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Synthesis of tetrazole containing 1,2,3-thiadiazole derivatives via U-4CR and their anti-TMV activity

Shou-Xin Wang ,  Zhen Fang ,  Zhi-Jin Fan ,  Dun Wang ,  Yue-Dong Li ,  Xiao-Tian Ji ,  Xue-Wen Hua ,  Yun Huang ,  Tatiana A. Kalinina ,  Vasiliy A. Bakulev ,  Yury Yu. Morzherin

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Citation:  Shou-Xin Wang, Zhen Fang, Zhi-Jin Fan, Dun Wang, Yue-Dong Li, Xiao-Tian Ji, Xue-Wen Hua, Yun Huang, Tatiana A. Kalinina, Vasiliy A. Bakulev, Yury Yu. Morzherin. Synthesis of tetrazole containing 1,2,3-thiadiazole derivatives via U-4CR and their anti-TMV activity[J]. Chinese Chemical Letters, 2013, 24(10): 889-892. shu

Synthesis of tetrazole containing 1,2,3-thiadiazole derivatives via U-4CR and their anti-TMV activity

    • 通讯作者: Zhi-Jin Fan,
    Yun Huang,
  • 基金项目:

    This study was funded in part by the NSF of Tianjin (No. 10JCZDJC17500) (No. 10JCZDJC17500)

    the National Key Project for Basic Research (No. 2010CB126105)  (No. 2010CB126105)

    Development Program (No. 2011BAE06B02)  (No. 2011BAE06B02)

    Technology (No. 201002250) (No. 201002250)

    Development Program (No. 11ZCGYNC00100) (No. 11ZCGYNC00100)

摘要: A series of novel tetrazole containing 1,2,3-thiadiazole derivatives were designed and synthesized via Ugi reaction. Their structures were confirmed by melting points, IR, 1H NMR, and HRMS (ESI). Preliminary bioassay indicated that most target compounds exhibited very good direct anti-TMV activity at 100 μg/mL, which was equal to or higher than that of ribavirin. Among them, compounds 4b, 4c and 4i also showed equivalent protection effect to ribavirin in vivo at 100 μg/mL.

English

  • 

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    26. [26] Selected characteristic data for the target compounds. 4a: White solid; yield 59%; mp 75-76 ℃; 1H NMR (400 MHz, CDCl3): δ 0.93 (t, 3H, J = 7.6 Hz, propyl-CH3), 1.26-2.07 (m, 13H, propyl-CH2, 10cyclohexyl-H, NH), 2.45-2.62 (m, 2H, propyl-CH2), 2.65 (s, 3H, thiadiazole-CH3), 4.58-4.66 (m, 1H, cyclobutyl-CH), 5.76 (s, 1H, CH). HRMS: Calcd. for C14H23N7S (M+Na)+: 344.1628, Found: 344.1630; IR (KBr pellet press, cm 1): v3325, 2951, 2863, 1495, 1450, 1229, 1106, 1009, 809, 759. 4b: White solid; yield 47%; mp 96-97 ℃; 1H NMR (400 MHz, CDCl3):d 1.13 (t, 6H, J = 6.0 Hz, 2 isopropyl-CH3), 1.26-2.07 (m, 11H, 10 cyclohexyl-H, NH), 2.63 (s, 3H, thiadiazole-CH3), 2.64-2.71 (m, 1H, isopropyl-CH), 4.54-4.62 (m, 1H, cyclobutyl-CH), 5.83 (s, 1H, CH). HRMS: Calcd. for C14H23N7S (M+Na)+: 344.1628, Found: 344.1626; IR (KBr pellet press, cm 1): v 3276, 2934, 2857, 1501, 1451, 1241, 1126, 1009, 832. 4c: White solid; yield 51%; mp 96-97 ℃; 1H NMR (400 (M+H)+z, CDCl3): (0.43-0.54 (m, 4H, cyclopropyl-H), 1.33-2.05 (m, 11H, cyclohexyl-H, NH), 2.58 (s, 1H, cyclopropyl-CH), 2.66 (s, 3H, thiadiazole-CH3), 4.27-4.35 (m, 1H, cyclohexyl-CH), 5.58 (s, 1H, CH). HRMS: Calcd. for C14H21N7S (M+H)+: 320.1652, Found: 320.1657; IR (KBr pellet press, cm-1): n 3268, 2938, 2856, 1501, 1446, 1239, 1162, 1022, 801, 680. 4d: White solid; yield 53%; mp 88-89 ℃; 1H NMR (400 (M+H)+z, CDCl3): δ 1.31-2.17 (m, 17H, 5 cyclopropyl-H, 10 cyclohexyl-H, CH2), 2.63 (s, 3H, thiadiazole-CH3), 3.13 (s, 1H, NH), 4.53-4.60 (m, 1H, cyclohexyl-H), 5.72 (s, 1H, CH). HRMS: Calcd. for C15H23N7S (M+Na)+: 356.1628, Found: 356.1623; IR (KBr pellet press, cm 1): v3265, 2941, 2856, 1501, 1466, 1241, 1151, 1009, 810. 4e: White solid; yield 57%; mp 119-120 ℃; 1H NMR (400 (M+H)+z, CDCl3): δ 1.10 (s, 9H, 3t-butyl-CH3), 1.26-2.07 (m, 11H, 10 cyclohexyl-H, NH), 2.57 (s, 3H, thiadiazole-CH3), 4.37-4.45 (m, 1H, cyclohexyl-CH), 5.84 (s, 1H, CH). HRMS: Calcd. for C15H25N7S (M+Na)+: 358.1784, Found: 358.1787; IR (KBr pellet press, cm-1): v3327, 2938, 2865, 1453, 1231, 1103, 1076, 861, 741. 4f: White solid; yield 60%; mp 87-88 ℃; 1H NMR (400 MHz, CDCl3):d 1.26-2.17 (m, 17H, 6 cyclobutyl-H, 10 cyclohexyl-H, NH), 2.63 (s, 3H, thiadiazole-CH3), 3.11-3.14 (m, 1H, cyclobutyl-CH), 4.49-4.56 (m, 1H, cyclohexyl-CH), 5.70 (s, 1H, CH). HRMS: Calcd. for C15H23N7S (M+Na)+: 356.1628, Found: 356.1629; IR (KBr pellet press, cm 1): v3264, 2941, 2856, 1501, 1451, 1241, 1150, 1105, 1009, 809, 759. 4g: White solid; yield 58%; mp 122-123 ℃; 1H NMR (400 MHz, CDCl3):d 1.32-2.00 (m, 19H, 8 cyclopentyl-H, 10 cyclohexyl-H, NH), 2.63 (s, 3H, thiadiazole-CH3), 2.89-2.95 (m, 1H, cyclopentyl-CH), 4.53-4.60 (m, 1H, cyclohexyl-CH), 5.72 (s, 1H, CH). HRMS: Calcd. for C16H25N7S (M H) : 346.1819, Found: 346.1814; IR (KBr pellet press, cm 1): v3271, 2938, 2857, 1499, 1449, 1236, 1087, 1005, 844, 732. 4h: White solid; yield 47%; mp 98-99 ℃; 1H NMR (400 (M+H)+z, CDCl3):d 1.11-2.05 (m, 21H, 20 cyclohexyl-H, NH), 2.30-2.32 (m, 1H, cyclohexyl-CH), 2.62 (s, 3H, thiadiazole-CH3), 4.56-4.64 (m, 1H, cyclohexyl-H), 5.90 (s, 1H, CH). HRMS: Calcd. for C17H27N7S (M H) : 360.1976, Found: 360.1973; IR (KBr pellet press, cm 1): v3286, 2927, 2850, 1451, 1236, 1106, 1012, 824, 686. 4i: White solid; yield 55%; mp 96-97 ℃; 1H NMR(400 (M+H)+z, CDCl3):d 1.26-1.99 (m, 10H, cyclohexyl-H), 2.65 (s, 3H, thiadiazole-CH3), 4.35-4.41 (m, 1H, cyclohexyl-H), 4.72 (d, 1H, J = 8.0 Hz, NH), 6.32 (d, 1H, J = 8.0 Hz, CH), 6.66-7.09 (m, 4H, Ph-H). HRMS: Calcd. for C17H20FN7S (M+H)+: 374.1558, Found: 374.1555; IR (KBr pellet press, cm 1): v3401, 2936, 2860, 1620, 1527, 1453, 1251, 1191, 1057, 738. 4j: Pale yellow solid; yield 50%; mp 115-116 ℃; 1H NMR (400 (M+H)+z, CDCl3):d 1.26-1.99 (m, 10H, 10 cyclohexyl-H), 2.66 (s, 3H, thiadiazole-CH3), 4.27-4.33 (m, 1H, cyclohexyl-CH), 5.09 (d, 1H, J = 6.0 Hz, NH), 6.23 (d, 1H, J = 7.6 Hz, CH), 6.56 (d, 1H, J = 8.4 Hz, Ph-H), 6.70 (s, 1H, Ph-H), 6.85 (d, 1H, J = 8.4 Hz, Ph-H), 7.12 (t, 1H, J = 8.0 Hz, Ph-H). HRMS: Calcd. for C17H20ClN7S (M H) : 388.1117, Found: 388.1112; IR (KBr pellet press, cm 1): v3410, 2937, 2861, 1598, 1484, 1446, 1272, 1158, 1012, 845, 759. 4k: Pale yellow solid; yield 46%; mp 152-153 ℃; 1H NMR (400 MHz, CDCl3):d 1.26-2.01 (m, 10H, 10 cyclohexyl-H), 2.66 (s, 3H, thiadiazole-CH3), 4.25-4.32 (m, 1H, cyclohexyl-CH), 4.80 (d, 1H, J = 7.2 Hz, NH), 6.20 (d, 1H, J = 7.2 Hz, CH), 6.63 (d, 2H, J = 8.8 Hz, Ph-H), 7.18 (d, 2H, J = 8.4 Hz, Ph-H). HRMS: Calcd. for C17H20ClN7S (M H) : 388.1117, Found: 388.1119; IR (KBr pellet press, cm 1): v3285, 2944, 2856, 1598, 1497, 1442, 1296, 1245, 1103, 1011, 837. 4l: White solid; yield 45%; mp 149-150 (oC; 1H NMR (400 MHz, CDCl3):d 1.17 (t, 3H, J = 7.6 Hz, ethyl-CH3), 1.24-2.00 (m, 10H, 10 cyclohexyl-H), 2.50 (q, 2H, J = 15.2 Hz, ethyl-CH2), 2.63 (s, 3H, thiadiazole-CH3), 4.27-4.34 (m, 1H, cyclohexyl-CH), 4.41 (d, 1H, J = 5.2 Hz, NH), 6.18 (d, 1H, J = 8.0 Hz, CH), 6.63 (d, 2H, J = 8.4 Hz, Ph-H), 7.05 (d, 2H,, J = 8.4 Hz, Ph-H). HRMS: Calcd. for C19H25N7S (M+Na)+: 406.1784, Found: 406.1783; IR (KBr pellet press, cm 1): v3419, 2935, 2862, 1616, 1523, 1446, 1281, 1102, 818, 756. 4m: White solid; yield 48%; mp 143-144 (C; 1H NMR (400 (M+H)+z, CDCl3): δ 1.27-2.00 (m, 10H, cyclohexyl-H), 2.15 (s, 3H, Ph-CH3), 2.65 (s, 3H, thiadiazole-CH3), 4.29-4.34 (m, 1H, cyclohexyl-CH), 4.75 (d, 1H, J = 7.6 Hz, NH), 6.19 (d, 1H, J = 7.6 Hz, CH), 6.36-6.41 (m, 2H, PhH), 7.00 (t, 1H, J = 8.4 Hz, PhH). HRMS: Calcd. for C18H22FN7S (M-H)-: 386.1569, Found: 386.1571; IR (KBr pellet press, cm-1): v3285, 2927, 2849, 1496, 1450, 1236, 1133, 1012, 824, 686.[26] Selected characteristic data for the target compounds. 4a: White solid; yield 59%; mp 75-76 ℃; 1H NMR (400 MHz, CDCl3): δ 0.93 (t, 3H, J = 7.6 Hz, propyl-CH3), 1.26-2.07 (m, 13H, propyl-CH2, 10cyclohexyl-H, NH), 2.45-2.62 (m, 2H, propyl-CH2), 2.65 (s, 3H, thiadiazole-CH3), 4.58-4.66 (m, 1H, cyclobutyl-CH), 5.76 (s, 1H, CH). HRMS: Calcd. for C14H23N7S (M+Na)+: 344.1628, Found: 344.1630; IR (KBr pellet press, cm 1): v3325, 2951, 2863, 1495, 1450, 1229, 1106, 1009, 809, 759. 4b: White solid; yield 47%; mp 96-97 ℃; 1H NMR (400 MHz, CDCl3):d 1.13 (t, 6H, J = 6.0 Hz, 2 isopropyl-CH3), 1.26-2.07 (m, 11H, 10 cyclohexyl-H, NH), 2.63 (s, 3H, thiadiazole-CH3), 2.64-2.71 (m, 1H, isopropyl-CH), 4.54-4.62 (m, 1H, cyclobutyl-CH), 5.83 (s, 1H, CH). HRMS: Calcd. for C14H23N7S (M+Na)+: 344.1628, Found: 344.1626; IR (KBr pellet press, cm 1): v 3276, 2934, 2857, 1501, 1451, 1241, 1126, 1009, 832. 4c: White solid; yield 51%; mp 96-97 ℃; 1H NMR (400 (M+H)+z, CDCl3): (0.43-0.54 (m, 4H, cyclopropyl-H), 1.33-2.05 (m, 11H, cyclohexyl-H, NH), 2.58 (s, 1H, cyclopropyl-CH), 2.66 (s, 3H, thiadiazole-CH3), 4.27-4.35 (m, 1H, cyclohexyl-CH), 5.58 (s, 1H, CH). HRMS: Calcd. for C14H21N7S (M+H)+: 320.1652, Found: 320.1657; IR (KBr pellet press, cm-1): n 3268, 2938, 2856, 1501, 1446, 1239, 1162, 1022, 801, 680. 4d: White solid; yield 53%; mp 88-89 ℃; 1H NMR (400 (M+H)+z, CDCl3): δ 1.31-2.17 (m, 17H, 5 cyclopropyl-H, 10 cyclohexyl-H, CH2), 2.63 (s, 3H, thiadiazole-CH3), 3.13 (s, 1H, NH), 4.53-4.60 (m, 1H, cyclohexyl-H), 5.72 (s, 1H, CH). HRMS: Calcd. for C15H23N7S (M+Na)+: 356.1628, Found: 356.1623; IR (KBr pellet press, cm 1): v3265, 2941, 2856, 1501, 1466, 1241, 1151, 1009, 810. 4e: White solid; yield 57%; mp 119-120 ℃; 1H NMR (400 (M+H)+z, CDCl3): δ 1.10 (s, 9H, 3t-butyl-CH3), 1.26-2.07 (m, 11H, 10 cyclohexyl-H, NH), 2.57 (s, 3H, thiadiazole-CH3), 4.37-4.45 (m, 1H, cyclohexyl-CH), 5.84 (s, 1H, CH). HRMS: Calcd. for C15H25N7S (M+Na)+: 358.1784, Found: 358.1787; IR (KBr pellet press, cm-1): v3327, 2938, 2865, 1453, 1231, 1103, 1076, 861, 741. 4f: White solid; yield 60%; mp 87-88 ℃; 1H NMR (400 MHz, CDCl3):d 1.26-2.17 (m, 17H, 6 cyclobutyl-H, 10 cyclohexyl-H, NH), 2.63 (s, 3H, thiadiazole-CH3), 3.11-3.14 (m, 1H, cyclobutyl-CH), 4.49-4.56 (m, 1H, cyclohexyl-CH), 5.70 (s, 1H, CH). HRMS: Calcd. for C15H23N7S (M+Na)+: 356.1628, Found: 356.1629; IR (KBr pellet press, cm 1): v3264, 2941, 2856, 1501, 1451, 1241, 1150, 1105, 1009, 809, 759. 4g: White solid; yield 58%; mp 122-123 ℃; 1H NMR (400 MHz, CDCl3):d 1.32-2.00 (m, 19H, 8 cyclopentyl-H, 10 cyclohexyl-H, NH), 2.63 (s, 3H, thiadiazole-CH3), 2.89-2.95 (m, 1H, cyclopentyl-CH), 4.53-4.60 (m, 1H, cyclohexyl-CH), 5.72 (s, 1H, CH). HRMS: Calcd. for C16H25N7S (M H) : 346.1819, Found: 346.1814; IR (KBr pellet press, cm 1): v3271, 2938, 2857, 1499, 1449, 1236, 1087, 1005, 844, 732. 4h: White solid; yield 47%; mp 98-99 ℃; 1H NMR (400 (M+H)+z, CDCl3):d 1.11-2.05 (m, 21H, 20 cyclohexyl-H, NH), 2.30-2.32 (m, 1H, cyclohexyl-CH), 2.62 (s, 3H, thiadiazole-CH3), 4.56-4.64 (m, 1H, cyclohexyl-H), 5.90 (s, 1H, CH). HRMS: Calcd. for C17H27N7S (M H) : 360.1976, Found: 360.1973; IR (KBr pellet press, cm 1): v3286, 2927, 2850, 1451, 1236, 1106, 1012, 824, 686. 4i: White solid; yield 55%; mp 96-97 ℃; 1H NMR(400 (M+H)+z, CDCl3):d 1.26-1.99 (m, 10H, cyclohexyl-H), 2.65 (s, 3H, thiadiazole-CH3), 4.35-4.41 (m, 1H, cyclohexyl-H), 4.72 (d, 1H, J = 8.0 Hz, NH), 6.32 (d, 1H, J = 8.0 Hz, CH), 6.66-7.09 (m, 4H, Ph-H). HRMS: Calcd. for C17H20FN7S (M+H)+: 374.1558, Found: 374.1555; IR (KBr pellet press, cm 1): v3401, 2936, 2860, 1620, 1527, 1453, 1251, 1191, 1057, 738. 4j: Pale yellow solid; yield 50%; mp 115-116 ℃; 1H NMR (400 (M+H)+z, CDCl3):d 1.26-1.99 (m, 10H, 10 cyclohexyl-H), 2.66 (s, 3H, thiadiazole-CH3), 4.27-4.33 (m, 1H, cyclohexyl-CH), 5.09 (d, 1H, J = 6.0 Hz, NH), 6.23 (d, 1H, J = 7.6 Hz, CH), 6.56 (d, 1H, J = 8.4 Hz, Ph-H), 6.70 (s, 1H, Ph-H), 6.85 (d, 1H, J = 8.4 Hz, Ph-H), 7.12 (t, 1H, J = 8.0 Hz, Ph-H). HRMS: Calcd. for C17H20ClN7S (M H) : 388.1117, Found: 388.1112; IR (KBr pellet press, cm 1): v3410, 2937, 2861, 1598, 1484, 1446, 1272, 1158, 1012, 845, 759. 4k: Pale yellow solid; yield 46%; mp 152-153 ℃; 1H NMR (400 MHz, CDCl3):d 1.26-2.01 (m, 10H, 10 cyclohexyl-H), 2.66 (s, 3H, thiadiazole-CH3), 4.25-4.32 (m, 1H, cyclohexyl-CH), 4.80 (d, 1H, J = 7.2 Hz, NH), 6.20 (d, 1H, J = 7.2 Hz, CH), 6.63 (d, 2H, J = 8.8 Hz, Ph-H), 7.18 (d, 2H, J = 8.4 Hz, Ph-H). HRMS: Calcd. for C17H20ClN7S (M H) : 388.1117, Found: 388.1119; IR (KBr pellet press, cm 1): v3285, 2944, 2856, 1598, 1497, 1442, 1296, 1245, 1103, 1011, 837. 4l: White solid; yield 45%; mp 149-150 (oC; 1H NMR (400 MHz, CDCl3):d 1.17 (t, 3H, J = 7.6 Hz, ethyl-CH3), 1.24-2.00 (m, 10H, 10 cyclohexyl-H), 2.50 (q, 2H, J = 15.2 Hz, ethyl-CH2), 2.63 (s, 3H, thiadiazole-CH3), 4.27-4.34 (m, 1H, cyclohexyl-CH), 4.41 (d, 1H, J = 5.2 Hz, NH), 6.18 (d, 1H, J = 8.0 Hz, CH), 6.63 (d, 2H, J = 8.4 Hz, Ph-H), 7.05 (d, 2H,, J = 8.4 Hz, Ph-H). HRMS: Calcd. for C19H25N7S (M+Na)+: 406.1784, Found: 406.1783; IR (KBr pellet press, cm 1): v3419, 2935, 2862, 1616, 1523, 1446, 1281, 1102, 818, 756. 4m: White solid; yield 48%; mp 143-144 (C; 1H NMR (400 (M+H)+z, CDCl3): δ 1.27-2.00 (m, 10H, cyclohexyl-H), 2.15 (s, 3H, Ph-CH3), 2.65 (s, 3H, thiadiazole-CH3), 4.29-4.34 (m, 1H, cyclohexyl-CH), 4.75 (d, 1H, J = 7.6 Hz, NH), 6.19 (d, 1H, J = 7.6 Hz, CH), 6.36-6.41 (m, 2H, PhH), 7.00 (t, 1H, J = 8.4 Hz, PhH). HRMS: Calcd. for C18H22FN7S (M-H)-: 386.1569, Found: 386.1571; IR (KBr pellet press, cm-1): v3285, 2927, 2849, 1496, 1450, 1236, 1133, 1012, 824, 686.

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  • 收稿日期:  2013-04-07
  • 网络出版日期:  2013-05-07
通讯作者: 陈斌, bchen63@163.com
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    沈阳化工大学材料科学与工程学院 沈阳 110142

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