation of 4-(4-Fluorobenzyl)piperazin-1-yl]-Based Compounds as Competitive Tyrosinase Inhibitors Endowed with Antimelanogenic Effects,ChemMedChem

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Evaluation of 4-(4-Fluorobenzyl)piperazin-1-yl]-Based Compounds as Competitive Tyrosinase Inhibitors Endowed with Antimelanogenic Effects
ChemMedChem ( IF 3.6 ) Pub Date : 2021-07-05 , DOI: 10.1002/cmdc.202100396
Salvatore Mirabile ₁ , Serena Vittorio ₁ , Maria Paola Germanò ₁ , Ilenia Adornato ₁ , Laura Ielo ₂ , Antonio Rapisarda ₁ , Rosaria Gitto ₁ , Francesca Pintus ₃ , Antonella Fais ₃ , Laura De Luca ₁

Affiliation

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：

4-(4-氟苄基)哌嗪-1-基]类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（TYR）抑制剂作为治疗人类色素沉着过度疾病的治疗策略的开发受到了相当大的关注。我们继续努力鉴定 TYR 抑制剂，描述了新小分子的设计、合成和药效团探索，其结构特征是 4-氟苄基哌嗪部分的存在，作为抑制双孢蘑菇TYR (AbTYR) 的关键药效团特征。我们的研究发现了竞争性抑制剂 [4-(4-氟苄基)哌嗪-1-基]-(3-氯-2-硝基-苯基)甲酮26 (IC ₅₀ =0.18 μM)，事实证明，它是 ∼活性比参考化合物曲酸高 100 倍 (IC ₅₀ =17.76 μM)。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 和模拟人 TYR 的结合模式。

更新日期：2021-07-05

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