Tyrosinase is involved in the production of melanin through the hydroxylation of monophenols to o-diphenols. The role of this enzyme was extensively studied in order to identify new therapeutics preventing skin pigmentation and melanoma. In this work we initially identified the 3-(4-benzylpiperidin-1-yl)-1-(1H-indol-3-yl)propan-1-one (1a) as promising mushroom tyrosinase inhibitor (IC₅₀ = 252 μM). Then, several chemical modifications were performed and new analogues related to compound 1a were synthesized. Biochemical assays demonstrated that several obtained compounds proved to be effective inhibitors showing IC₅₀ values lower both than “lead compound” 1a and reference inhibitor kojic acid, as a well-known tyrosinase inhibitor. The inhibition kinetics analyzed by Lineweaver–Burk plots revealed that compounds 2 a-c and 10b act as non-competitive inhibitors while the most active inhibitor 2d (IC₅₀ = 7.56 μM) is a mixed-type inhibitor. Furthermore, experimental and computational structural studies were performed in order to clarify the binding mode of the derivative 2d.

酪氨酸酶通过单酚羟基化为邻二酚而参与黑色素的产生。为了确定防止皮肤色素沉着和黑色素瘤的新疗法，对该酶的作用进行了广泛的研究。在这项工作中，我们最初确定了3-（4-苄基哌啶-1-基）-1-（1 H-吲哚-3-基）丙-1-酮（1a）是有希望的蘑菇酪氨酸酶抑制剂（IC ₅₀  = 252μM）。 ）。然后，进行了几种化学修饰，并合成了与化合物1a相关的新类似物。生化分析表明，所获得的几种化合物被证明是有效的抑制剂，其IC ₅₀值均低于“先导化合物” 1a和参考抑制剂曲酸，作为众所周知的酪氨酸酶抑制剂。通过Lineweaver-Burk图分析的抑制动力学表明，化合物2 ac和10b充当非竞争性抑制剂，而活性最高的抑制剂2d（IC ₅₀  = 7.56μM）是混合型抑制剂。此外，进行了实验和计算结构研究，以阐明衍生物2d的结合模式。