4-苯基-1,3-硒唑衍生物的合成及其对蛋白酪氨酸磷酸酯酶-1B抑制活性

doi:10.11944/j.issn.1000-0518.2019.07.180381

摘要/Abstract

摘要：

蛋白酪氨酸磷酸酯酶-1B(PTP1B)是抗糖尿病治疗的重要靶点,因此创制活性优良的PTP1B抑制剂具有重要意义。本文设计并合成了11个含1,3-硒唑和1,2,4-三唑活性组块新型结构目标分子(ZLXZ1-ZLXZ11),并利用傅里叶变换红外光谱仪(FTIR)、核磁共振波谱仪(NMR)和高分辨质谱(HRMS)等对其进行了结构表征。首先选择ZLXZ1和ZLXZ11在MOE 2015.10程序上,与PTP1B进行分子对接模拟,结果表明,在ZLXZ1分子中硒唑环上的硒原子与PTP1B中副催化位点Tyr46、Ala217、Lys120和Asp 48分别形成了π-H作用和氢键作用。在ZLXZ11分子中硒唑上的硒原子与PTP1B中Asp181、Arg221和Asp48形成了氢键作用。在分子对接模拟的基础上,测试了11个目标分子的抑制活性,结果表明,所有目标分子的抑制率均在87.02%以上,其中3个目标分子PTP1B抑制活性高于阳性参照物齐墩果酸,抑制活性优良,有望成为潜在的PTP1B抑制剂。

关键词: 1,3-硒唑, 1,2,4-三唑席夫碱, 分子对接模拟, 蛋白酪氨酸磷酸酯酶-1B抑制剂

Abstract:

Protein tyrosine phosphatase-1B(PTP1B) is an important target for anti-diabetic treatment. That means the creation of PTP1B inhibitors with excellent activity is undoubtedly of great significance. In this paper, eleven molecules with novel structures(ZLXZ1-ZLXZ11) containing 1,3-selenazole and 1,2,4-triazole active blocks were designed and synthesized. Their structures were characterized by Fourier transform infrared spectrometer(FTIR), nuclear magnetic resonance spectroscopy(NMR) and high resolution mass spectrometry(HRMS). First, ZLXZ1 and ZLXZ11 were selected for molecular docking simulation with PTP1B on MOE 2015.10. As a result, π-H action and hydrogen bonding are formed respectively between the selenium atom on the selenazole ring in ZLXZ1 and the secondary catalytic sites Tyr46 and Asp48 in PTP1B. The selenium atom on the selenazole in the ZLXZ11 molecule forms a hydrogen bond with Asp 181, which facilitates the binding of the molecule to PTP1B. On this basis, the inhibitory activities of 11 target molecules were evaluated. The results show that the inhibition rates of the target molecules are all above 87.02%, in which three target molecules are better than that of the positive control, oleanolic acid, which indicates that these novel structures are expected to be potential PTP1B inhibitors.

Key words: 1,3-selenazole, 1,2,4-triazole Schiff base, molecular docking simulation, protein tyrosine phosphatase-1B inhibitor

张成路, 王华玉, 李奕嶙, 王一鸣, 宫荣庆, 孙越冬, 宋府璐. 4-苯基-1,3-硒唑衍生物的合成及其对蛋白酪氨酸磷酸酯酶-1B抑制活性[J]. 应用化学, 2019, 36(7): 749-757.

ZHANG Chenglu, WANG Huayu , LI Yilin, WANG Yiming, GONG Rongqing, SUN Yuedong, SONG Fulu. Synthesis of 4-Phenyl-1,3-selenazole Derivative and Evaluation of Its Inhibitory Activity Against Protein Tyrosine Phosphatase-1B[J]. Chinese Journal of Applied Chemistry, 2019, 36(7): 749-757.

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