Larik Fayaz Ali, Saeed Aamer, Channar Pervaiz Ali, Muqadar Urooj, Abbas Qamar, Hassan Mubashir, Seo Sung-Yum, Bolte Michael
Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan.
Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan.
Eur J Med Chem. 2017 Dec 1;141:273-281. doi: 10.1016/j.ejmech.2017.09.059. Epub 2017 Sep 29.
A series of novel 1-pentanoyl-3-arylthioureas was designed as new mushroom tyrosinase inhibitors and free radical scavengers. The title compounds were obtained in excellent yield and characterized by FTIR, H NMR, C NMR and X-ray crystallography in case of compound (4a). The inhibitory effects on mushroom tyrosinase and DPPH were evaluated and it was observed that 1-Pentanoyl-3-(4-methoxyphenyl) thiourea (4f) showed tyrosinase inhibitory activity (IC 1.568 ± 0.01 mM) comparable to Kojic acid (IC 16.051 ± 1.27 mM). Interestingly compound 4f exhibited higher antioxidant potential compared to other derivatives. The docking studies of synthesized 1-Pentanoyl-3-arylthioureas analogues were also carried out against tyrosinase protein (PDBID 2ZMX) to compare the binding affinities with IC values. The predicted binding affinities are in good agreement with the IC values as compound (4f) showed highest binding affinity (-7.50 kcal/mol) compared to others derivatives. The kinetic mechanism analyzed by Line-weavere Burk plots exhibited that compound (4f) inhibit the enzyme inhibits the tyrosinase non-competitively to form an enzyme inhibitor complex. The inhibition constants Ki calculated from Dixon plots for compound (4f) is 1.10 μM. It was also found from kinetic analysis that derivative 4f irreversible enzyme inhibitor complex. It is proposed on the basis of our investigation that title compound (4f) may serve as lead structure for the design of more potent tyrosinase inhibitors.
设计了一系列新型的1-戊酰基-3-芳基硫脲作为新型蘑菇酪氨酸酶抑制剂和自由基清除剂。以优异的产率获得了目标化合物，并通过傅里叶变换红外光谱（FTIR）、氢核磁共振（H NMR）、碳核磁共振（C NMR）对其进行了表征，化合物（4a）还通过X射线晶体学进行了表征。评估了它们对蘑菇酪氨酸酶和二苯基苦味酰基自由基（DPPH）的抑制作用，观察到1-戊酰基-3-（4-甲氧基苯基）硫脲（4f）表现出与曲酸（IC 16.051±1.27 mM）相当的酪氨酸酶抑制活性（IC 1.568±0.01 mM）。有趣的是，与其他衍生物相比，化合物4f表现出更高的抗氧化潜力。还针对酪氨酸酶蛋白（PDBID 2ZMX）对合成的1-戊酰基-3-芳基硫脲类似物进行了对接研究，以比较其与IC值的结合亲和力。预测的结合亲和力与IC值吻合良好，因为化合物（4f）与其他衍生物相比表现出最高的结合亲和力（-7.50 kcal/mol）。通过Line-weavere Burk图分析的动力学机制表明，化合物（4f）抑制该酶对酪氨酸酶的抑制作用为非竞争性，形成酶-抑制剂复合物。根据Dixon图计算出化合物（4f）的抑制常数Ki为1.10 μM。动力学分析还发现衍生物4f形成不可逆的酶抑制剂复合物。根据我们的研究提出，标题化合物（4f）可作为设计更有效酪氨酸酶抑制剂的先导结构。
