Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Central Research Laboratory, Shiraz University of Medical Sciences, Shiraz, Iran.
Department of Medicinal Chemistry, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran.
Bioorg Chem. 2022 Dec;129:106140. doi: 10.1016/j.bioorg.2022.106140. Epub 2022 Sep 11.
In the current study, twenty-five indole-carbohydrazide derivatives linked to different aryl substitutions were rationally designed and synthesized. The structures of all derivatives were confirmed using different spectroscopic techniques including H NMR, C NMR, Mass spectrometry, and elemental analysis. The tyrosinase inhibitory activities of all synthetic compounds exhibited IC values in the range of 0.070 to > 100 μM. Structure-activity relationships showed that compounds 4f (R = 4-OH, IC = 0.070 μM), 8f (R = 4-OH, IC = 0.072 μM), and 19e (IC = 0.19 μM) with para-OH substituent at the R position was found to be the most active members of all three tested series. Kinetic studies exhibited that compounds 4f, 8f, and 19e are mixed-type inhibitors. Furthermore, toxicity and cell-based anti-melanogenesis assessments were performed on the most potent derivatives and it was shown that 4f, 8f, and 19e had no toxicity at 8 µM and reduced the percent of melanin content to 68.43, 72.61, 73.47 at 8 μM, respectively. In silico analyses of absorption, distribution, metabolism, and excretion (ADME) profile of synthesized compounds showed that these molecules followed drug-likeness rules and acceptable predictive ADMET features. Results of the docking study were almost in line with biological results with ChemPLP values of 53.56 to 79.33. Also, the docking study showed the critical interactions of potent inhibitors with the active site of the enzyme which affects the potency of the synthesized hybrids. Based on molecular dynamic simulations, compound 4f exhibited pronounced interaction with the critical residues of the tyrosinase active site so that the indole ring participated in H-bond interaction with Gly281 and 4-hydroxy benzylidene recorded another H-bond interaction with Asp289 plus hydrophobic interactions with Phe292. Hydrazide linker also exhibited three H-bond interactions with His263 and Gly281.
在当前的研究中，设计并合成了 25 种吲哚-碳酰肼衍生物，这些衍生物与不同的芳基取代基相连。所有衍生物的结构均通过不同的光谱技术（包括 1H NMR、13C NMR、质谱和元素分析）得到确认。所有合成化合物的酪氨酸酶抑制活性均表现出 IC 值范围为 0.070->100 μM。构效关系研究表明，化合物 4f（R=4-OH，IC=0.070 μM）、8f（R=4-OH，IC=0.072 μM）和 19e（IC=0.19 μM）具有对位-OH 取代基的化合物是三个测试系列中最活跃的成员。动力学研究表明，化合物 4f、8f 和 19e 是混合抑制剂。此外，对最有效的衍生物进行了毒性和基于细胞的抗黑色素生成评估，结果表明 4f、8f 和 19e 在 8 μM 时没有毒性，并且将黑色素含量降低至 68.43%、72.61%和 73.47%。合成化合物的吸收、分布、代谢和排泄（ADME）特性的计算分析表明，这些分子遵循药物相似性规则和可接受的预测 ADMET 特征。对接研究的结果与生物学结果几乎一致，ChemPLP 值为 53.56 至 79.33。此外，对接研究表明，强抑制剂与酶活性位点的关键相互作用影响了合成杂化物的效力。基于分子动力学模拟，化合物 4f 与酪氨酸酶活性位点的关键残基表现出明显的相互作用，使吲哚环与 Gly281 发生氢键相互作用，4-羟基苯亚甲基与 Asp289 发生另一个氢键相互作用，并与 Phe292 发生疏水相互作用。酰肼连接基团还与 His263 和 Gly281 发生了三个氢键相互作用。
