Exploiting the 1-(4-fluorobenzyl)piperazine fragment for the development of novel tyrosinase inhibitors as anti-melanogenic agents: Design, synthesis, structural insights and biological profile.,European Journal of Medicinal Chemistry

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Exploiting the 1-(4-fluorobenzyl)piperazine fragment for the development of novel tyrosinase inhibitors as anti-melanogenic agents: Design, synthesis, structural insights and biological profile.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2019-06-06 , DOI: 10.1016/j.ejmech.2019.06.019
Laura Ielo ₁ , Batel Deri ₂ , Maria Paola Germanò ₁ , Serena Vittorio ₁ , Salvatore Mirabile ₁ , Rosaria Gitto ₁ , Antonio Rapisarda ₁ , Simone Ronsisvalle ₃ , Sonia Floris ₄ , Yael Pazy ₅ , Antonella Fais ₄ , Ayelet Fishman ₂ , Laura De Luca ₁

Affiliation

The development of Tyrosinase inhibitors (TYRIs) could represent an efficacious strategy for pharmacological intervention on skin pathologies related to aberrant production of melanin. Based on in silico studies we designed and tested a library of twenty-four compounds bearing the 4-(4-fluorobenzyl)piperazin-1-yl]-fragment. As result, we identified several compounds with excellent inhibit effects at low micromolar concentration against TYR from Agaricus bisporus (TyM). Among them, compound 25 (IC50 = 0.96 μM) proved to be ∼20-fold more potent than the reference compound kojic acid (IC50 = 17.76 μM) having wide applications in the cosmetics and pharmaceutical industries. The mode of interaction of active inhibitor 25 was deciphered by means of crystallography as well as molecular docking and these results were consistent with kinetic experiments. Moreover, the identified compound 25 exhibited no considerable cytotoxicity and showed anti-melanogenic effects on B16F10 melanoma cells. Therefore, a combination of computational and biochemical approaches could represent a rational guidelines for further structural modification of this class of compounds as future anti-melanogenic agents.

中文翻译：

利用1-（4-氟苄基）哌嗪片段开发新型酪氨酸酶抑制剂作为抗黑色素生成剂：设计，合成，结构见解和生物学特性。

酪氨酸酶抑制剂（TYRIs）的发展可能代表了一种针对与黑色素异常产生有关的皮肤病理学进行药理干预的有效策略。根据计算机研究，我们设计并测试了24种带有4-（4-氟苄基）哌嗪-1-基]片段的化合物的库。结果，我们鉴定了几种化合物，它们在低微摩尔浓度下对双孢蘑菇（TyM）的TYR具有优异的抑制作用。其中，化合物25（IC50 = 0.96μM）的效力比在化妆品和制药行业中广泛应用的参考化合物曲酸（IC50 = 17.76μM）高约20倍。活性抑制剂25的相互作用方式通过晶体学以及分子对接的方法进行了破译，这些结果与动力学实验是一致的。此外，所鉴定的化合物25没有表现出明显的细胞毒性，并且对B16F10黑素瘤细胞显示出抗黑素生成作用。因此，计算和生化方法的结合可能代表了对这类化合物作进一步结构修饰的合理指导方针，以作为将来的抗黑色素生成剂。

更新日期：2019-06-06

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