摘要/Abstract

合成出了一系列新型基于咔唑的单-/双-碳酰腙衍生物3和4.利用¹H NMR、¹³C NMR、IR和元素分析对其进行了结构表征.评价了目标化合物对蛋白酪氨酸磷酸酶1B（PTP1B）的抑制活性，讨论了结构与活性的关系.实验结果显示，大部分化合物对PTP1B具有良好的抑制活性，其中1，5-双[（9-丁基-3-咔唑基）亚甲基]碳酰腙（4c）的抑制活性最高，IC₅₀=（4.81±0.41）μmol/L，且活性高于对照药物齐墩果酸.对目标化合物1-[（9-庚基-3-咔唑基）亚甲基]碳酰腙（3f）和4c进行分子对接研究和密度泛函理论（DFT）计算.分子对接结果表明，化合物3f和4c结合到PTP1B酶由螺旋α3和α6形成的活性位点，与PTP1B酶通过氢键、极性、疏水和π-π等相互作用形成了稳定的复合物.
关键词: 碳酰腙, 咔唑, 合成, PTP1B抑制剂, 分子对接, DFT计算
A series of novel carbazole-based mono-/bis-carbohydrazone derivatives 3 and 4 were synthesized. Their structures were characterized by ¹H NMR, ¹³C NMR, IR spectra and elemental analysis. The inhibitory activities of all synthesized compounds against protein tyrosine phosphatase 1B (PTP1B) were evaluated, and the structure-activity relationship was discussed. The results indicated that most of the compounds had good inhibitory activity against PTP1B, and 1,5-bis[(9-butyl-3-carba-zolyl)methylene]carbohydrazone (4c) showed the highest inhibitory activity against PTP1B with IC₅₀=(4.81±0.41) μmol/L and the activity was higher than that of the control drug oleanolic acid. Molecular docking and density functional theory (DFT) calculations of 3f and 4c were carried out. The results of molecular docking indicated that 1-[(9-heptyl-3-carbazolyl)meth-ylene]carbohydrazone (3f) and 4c bind to an active site of PTP1B enzyme formed by the helices α3 and α6, and formed a stable complex respectively with PTP1B enzyme by hydrogen bonds, polar, hydrophobic and π-π interactions.
Key words: carbohydrazone, carbazole, synthesis, PTP1B inhibitor, molecular docking, DFT calculations


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