3, 6-二取代三唑并噻二唑衍生物的合成及其对细胞分裂周期25B磷酸酶和蛋白酪氨酸磷酸酶1B抑制活性评价

李英俊 杨鸿境 曹欣 高立信 靳焜 盛丽 刘季红 刘雪洁 李佳

引用本文: 李英俊, 杨鸿境, 曹欣, 高立信, 靳焜, 盛丽, 刘季红, 刘雪洁, 李佳. 3, 6-二取代三唑并噻二唑衍生物的合成及其对细胞分裂周期25B磷酸酶和蛋白酪氨酸磷酸酶1B抑制活性评价[J]. 应用化学, 2020, 37(9): 994-1002. doi: 10.11944/j.issn.1000-0518.2020.09.200040 shu
Citation:  LI Yingjun, YANG Hongjing, CAO Xin, GAO Lixin, JIN Kun, SHENG Li, LIU Jihong, LIU Xuejie, LI Jia. Synthesis of 3, 6-Disubstituted Triazolothiadiazole Derivatives and Their Inhibitory Activities Against Cell Division Cycle 25B Phosphatase and Protein Tyrosine Phosphatase 1B[J]. Chinese Journal of Applied Chemistry, 2020, 37(9): 994-1002. doi: 10.11944/j.issn.1000-0518.2020.09.200040 shu

3, 6-二取代三唑并噻二唑衍生物的合成及其对细胞分裂周期25B磷酸酶和蛋白酪氨酸磷酸酶1B抑制活性评价

    通讯作者: 李英俊, 教授; Tel:0411-82158329;E-mail:chemlab.lnnu@163.com; 研究方向:有机合成; 李佳, 教授; Tel:021-50801313-246;E-mail:jli@simm.ac.cn; 研究方向:药物研发
  • 基金项目:

    辽宁省自然科学基金(20102126)项目资助

摘要: 合成出了一系列含苯并咪唑/芳氧甲基骨架的3,6-二取代三唑并噻二唑衍生物3a~3l,其结构经傅里叶变换红外光谱仪(FT-IR)、核磁共振波谱仪(NMR)和元素分析得以确认。评价了它们对细胞分裂周期25B磷酸酶(Cdc25B)/蛋白酪氨酸磷酸酶1B(PTP1B)的抑制活性,讨论了构效关系。生物活性测试结果显示,化合物3a对Cdc25B和PTP1B的抑制活性最高,其半数抑制浓度(IC50)值分别为(0.46±0.02)μg/mL和(1.77±0.40)μg/mL。所得研究结果为开发新型Cdc25B/PTP1B抑制剂提供了参考依据。

English

  • 三唑并噻二唑代表一类有意义的杂环化合物,因含有N—C—S结构而具有广谱的生物活性。大量研究表明,3, 6-二取代三唑并噻二唑衍生物具有抗癌[1-3]、抗菌[4]、抗氧化[5]、抗炎[6]、抗结核[7]、抗惊厥[8]和治疗阿尔茨海默症[9]等多种生物活性。在抗癌方面的活性得到了人们的关注,如化合物I[1]和II[3](图 1)分别具有抗结肠癌和肺癌的活性。

    图 1

    图 1.  含三唑并噻二唑/苯并咪唑/芳氧甲基结构的一些活性化合物
    Figure 1.  Some active compounds containing triazolothiadiazole/benzimidazole/aryloxymethyl moiety

    苯并咪唑(BZM)骨架因其存在富电子的芳香体系和两个氮杂原子,使其可以以非共价方式与一系列生物目标相互作用[10],因而是药物化学领域中的一个有价值的药效团,被用于开发各种药物。苯并咪唑衍生物具有广谱的生物活性,如抗癌[10-11]、抗糖尿病[12]、抗菌[13-14]、抗炎[15]、抗氧化[14-15]和杀虫[15]等活性。在抗癌方面已得到临床上的应用。例如,苯达莫司汀(Bendamustine)[10](III)(图 1)是已获得美国食品药品监督管理局(FDA)批准的一种抗癌药物[11],用于治疗慢性淋巴细胞白血病(CLL)。

    苯氧乙酸及其衍生物也与多种生物活性相关,例如抗癌、降血糖、降血脂、抗高血压、抗菌、抗病毒、抗结核、抗炎、镇痛和抗氧化等活性[16]。而抗癌活性也受到了人们的重视,如化合物IV[17](图 1)具有抗肝癌的活性。

    蛋白酪氨酸磷酸酶(PTPs)在蛋白质细胞内磷酸化状态中起重要的调节作用[18]。蛋白质酪氨酸磷酸化的失调是人类疾病的主要原因,例如癌症、糖尿病、自身免疫性疾病和神经疾病[19]。在PTPs中,蛋白酪氨酸磷酸酶1B(PTP1B)通过激活非受体酪氨酸激酶(Src)促进肿瘤的致癌性,这种激活在许多人癌细胞系(如乳腺癌、肺癌和结肠癌)中都有升高的趋势[20-21]。因此,PTP1B是一种很有前途的癌症治疗靶点。在PTPs的超家族中,细胞分裂周期25磷酸酶(包括Cdc25A、B和C亚型)是细胞分裂周期的关键调控因子[22]。大量研究证明,Cdc25B在多种人类癌症中是过度表达的,如食管癌、结肠癌、血癌和肺癌[23]。Cdc25B/PTP1B已成为一个重要癌症治疗靶点[20, 24]。虽然已经开发了许多Cdc25B/PTP1B抑制剂,但由于生物活性浓度的细胞毒性[25]/低细胞通透性和生物利用度[26],目前尚无临床应用的Cdc25B/PTP1B抑制剂。因此,仍需开发新的高效低毒的Cdc25B/PTP1B抑制剂。

    本课题组前期研究工作显示,含有苯并咪唑环的3, 6-二取代三唑并噻二唑衍生物,如化合物V(图 1)对Cdc25B和PTP1B显示出良好的抑制活性[27];在苯并咪唑环的2-位引入4-氯苯氧甲基时对Cdc25B具有较高的抑制活性[28]。此外,3, 6-二取代三唑并噻二唑衍生物具有抑制PTP1B的活性[29]。为了继续我们的研究工作,寻找在抗癌方面具有潜在应用价值的新型Cdc25B/PTP1B抑制剂,基于三唑并噻二唑、苯并咪唑和芳氧甲基三个药效团在抗癌方面的优良活性,及其对Cdc25B/PTP1B显示出的良好抑制活性,本研究设计以三唑并噻二唑骨架为核心,在其3-和6-位引入苯并咪唑/芳氧甲基骨架,形成新型含苯并咪唑/芳氧甲基骨架的3, 6-二取代三唑并噻二唑衍生物,并评价其对Cdc25B/PTP1B的抑制活性,期望化合物有良好的活性。以自行合成的4-氨基-5-[2-(4-氯苯氧甲基)苯并咪唑-1-甲基]-3-巯基-1, 2, 4-三唑(1)和芳氧乙酸(2)为原料,在POCl3的作用下合成出目标化合物3。化合物的合成路线见Scheme 1

    Scheme 1

    Scheme 1.  Synthetic route of target compounds

    4-氨基-5-[2-(4-氯苯氧甲基)苯并咪唑-1-甲基]-3-巯基-1, 2, 4-三唑(1)和芳氧乙酸(2)按参考文献[30-31]方法合成,所用其它试剂均为市售分析纯。

    TENSOR 27型傅里叶变换红外光谱仪(FT-IR,德国Bruker公司);BRUKER500 MHz型核磁共振波谱仪(NMR,德国Bruker公司);Vario EL型元素分析仪(德国Elementar公司);X-5型显微熔点测定仪(控温型,北京泰克仪器有限公司),温度计未经校正。

    化合物3的合成通法  在30 mL干燥的圆底烧瓶中加入2 mmol原料化合物1,2 mmol芳氧乙酸2和8 mL POCl3,控制油浴温度在125~130 ℃,加热搅拌回流反应7 h后,蒸出过量的POCl3,搅拌下加入少量冰水,用10%NaOH调节溶液pH值8~9,抽滤出固体,水洗滤饼至滤液呈中性,抽干后,将粗产品于空气中晾干。用DMF-H2O重结晶后,即得到化合物3a-3l纯品。

    3-[2-(4-氯苯氧甲基)苯并咪唑-1-甲基]-6-苯氧甲基-1, 2, 4-三唑[3, 4-b]-1, 3, 4-噻二唑(3a)  深棕色粉末,产率39.0%;mp 198.7~200.2 ℃; 1H NMR(DMSO-d6, 500 MHz), δ:7.70(d, J=8.5 Hz, 1H, BZM-H4), 7.68(d, J=8.5 Hz, 1H, BZM-H7), 7.28~7.38(m, 5H, BZM-H6, ArH×2, Ar′H×2), 7.25(t, J=7.0 Hz, 1H, BZM-H5), 7.05(d, J=8.5 Hz, 2H, ArH), 7.03(t, J=8.5 Hz, 1H, Ar′H), 6.99(d, J=9.0 Hz, 2H, Ar′H), 6.07(s, 2H, NCH2), 5.53(s, 2H, CH2OAr), 5.42(s, 2H, CH2OAr′); 13C NMR(DMSO-d6, 125 MHz), δ:168.49, 157.46, 157.01, 154.31, 149.71, 143.62, 142.29, 135.91, 130.21, 129.69, 125.53, 123.68, 122.78, 122.58, 119.95, 116.98, 115.45, 111.40, 65.07(CH2OAr′), 63.37(CH2OAr), 38.19 (NCH2); IR(KBr), σ/cm-1:3059, 2948, 2871, 1612, 1598, 1576, 1490, 1462, 1236, 1020; Anal. calcd for C25H19ClN6O2S:C 59.70, H 3.81, N 16.71;found:C 59.95, H 4.02, N 16.53。

    3-[2-(4-氯苯氧甲基)苯并咪唑-1-甲基]-6-(2-甲基苯氧甲基)-1, 2, 4-三唑[3, 4-b]-1, 3, 4-噻二唑(3b)  棕色针状晶体, 产率64.0%;mp 200.2~201.6 ℃; 1H NMR(DMSO-d6, 500 MHz), δ:7.70(d, J=8.0 Hz, 1H, BZM-H4), 7.68(d, J=7.5 Hz, 1H, BZM-H7), 7.31(d, J=9.0 Hz, 2H, ArH), 7.31(td, J1=7.5 Hz, J2=1.0 Hz, 1H, BZM-H6), 7.25(td, J1=7.8 Hz, J2=1.0 Hz, 1H, BZM-H5), 7.21(d, J=7.5 Hz, 1H, Ar′H), 7.18(t, J=7.8 Hz, 1H, Ar′H), 7.03(d, J=8.5 Hz, 1H, Ar′H), 6.99(d, J=9.0 Hz, 2H, ArH), 6.94(t, J=7.5 Hz, 1H, Ar′H), 6.08(s, 2H, NCH2), 5.53(s, 2H, CH2OAr), 5.41(s, 2H, CH2OAr′), 2.22(s, 3H, CH3); 13C NMR(DMSO-d6, 125 MHz), δ:168.95, 157.02, 155.57, 154.22, 149.71, 143.61, 142.29, 135.91, 131.29, 129.69, 127.57, 126.58, 125.52, 123.68, 122.78, 122.28, 119.96, 116.97, 112.57, 111.40, 65.16(CH2OAr′), 63.37(CH2OAr), 38.18(NCH2), 16.33(CH3); IR(KBr), σ/cm-1:3059, 2926, 2860, 1615, 1591, 1493, 1465, 1239, 1020;Anal. calcd for C26H21ClN6O2S:C 60.40, H 4.09, N 16.26;found:C 60.24, H 4.22, N 16.02。

    3-[2-(4-氯苯氧甲基)苯并咪唑-1-甲基]-6-(3-甲基苯氧甲基)-1, 2, 4-三唑[3, 4-b]-1, 3, 4-噻二唑(3c)  浅棕色粉末,产率45.6%;mp 187.6~188.9 ℃; 1H NMR(DMSO-d6, 500 MHz), δ:7.70(d, J=8.0 Hz, 1H, BZM-H4), 7.68(d, J=8.0 Hz, 1H, BZM-H7), 7.31(d, J=9.5 Hz, 2H, ArH), 7.30(td, J1=7.0 Hz, J2=1.0 Hz, 1H, BZM-H6), 7.25(td, J1=7.5 Hz, J2=1.0 Hz, 1H, BZM-H5), 7.20(t, J=8.0 Hz, 1H, Ar′H), 6.99(d, J=9.0 Hz, 2H, ArH), 6.89(s, 1H, Ar′H), 6.80~6.88(m, 2H, Ar′H), 6.07(s, 2H, NCH2), 5.52(s, 2H, CH2OAr), 5.39(s, 2H, CH2OAr′), 2.28(s, 3H, CH3); 13C NMR(DMSO-d6, 125 MHz), δ: 168.63, 157.47, 157.02, 154.30, 149.70, 143.61, 142.29, 139.90, 135.90, 129.92, 129.69, 125.52, 123.68, 123.32, 122.78, 119.95, 116.98, 116.11, 112.34, 111.40, 65.02(CH2OAr′), 63.37(CH2OAr), 38.18(NCH2), 21.50(CH3); IR(KBr), σ/cm-1:3055, 2920, 2860, 1615, 1594, 1584, 1493, 1465, 1239, 1023;Anal. calcd for C26H21ClN6O2S:C 60.40, H 4.09, N 16.26;found:C 60.62, H 3.90, N 16.37。

    3-[2-(4-氯苯氧甲基)苯并咪唑-1-甲基]-6-(4-甲基苯氧甲基)-1, 2, 4-三唑[3, 4-b]-1, 3, 4-噻二唑(3d)  浅棕色针状晶体,产率48.6%;mp 187.9~188.7 ℃; 1H NMR(DMSO-d6, 500 MHz), δ:7.70(d, J=8.0 Hz, 1H, BZM-H4), 7.69(d, J=7.5 Hz, 1H, BZM-H7), 7.31(d, J=9.0 Hz, 2H, ArH), 7.31(td, J1=7.5 Hz, J2=1.0 Hz, 1H, BZM-H6), 7.26(td, J1=7.5 Hz, J2=1.5 Hz, 1H, BZM-H5), 7.12(d, J=8.0 Hz, 2H, Ar′H), 7.00(d, J=9.0 Hz, 2H, ArH), 6.94(d, J=9.0 Hz, 2H, Ar′H), 6.07(s, 2H, NCH2), 5.54(s, 2H, CH2OAr), 5.38(s, 2H, CH2OAr′), 2.24(s, 3H, CH3); 13C NMR(DMSO-d6, 125 MHz), δ:168.68, 157.02, 155.37, 154.29, 149.71, 143.61, 142.29, 135.90, 131.46, 130.51, 129.69, 125.53, 123.67, 122.77, 119.95, 116.98, 115.36, 111.40, 65.20(CH2OAr′), 63.38(CH2OAr), 38.19(NCH2), 20.55(CH3); IR(KBr), σ/cm-1:3055, 2920, 2860, 1615, 1584, 1511, 1490, 1462, 1239, 1020;Anal. calcd for C26H21ClN6O2S:C 60.40, H 4.09, N 16.26;found:C 60.26, H 3.94, N 16.06。

    3-[2-(4-氯苯氧甲基)苯并咪唑-1-甲基]-6-(2-甲氧基苯氧甲基)-1, 2, 4-三唑[3, 4-b]-1, 3, 4-噻二唑(3e)  棕黄色粉末,产率49.5%;mp 209.3~210.4 ℃; 1H NMR(DMSO-d6, 500 MHz), δ:7.70(d, J=9.0 Hz, 1H, BZM-H4), 7.68(d, J=8.5 Hz, 1H, BZM-H7), 7.28~7.38(m, 3H, ArH×2, BZM-H6), 7.25(t, J=7.5 Hz, 1H, BZM-H5), 7.01~7.10(m, 3H, Ar′H), 6.99(d, J=8.5 Hz, 2H, ArH), 6.88(t, J=7.5 Hz, 1H, Ar′H), 6.07(s, 2H, NCH2), 5.53(s, 2H, CH2OAr), 5.36(s, 2H, CH2OAr′), 3.79(s, 3H, CH3O); 13C NMR(DMSO-d6, 125 MHz), δ:168.80, 157.02, 154.39, 150.07, 149.71, 146.91, 143.59, 142.29, 135.91, 129.68, 125.52, 123.76, 123.67, 122.77, 121.17, 119.94, 116.99, 116.27, 113.30, 111.40, 66.55(CH2OAr′), 63.38(CH2OAr), 56.17(OCH3), 38.19(NCH2); IR(KBr), σ/cm-1:3062, 2937, 2836, 1615, 1598, 1500, 1465, 1236, 1023;Anal. calcd for C26H21ClN6O3S:C 58.59, H 3.97, N 15.77;found:C 58.76, H 4.17, N 15.62。

    3-[2-(4-氯苯氧甲基)苯并咪唑-1-甲基]-6-(4-甲氧基苯氧甲基)-1, 2, 4-三唑[3, 4-b]-1, 3, 4-噻二唑(3f)  米白色晶体,产率57.0%;mp 176.7~177.8 ℃; 1H NMR(DMSO-d6, 500 MHz), δ:7.70(d, J=8.0 Hz, 1H, BZM-H4), 7.68(d, J=8.0 Hz, 1H, BZM-H7), 7.31(d, J=9.0 Hz, 2H, ArH), 7.31(t, J=6.5 Hz, 1H, BZM-H6), 7.25(t, J=7.5 Hz, 1H, BZM-H5), 6.95~7.05(m, 4H, ArH×2, Ar′H×2), 6.87(d, J=9.0 Hz, 2H, Ar′H), 6.07(s, 2H, NCH2), 5.53(s, 2H, CH2OAr), 5.35(s, 2H, CH2OAr′), 3.71(s, 3H, CH3O); 13C NMR(DMSO-d6, 125 MHz), δ:168.79, 157.01, 154.93, 154.29, 151.39, 149.71, 143.61, 142.29, 135.90, 129.69, 125.52, 123.68, 122.77, 119.95, 116.98, 116.71, 115.22, 111.40, 65.80(CH2OAr′), 63.37(CH2OAr), 55.88(OCH3), 38.18(NCH2); IR(KBr), σ/cm-1:3055, 2958, 2836, 1615, 1594, 1510, 1490, 1459, 1225, 1016;Anal. calcd for C26H21ClN6O3S:C 58.59, H 3.97, N 15.77;found:C 58.80, H 3.72, N 15.93。

    3-[2-(4-氯苯氧甲基)苯并咪唑-1-甲基]-6-(2-氯苯氧甲基)-1, 2, 4-三唑[3, 4-b]-1, 3, 4-噻二唑(3g)  米色粉末,产率42.6%;mp 214.8~215.5 ℃; 1H NMR(DMSO-d6, 500 MHz), δ:7.70(d, J=9.0 Hz, 1H, BZM-H4), 7.68(d, J=9.0 Hz, 1H, BZM-H7), 7.50 (dd, J1=8.0 Hz, J2=1.5 Hz, 1H, Ar′H), 7.33(td, J1=7.5 Hz, J2=1.0 Hz, 1H, BZM-H6), 7.31(d, J=9.0 Hz, 2H, ArH), 7.30(td, J1=7.0 Hz, J2=1.0 Hz, 1H, Ar′H), 7.26(d, J=8.0 Hz, 1H, Ar′H), 7.25(t, J=7.0 Hz, 1H, BZM-H5), 7.07(td, J1=7.6 Hz, J2=1.3 Hz, 1H, Ar′H), 6.99(d, J=9.0 Hz, 2H, ArH), 6.08(s, 2H, NCH2), 5.52(s, 4H, CH2OAr′, CH2OAr); 13C NMR(DMSO-d6, 125 MHz), δ:167.96, 157.01, 154.33, 152.89, 149.71, 143.64, 142.30, 135.90, 130.72, 129.69, 128.91, 125.54, 123.68, 123.64, 122.77, 122.19, 119.96, 116.99, 115.29, 111.39, 65.96(CH2OAr′), 63.38(CH2OAr), 38.19(NCH2); IR(KBr), σ/cm-1:3055, 2937, 2864, 1615, 1584, 1493, 1465, 1236, 1020;Anal. calcd for C25H18Cl2N6O2S:C 55.87, H 3.38, N 15.64;found:C 55.61, H 3.20, N 15.87。

    3-[2-(4-氯苯氧甲基)苯并咪唑-1-甲基]-6-(3-氯苯氧甲基)-1, 2, 4-三唑[3, 4-b]-1, 3, 4-噻二唑(3h)  浅棕色粉末,产率38.9%;mp 179.6~180.7 ℃; 1H NMR(DMSO-d6, 500 MHz), δ:7.70(d, J=8.5 Hz, 1H, BZM-H4), 7.68(d, J=8.0 Hz, 1H, BZM-H7), 7.36(t, J=8.3 Hz, 1H, Ar′H), 7.31(d, J=8.5 Hz, 2H, ArH), 7.30(td, J1=7.0 Hz, J2=1.0 Hz, 1H, BZM-H6), 7.25(td, J1=7.0 Hz, J2=1.0 Hz, 1H, BZM-H5), 7.20(t, J=2.3 Hz, 1H, Ar′H), 7.11(dd, J1=7.8 Hz, J2=1.2 Hz, 1H, Ar′H), 7.03(dd, J1=8.3 Hz, J2=2.3 Hz, 1H, Ar′H), 6.98(d, J=9.0 Hz, 2H, ArH), 6.07(s, 2H, NCH2), 5.52(s, 2H, CH2OAr), 5.47(s, 2H, CH2OAr′); 13C NMR(DMSO-d6, 125 MHz), δ:167.81, 158.35, 157.00, 154.35, 149.70, 143.65, 142.28, 135.90, 134.42, 131.57, 129.68, 125.52, 123.67, 122.77, 122.58, 119.95, 116.96, 115.68, 114.50, 111.39, 65.38(CH2OAr′), 63.36(CH2OAr), 38.19(NCH2); IR(KBr), σ/cm-1:3062, 2937, 2860, 1615, 1594, 1493, 1472, 1465, 1239, 1020;Anal. calcd for C25H18Cl2N6O2S:C 55.87, H 3.38, N 15.64;found:C 55.72, H 3.59, N 15.52。

    3-[2-(4-氯苯氧甲基)苯并咪唑-1-甲基]-6-(4-氯苯氧甲基)-1, 2, 4-三唑[3, 4-b]-1, 3, 4-噻二唑(3i)  白色粉末,产率39.5%;mp 218.3~219.3 ℃; 1H NMR(DMSO-d6, 500 MHz), δ:7.69(d, J=8.0 Hz, 1H, BZM-H4), 7.68(d, J=7.0 Hz, 1H, BZM-H7), 7.37(d, J=9.0 Hz, 2H, Ar′H), 7.31(d, J=8.5 Hz, 2H, ArH), 7.30(t, J=7.0 Hz, 1H, BZM-H6), 7.25(t, J=7.5 Hz, 1H, BZM-H5), 7.08(d, J=9.0 Hz, 2H, Ar′H), 6.98(d, J=9.0 Hz, 2H, ArH), 6.07(s, 2H, NCH2), 5.52(s, 2H, CH2OAr), 5.43(s, 2H, CH2OAr′); 13C NMR(DMSO-d6, 125 MHz), δ:167.45, 156.48, 155.79, 153.84, 149.20, 143.14, 141.76, 135.38, 129.44, 129.18, 125.83, 125.00, 123.17, 122.27, 119.44, 116.80, 116.44, 110.90, 64.86(CH2OAr′), 62.82(CH2OAr), 37.67(NCH2); IR(KBr), σ/cm-1:3059, 2948, 2867, 1615, 1597, 1584, 1490, 1462, 1229, 1017;Anal. calcd for C25H18Cl2N6O2S:C 55.87, H 3.38, N 15.64;found:C 56.10, H 3.22, N 15.43。

    3-[2-(4-氯苯氧甲基)苯并咪唑-1-甲基]-6-(2, 4-二氯苯氧甲基)-1, 2, 4-三唑[3, 4-b]-1, 3, 4-噻二唑(3j)  白色粉末,产率39.5%;mp 218.3~219.3 ℃; 1H NMR(DMSO-d6, 500 MHz), δ:7.69(d, J=7.0 Hz, 1H, BZM-H4), 7.67(d, J=7.0 Hz, 1H, BZM-H7), 7.66(d, J=2.5 Hz, 1H, Ar′H), 7.40 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H, Ar′H), 7.27~7.34(m, 4H, BZM-H6, ArH×2, Ar′H), 7.25(td, J1=7.8 Hz, J2=0.7 Hz, 1H, BZM-H5), 6.98(d, J=9.0 Hz, 2H, ArH), 6.07(s, 2H, NCH2), 5.54(s, 2H, CH2OAr′), 5.52(s, 2H, CH2OAr); 13C NMR (DMSO-d6, 125 MHz), δ:167.45, 157.01, 154.38, 152.04, 149.70, 143.65, 142.30, 135.89, 130.07, 129.68, 128.69, 126.70, 125.55, 123.67, 123.30, 122.76, 119.95, 116.99, 116.55, 111.36, 66.26(CH2OAr′), 63.40(CH2OAr), 38.20(NCH2); IR(KBr), σ/cm-1:3059, 2934, 2860, 1615, 1584, 1490, 1476, 1465, 1239, 1017;Anal. calcd for C25H17Cl3N6O2S:C 52.51, H 3.00, N 14.70;found:C 53.23, H 3.23, N 14.89。

    3-[2-(4-氯苯氧甲基)苯并咪唑-1-甲基]-6-(3-硝基苯氧甲基)-1, 2, 4-三唑[3, 4-b]-1, 3, 4-噻二唑(3k)  浅棕色粉末,产率48.6%;mp 211.4~212.4 ℃; 1H NMR(DMSO-d6, 500 MHz), δ:7.92 (dd, J1=8.0 Hz, J2=1.5 Hz, 1H, Ar′H), 7.89(t, J=2.3 Hz, 1H, Ar′H), 7.65~7.70(m, 2H, BZM-H4, Ar′H), 7.64(t, J=8.3 Hz, 1H, BZM-H7), 7.53(dd, J1=8.3 Hz, J2=2.3 Hz, 1H, Ar′H), 7.30(d, J=9.0 Hz, 2H, ArH), 7.29(td, J1=7.0 Hz, J2=1.0 Hz, 1H, BZM-H6), 7.24(td, J1=7.5 Hz, J2=1.0 Hz, 1H, BZM-H5), 6.98(d, J=9.0 Hz, 2H, ArH), 6.07(s, 2H, NCH2), 5.60(s, 2H, CH2OAr′), 5.51(s, 2H, CH2OAr); 13C NMR(DMSO-d6, 125 MHz), δ:167.29, 157.97, 156.98, 154.43, 149.69, 149.24, 143.67, 142.28, 135.88, 131.43, 129.67, 125.52, 123.65, 122.76, 122.73, 119.95, 117.44, 116.96, 111.37, 110.12, 65.70(CH2OAr′), 63.35(CH2OAr), 38.19(NCH2); IR(KBr), σ/cm-1:3090, 3069, 2934, 2867, 1615, 1584, 1525, 1490, 1465, 1354, 1236, 1031;Anal. calcd for C25H18ClN7O4S:C 54.80, H 3.31, N 15.16;found:C 54.59, H 3.14, N 14.92。

    3-[2-(4-氯苯氧甲基)苯并咪唑-1-甲基]-6-(4-硝基苯氧甲基)-1, 2, 4-三唑[3, 4-b]-1, 3, 4-噻二唑(3l)  淡黄色粉末,产率34.8%;mp 220.7~221.4 ℃; 1H NMR(DMSO-d6, 500 MHz), δ:8.23(d, J=9.5 Hz, 2H, Ar′H), 7.68(d, J=7.0 Hz, 1H, BZM-H4), 7.67(d, J=6.5 Hz, 1H, BZM-H7), 7.30(d, J=9.0 Hz, 2H, ArH), 7.20~7.29(m, 4H, BZM-H5, H6, Ar′H×2), 6.98(d, J=9.0 Hz, 2H, ArH), 6.07(s, 2H, NCH2), 5.61(s, 2H, CH2OAr′), 5.51(s, 2H, CH2OAr); 13C NMR(DMSO-d6, 125 MHz), δ:166.92, 162.48, 157.00, 154.48, 149.71, 143.67, 142.40, 142.29, 135.88, 129.67, 126.36, 125.54, 123.65, 122.75, 119.93, 116.99, 116.09, 111.36, 65.65(CH2OAr′), 63.39(CH2OAr), 38.22(NCH2); IR(KBr), σ/cm-1:3086, 2926, 2864, 1612, 1591, 1514, 1490, 1465, 1340, 1246, 1013;Anal. calcd for C25H18ClN7O4S:C 54.80, H 3.31, N 15.16;found:C 55.04, H 3.53, N 14.97。

    由化合物3的IR光谱可知,在3055~3090 cm-1处出现苯并咪唑和芳环上的不饱和C—H的伸缩振动吸收峰;在2836~2871 cm-1和2920~2958 cm-1处出现饱和C—H的伸缩振动吸收峰;在1612~1615 cm-1以及1600、1500、1460 cm-1处出现苯并咪唑和三唑并噻二唑骨架中C=N/C=C伸缩振动吸收峰;在1225~1246 cm-1和1013~1031 cm-1处出现芳氧甲基骨架中的C—O伸缩振动强吸收峰;在1514~1525 cm-1和1340~1354 cm-1处出现NO2的反对称与对称伸缩振动强吸收峰。在3200~3300 cm-1处N—H伸缩振动吸收峰的消失,说明原料三氮唑化合物1已转化为产物3

    由化合物31H NMR数据可知,在6.80~8.23之间出现了芳香体系(苯并咪唑/芳环)中的质子吸收峰;在6.07~6.08、5.51~5.53和5.35~5.61处出现的单峰可分别归属为NCH2、CH2OAr和CH2OAr′中的CH2的质子吸收峰;在3.71~3.79和2.22~2.28处出现的单峰可分别归属为OCH3和CH3中的质子吸收峰。新的亚甲基质子吸收峰(CH2OAr′)的出现,原料三氮唑化合物1中NH2(13.59)和SH(9.48)峰的消失,说明芳氧乙酸2中的COOH与三氮唑1的NH2和SH发生了缩合、关环反应,生成了化合物3。由此证明,化合物3已被成功合成出来。

    由化合物313C NMR谱可知,在110.12~168.95之间出现的峰可归属为BZM环和芳环上的碳吸收峰;在62.82~63.40之间出现的峰为CH2OAr′中CH2的碳吸收峰;在66.55~64.86之间出现的峰为CH2OAr中CH2的碳吸收峰;在37.67~38.22之间出现的峰为NCH2中CH2的碳吸收峰;在55.88~56.17之间出现的峰为OCH3的碳吸收峰;在16.33~21.50之间出现的峰为CH3的碳吸收峰。以上结果表明,化合物3已被成功合成。

    对所合成的化合物3进行了Cdc25B和PTP1B抑制活性的筛选,此部分工作由国家新药筛选中心协助完成。利用Molinspiration Property Calculator(MIPC)程序软件计算了化合物3的药代动力学参数——脂水分配系数(log P)。测试与计算结果见表 1

    表 1

    表 1  化合物3a-3l对Cdc25B和PTP1B的抑制活性
    Table 1.  Inhibitory activities of target compounds 3a-3l against Cdc25B and PTP1B
    下载: 导出CSV
    Compd. Ar′ log P Cdc25Ba PTP1Bb
    Inhibition/%
    (at 20 μg/mL)
    IC50/(μg·mL-1) Inhibition/%
    (at 20 μg/mL)
    IC50/(μg·mL-1)
    3a C6H5 5.24 99.75±0.01 0.46±0.02 66.56±0.02 1.77±0.40
    3b 2-CH3C6H4 5.64 16.76±2.60 c 84.87±1.62 2.91±0.58
    3c 3-CH3C6H4 5.67 12.50±0.03 94.02± 5.58 5.92±0.39
    3d 4-CH3C6H4 5.69 11.59±7.31 83.52± 9.32 9.38±1.78
    3e 2-CH3OC6H4 4.86 34.72±0.24 79.23±5.68 9.01±1.45
    3f 4-CH3OC6H4 5.30 20.42±1.22 87.85±0.90 7.45±0.25
    3g 2-ClC6H4 5.87 30.38±1.98 93.62±6.10 4.99±0.36
    3h 3-ClC6H4 5.89 98.60±0.23 2.99±0.63 83.74±1.12 5.19±1.36
    3i 4-ClC6H4 5.92 18.22±4.45 94.76±0.82 7.38±0.26
    3j 2, 4-Cl2C6H3 6.53 3.29±3.16 87.30±1.84 4.76±0.87
    3k 3-O2NC6H4 5.18 98.40±0.27 1.03±0.03 86.32±2.30 5.20±0.27
    3l 4-O2NC6H4 5.20 94.00±4.09 1.76±0.06 90.51±3.97 6.29±1.09
      a.Positive control:Na3VO4, IC50=(0.21±0.00) μmol/L; b.positive control: oleanolic acid, IC50= (1.20±0.02) μg/mL; c.“-”: not calculated, because the inhibition rate is less than 50%.

    表 1测试结果可知,化合物3a、3h、3k和3l对Cdc25B具有较高的抑制活性,抑制率为94.00%~99.75%,IC50=(0.46±0.02)~(2.99±0.63) μg/mL,其中化合物3a的活性最高,IC50=(0.46±0.02) μg/mL,但活性低于阳性对照物Na3VO4。所有化合物对PTP1B均具有较高的抑制活性,抑制率为66.56%~94.76%,IC50=(1.77±0.40)~(9.38±1.78) μg/mL,其中化合物3a的抑制活性最高,IC50=(1.77±0.40) μg/mL,与对照药物齐墩果酸的抑制活性相当[IC50=(1.20±0.02) μg/mL]。值得注意的是,化合物3a、3h、3k和3l显示出对Cdc25B和PTP1B的双重抑制活性。其中化合物3a的抑制活性最高。

    研究构效关系发现,化合物3a、3h、3k和3l对Cdc25B的抑制活性与Ar′中苯环上的取代基性质及其取代位置有关。当苯环上无取代基(Ar′=C6H53a)或苯环的3-位含有吸电子基Cl/NO2(Ar′=3-ClC6H43h或3-O2NC6H43k)或4-位含有强吸电子基NO2时(Ar′=4-O2NC6H43l)活性大大增强,且苯环上无取代基时(Ar′=C6H53a)化合物的活性最高。苯环上引入供电子基团(3b~3f)或2-位/4-位引入Cl原子时(3g、3i和3j)活性消失。同样,化合物3对PTP1B的抑制活性也与Ar′中苯环上的取代基性质及其取代位置有关。当苯环上无取代基时(Ar′=C6H53a)化合物的活性最高,当引入取代基后活性大幅度降低。当苯环的4-位引入取代基时,取代基引起的活性次序为NO2>Cl>CH3O>CH3(3l>3i>3f>3d)。当苯环的3-位引入取代基时,化合物的活性基本相当(3c、3h和3k)。当苯环的2-位引入供电子取代基团(CH3/CH3O)或吸电子取代基团时(Cl),化合物的活性差别较大(3b>3g>3e)。值得注意的是,Ar′的苯环上无取代基(Ar′=C6H53a)时,化合物对Cdc25B和PTP1B均具有最高的抑制活性。

    化合物的活性与脂水分配系数(log P)也有关系,当log P=5.24时化合物3a的活性最高,而低于此值时化合物的水溶性较大脂溶性较小,而高于此值化合物的水溶性较小脂溶性较大,这均导致活性降低。由此可知,化合物的活性与其亲水性和亲脂性的良好匹配有关。

    合成出了12个新型含苯并咪唑/芳氧甲基骨架的3, 6-二取代三唑并噻二唑衍生物3a-3l,评价了其对Cdc25B/PTP1B的抑制活性,讨论了构效关系。生物活性测试结果显示,化合物3a-3l对PTP1B均显示出较高的抑制活性,化合物3a、3h、3k和3l对Cdc25B显示出良好的抑制活性。化合物3a对Cdc25B和PTP1B的抑制活性最高,IC50值分别为(0.46±0.02) μg/mL和(1.77±0.40) μg/mL。值得注意的是,化合物3a、3h、3k和3l对Cdc25B和PTP1B具有双重抑制活性。研究结果表明,将三唑并噻二唑、苯并咪唑和芳氧甲基3个药效团杂交所形成新型3, 6-二取代三唑并噻二唑衍生物是潜在的Cdc25B/PTP1B抑制剂,这将为开发新型Cdc25B/PTP1B抑制剂提供参考。


    1. [1]

      Ramaprasad G C, Kalluraya B, Kumar B S. Microwave-assisted of Triazolothiadiazole Analogs as Anticancer Agents[J]. Med Chem Res, 2014, 23:  3644-3651. doi: 10.1007/s00044-014-0944-x doi: 10.1007/s00044-014-0944-x

    2. [2]

      Jubie S, Bincy B, Begam A J. A New Class of Human Fatty Acid Synthase Inhibitors:Synthesis and Their Anticancer Evaluation[J]. Indian J Chem, 2018, 57B:  671-678.  

    3. [3]

      Liu X J, Liu H Y, Wang H X. Synthesis and Antitumor Evaluation of Novel Fused Heterocyclic 1, 2, 4-Triazolo[3, 4-b]-1, 3, 4-Thiadiazole Derivatives[J]. Med Chem Res, 2019, 28(10):  1718-1725. doi: 10.1007/s00044-019-02409-2 doi: 10.1007/s00044-019-02409-2

    4. [4]

      Joshi H H, Parsania M V. Synthesis, Characterization 3-(5-Bromothiophen-2-yl)-6-Phenyl-1, 7a-Dihydro-[1, 2, 4] triazolo[3, 4-b] [1, 3, 4] thiadiazole Derivatives and Biological Property[J]. World Sci News, 2019, 126:  291-297.

    5. [5]

      Asma K B, Manju N, Chandra M M. Synthesis, Antimicrobial, Antioxidant and Molecular Docking Study of Some Novel Bis-1, 2, 4-Triazolo[3, 4-B]-1, 3, 4-Thiadiazoles[J]. J Med Chem Drug Des, 2018, 1(1):  1-6.  

    6. [6]

      Ahmed M S, Essa H J, Khan A K. Synthesis, Characterization and Preliminary Pharmacological Evaluation of Triazolothiadiazoles Derived from Some NSAIDs and Thiocarbohydrazide[J]. Al-Mustansiriyah J Pharm Sci, 2018, 18(1):  73-92.

    7. [7]

      Deng Q, Meng J, Liu Y. IMB-SD62, A Triazolothiadiazoles Derivative with Promising Action Against Tuberculosis[J]. Tuberculosis, 2018, 112:  37-44. doi: 10.1016/j.tube.2018.07.006 doi: 10.1016/j.tube.2018.07.006

    8. [8]

      Sarafroz M, Khatoon Y, Ahmad N. Synthesis, Characterization and Anticonvulsant Activity of Novel Fused 1, 2, 4-Triazolo-1, 3, 4-Thiadiazoles[J]. Orient J Chem, 2019, 35(1):  64-70. doi: 10.13005/ojc/350107 doi: 10.13005/ojc/350107

    9. [9]

      Hiremathad A, Piemontese L. Heterocyclic Compounds as Key Structures for the Interaction with Old and New Targets in Alzheimer's Disease Therapy[J]. Neural Regener Res, 2017, 12(8):  1256-1261. doi: 10.4103/1673-5374.213541 doi: 10.4103/1673-5374.213541

    10. [10]

      Purushottamachar P, Ramalingam S, Njar V C O. Development of Benzimidazole Compounds for Cancer Therapy[M]//Chemistry and Applications of Benzimidazole and Its Derivatives. Intech Open, 2019: 1-15.

    11. [11]

      Dennie T W, Kolesar J M. Bendamustine for the treatment of Chronic Lymphocytic Leukemia and Rituximab-Refractory, Indolent B-Cell Non-hodgkin Lymphoma[J]. Clin Ther, 2009, 31:  2290-2311. doi: 10.1016/j.clinthera.2009.11.031 doi: 10.1016/j.clinthera.2009.11.031

    12. [12]

      Özil M, Emirik M, Etlik S Y. A Simple and Efficient Synthesis of Novel Inhibitors of alpha-Glucosidase Based on Benzimidazole Skeleton and Molecular Docking Studies[J]. Bioorg Chem, 2016, 68:  226-235. doi: 10.1016/j.bioorg.2016.08.011 doi: 10.1016/j.bioorg.2016.08.011

    13. [13]

      Mahmoud M A, Redayan M A. Synthesis, Characterization, and Antibacterial Screening of Some New Benzimidazole Derivatives Having 1, 3, 4-Thiadiazole Ring[J]. Int J Pharm Res, 2019, 11(3):  247-251.  

    14. [14]

      Kashid B B, Ghanwat A A, Khedkar V M. Design, Synthesis, in vitro Antimicrobial, Antioxidant Evaluation, and Molecular Docking Study of Novel Benzimidazole and Benzoxazole Derivatives[J]. J Heterocycl Chem, 2019, 56(3):  895-908. doi: 10.1002/jhet.3467 doi: 10.1002/jhet.3467

    15. [15]

      Sethi P, Bansal Y, Bansal G. Synthesis and PASS-assisted Evaluation of Coumarin Benzimidazole Derivatives as Potential Anti-inflammatory and Anthelmintic Agents[J]. Med Chem Res, 2018, 27(1):  61-71.  

    16. [16]

      Begum S, Bharathi K, Prasad K. Mini Review on Therapeutic Profile of Phenoxy Acids and Thier Derivatives[J]. Int J Pharm Pharm Sci, 2016, 8(10):  66-71. doi: 10.22159/ijpps.2016v8i10.5005 doi: 10.22159/ijpps.2016v8i10.5005

    17. [17]

      Lee K, Lee J H, Boovanahalli S K. (Aryloxyacetylamino)benzoic Acid Analogues:A New Class of Hypoxia-Inducible Factor-1 Inhibitors[J]. J Med Chem, 2007, 50(7):  1675-1684. doi: 10.1021/jm0610292 doi: 10.1021/jm0610292

    18. [18]

      Liu H, Sun D, Du H. Synthesis and Biological Evaluation of Tryptophan-Derived Rhodanine Derivatives as PTP1B Inhibitors and Anti-bacterial Agents[J]. Eur J Med Chem, 2019, 172:  163-173. doi: 10.1016/j.ejmech.2019.03.059 doi: 10.1016/j.ejmech.2019.03.059

    19. [19]

      He R, Yu Z, Zhang R. Protein Tyrosine Phosphatases as Potential Therapeutic Targets[J]. Acta Pharmacol Sin, 2014, 35(10):  1227-1246. doi: 10.1038/aps.2014.80 doi: 10.1038/aps.2014.80

    20. [20]

      Kostrzewa T, Styszko J, Gorska-Ponikowska M. Inhibitors of Protein Tyrosine Phosphatase PTP1B with Anticancer Potential[J]. Anticancer Res, 2019, 39(7):  3379-3384. doi: 10.21873/anticanres.13481 doi: 10.21873/anticanres.13481

    21. [21]

      Lazo J S, McQueeney K E, Burnett J C. Small Molecule Targeting of PTPs in Cancer[J]. Int J Biochem Cell Biol, 2018, 96:  171-181. doi: 10.1016/j.biocel.2017.09.011 doi: 10.1016/j.biocel.2017.09.011

    22. [22]

      Li Y, Yu Y, Jin K. Synthesis and Biological Evaluation of Novel Thiadiazole Amides as Potent Cdc25B and PTP1B Inhibitors[J]. Bioorg Med Chem Lett, 2014, 24(17):  4125-4128. doi: 10.1016/j.bmcl.2014.07.055 doi: 10.1016/j.bmcl.2014.07.055

    23. [23]

      Ha G S, Lee C M, Kim C. Development of a Novel Nonradioisotopic Assay and Cdc25B Overexpression Cell Lines for Use in Screening for Cdc25B Inhibitors[J]. Yonsei Med J, 2018, 59(8):  995-1003. doi: 10.3349/ymj.2018.59.8.995 doi: 10.3349/ymj.2018.59.8.995

    24. [24]

      Ma Y, Li H L, Chen X B. 3D QSAR Pharmacophore Based Virtual Screening for Identification of Potential Inhibitors for CDC25B[J]. Comput Biol Chem, 2018, 73:  1-12. doi: 10.1016/j.compbiolchem.2018.01.005 doi: 10.1016/j.compbiolchem.2018.01.005

    25. [25]

      Evain-Bana E, Schiavo L, Bour C. Synthesis, Biological Evaluation and Molecular Modeling Studies on Novel Quinonoid Inhibitors of CDC25 Phosphatases[J]. J Enzym Inhib Med Chem, 2017, 32(1):  113-118. doi: 10.1080/14756366.2016.1238364 doi: 10.1080/14756366.2016.1238364

    26. [26]

      Paudel P, Seong S H, Park H J. Anti-Diabetic Activity of 2, 3, 6-Tribromo-4, 5-Dihydroxybenzyl Derivatives from Symphyocladia latiuscula Through PTP1B Downregulation and α-Glucosidase Inhibition[J]. Mar Drugs, 2019, 17(3):  166-184. doi: 10.3390/md17030166 doi: 10.3390/md17030166

    27. [27]

      李英俊, 李继阳, 彭立娜. 新型3, 6-二取代三唑并噻二唑衍生物的合成及细胞分裂周期25B磷酸酶和蛋白酪氨酸磷酸酶1B抑制活性研究[J]. 有机化学, 2017,37,(2): 485-495. LI Yingjun, LI Jiyang, PENG Lina. Synthesis and Cell Division Cycle 25B Phosphatase and Protein Tyrosine Phosphatase 1B Inhibitory Activity Evaluation of Novel 3, 6-Disubstituted Triazolothiadiazole Derivatives[J]. Chinese J Org Chem, 2017, 37(2):  485-495.

    28. [28]

      李英俊, 刘丽军, 靳焜. 新型3, 6-二取代-1, 2, 4-三唑[3, 4-b]-1, 3, 4-噻二唑衍生物的合成、表征及生物活性[J]. 化学学报, 2010,68,(16): 1577-1584. LI Yingjun, LIU Lijun, JIN Kun. Synthesis and Biological Activity of Novel 3, 6-Disubstituted 1, 2, 4-Triazolo[3, 4-b]-1, 3, 4-thiadiazoles[J]. Acta Chim Sin, 2010, 68(16):  1577-1584.  

    29. [29]

      Baburajeev C P, Mohan C D, Ananda H. Development of Novel Triazolo-Thiadiazoles from Heterogeneous "Green" Catalysis as Protein Tyrosine Phosphatase 1B Inhibitors[J]. Sci Rep, 2015, 5(1):  14195-14205. doi: 10.1038/srep14195 doi: 10.1038/srep14195

    30. [30]

      李英俊, 刘丽军, 许永廷. 4-氨基-5-[2-(4-氯苯氧甲基)苯并咪唑-1-亚甲基]-1, 2, 4-三唑-3-硫酮的核磁共振研究[J]. 分析化学, 2011,39,(6): 902-905. LI Yingjun, LIU Lijun, XU Yongting. Study on Nuclear Magnetic Resonance of 4-Amino-5-[2-(4-chlorophenoxymethyl)benzimidazole-1-methylene]-1, 2, 4-triazole-3-thione[J]. Chinese J Anal Chem, 2011, 39(6):  902-905.  

    31. [31]

      李英俊, 付兴吉, 许永廷. 超声波辐射固-液相芳氧(硫)基羧酸的合成[J]. 应用化学, 1993,10,(6): 97-98. LI Yingjun, FU Xingji, XU Yongting. Syntheses of Aryloxy (Arylthio) Carboxylic Acids in Solid-Liquid Phase under Supersonic Radiation[J]. Chinese J Appl Chem, 1993, 10(6):  97-98.  

  • 图 1  含三唑并噻二唑/苯并咪唑/芳氧甲基结构的一些活性化合物

    Figure 1  Some active compounds containing triazolothiadiazole/benzimidazole/aryloxymethyl moiety

    Scheme 1  Synthetic route of target compounds

    表 1  化合物3a-3l对Cdc25B和PTP1B的抑制活性

    Table 1.  Inhibitory activities of target compounds 3a-3l against Cdc25B and PTP1B

    Compd. Ar′ log P Cdc25Ba PTP1Bb
    Inhibition/%
    (at 20 μg/mL)
    IC50/(μg·mL-1) Inhibition/%
    (at 20 μg/mL)
    IC50/(μg·mL-1)
    3a C6H5 5.24 99.75±0.01 0.46±0.02 66.56±0.02 1.77±0.40
    3b 2-CH3C6H4 5.64 16.76±2.60 c 84.87±1.62 2.91±0.58
    3c 3-CH3C6H4 5.67 12.50±0.03 94.02± 5.58 5.92±0.39
    3d 4-CH3C6H4 5.69 11.59±7.31 83.52± 9.32 9.38±1.78
    3e 2-CH3OC6H4 4.86 34.72±0.24 79.23±5.68 9.01±1.45
    3f 4-CH3OC6H4 5.30 20.42±1.22 87.85±0.90 7.45±0.25
    3g 2-ClC6H4 5.87 30.38±1.98 93.62±6.10 4.99±0.36
    3h 3-ClC6H4 5.89 98.60±0.23 2.99±0.63 83.74±1.12 5.19±1.36
    3i 4-ClC6H4 5.92 18.22±4.45 94.76±0.82 7.38±0.26
    3j 2, 4-Cl2C6H3 6.53 3.29±3.16 87.30±1.84 4.76±0.87
    3k 3-O2NC6H4 5.18 98.40±0.27 1.03±0.03 86.32±2.30 5.20±0.27
    3l 4-O2NC6H4 5.20 94.00±4.09 1.76±0.06 90.51±3.97 6.29±1.09
      a.Positive control:Na3VO4, IC50=(0.21±0.00) μmol/L; b.positive control: oleanolic acid, IC50= (1.20±0.02) μg/mL; c.“-”: not calculated, because the inhibition rate is less than 50%.
    下载: 导出CSV
  • 加载中
计量
  • PDF下载量:  0
  • 文章访问数:  55
  • HTML全文浏览量:  2
文章相关
  • 发布日期:  2020-09-01
  • 收稿日期:  2020-02-16
  • 接受日期:  2020-06-05
  • 修回日期:  2020-04-13
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

/

返回文章