摘要/Abstract

为寻找高效、低毒的新型蛋白酪氨酸磷酸酶1B (PTP1B)抑制剂, 设计并合成出了一系列新型含咔唑环和芳环/芳稠杂环的N-酰腙衍生物6~8和11. 利用IR、¹H NMR、¹³C NMR和2D NMR(包括¹H-¹H COSY和NOESY)谱及元素分析确定了其结构和构型. 评价了目标化合物对PTP1B的抑制活性. 实验结果表明, 目标化合物对PTP1B均有较强的抑制活性, 除了化合物N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-苯氨基乙酰肼(6a)、N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-(4-甲基苯氨基)乙酰肼(6b)、N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-(3-硝基苯氨基)乙酰肼(6g)和N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-(4-硝基苯氨基)乙酰肼(6h)外, 其它化合物的活性均高于阳性对照药物齐墩果酸, 其中N,N'-[(9-丁基咔唑基)-3,6-二亚甲基]-2,2'-[二(4-硝基苯氨基)]双乙酰肼(11b)的活性最高, IC₅₀=(0.89±0.06) μmol/L. 利用分子对接分别研究了代表目标化合物N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-(4-溴苯氨基)乙酰肼(6d)、N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-((2-(1-萘氧基)甲基)苯并咪唑-1-基)乙酰肼(7f)和11b与PTP1B酶的结合模式.
关键词: PTP1B抑制剂, 咔唑, N-酰腙, 合成, 分子对接
In order to find more efficient and low toxicity protein tyrosine phosphatase 1B (PTP1B) inhibitors, a series of novel N-acylhydrazone derivatives containing carbazole and aromatic ring/aromatic fused heterocycle 6~8 and 11 were designed and synthesized. Their structures and configurations were confirmed by IR, ¹H NMR, ¹³C NMR, two-dimensional NMR spectra (including ¹H-¹H COSY and NOESY) and elemental analysis. The inhibitory activities of all the target compounds against PTP1B were evaluated. The experimental results indicated that all the target compounds had potent inhibitory activity against PTP1B, and the activities were higher than the control drug oleanolic acid except for N'-[9-(2-chlorothiazole-5-methyl)carbazole-3-methylene]-2-phenylaminoacethydrazide (6a), N'-[9-(2-chlorothiazole-5-methyl)carbazole-3-methylene]- 2-(4-methylphenylamino)acethydrazide (6b), N'-[9-(2-chlorothiazole-5-methyl)carbazole-3-methylene]-2-(3-nitrophenylamino)acethydrazide (6g) and N'-[9-(2-chlorothiazole-5-methyl)carbazole-3-methylene)-2-(4-nitrophenylamino) acethydrazide (6h). Among them, N,N'-[(9-butylcarbazolyl)-3,6-dimethylene]-2,2'-[di(4-nitrophenylamino)]bisacetohydrazide (11b) had the highest inhibitory activity against PTP1B with IC₅₀ of (0.89±0.06) μmol/L. Molecular docking was used to study the bind of the representative target compounds N'-[9-(2-chlorothiazole-5-methyl)carbazole-3-methylene]-2-(4-bromophenylamino)acethydrazide (6d), N'-[9-(2-chlorothiazole-5-methyl)carbazole-3-methylene)-2-((2-(1-naphthyloxy)methyl)benzimidazol-1-yl)- acethydrazide (7f) and 11b with PTP1B enzyme, respectively.
Key words: PTP1B inhibitor, carbazole, N-actylhydrazone, synthesis, molecular docking


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