Design, Synthesis and Anticancer Activity of a New Series of N-aryl-N′-[4-(pyridin-2-ylmethoxy)benzyl]urea Derivatives
Abstract
:1. Introduction
2. Results and discussion
2.1. Chemistry
2.2. Biological Activity Evaluation
2.3. Cell Cycle Analysis
3. Materials and Methods
3.1. Chemistry
3.1.1. General Information
3.1.2. Synthesis of 3-methoxy-4-[(3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy] benzaldehyde (3)
3.1.3. Synthesis of (E)-3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl) methoxy)benzaldehyde oxime (4)
3.1.4. Synthesis of (3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)phenyl)methanamine (5)
3.1.5. Synthesis of N-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl) methoxy)benzyl)-1-methylpiperidin-4-amine (6)
3.1.6. General Procedure for the Synthesis of the Target Urea Derivatives
- 1-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)benzyl)-3-(4-(trifluoromethoxy)phenyl)urea (8a), white powder 0.99 g, yield 89%; m.p.: 158.8–159.3 °C; MS: 560.4([M + H]+); 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.34 (d, J = 5.7 Hz, 1H), 7.54–7.47 (m, 2H), 7.23 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 5.7 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.81 (dd, J = 8.2, 2.0 Hz, 1H), 6.59 (t, J = 5.9 Hz, 1H), 5.14 (s, 2H), 4.92 (q, J = 8.8 Hz, 2H), 4.23 (d, J = 5.7 Hz, 2H), 3.74 (s, 3H), 2.22 (s, 3H).; 13C NMR (101 MHz, DMSO-d6) δ 161.82, 155.94, 155.51, 149.63, 148.02, 147.18, 142.55, 140.26, 133.67, 124.25 (q, J = 277.9 Hz), 122.08, 121.99, 120.69 (q, J = 254.9 Hz), 119.69, 119.19, 114.27, 112.07, 108.02, 71.56, 65.11 (q, J = 34.7 Hz), 55.95, 43.10, 10.30; IR: 3399, 3053, 3008, 2971, 2829, 1706, 1556, 1507, 1454, 1416, 1256, 1220, 1194, 1154, 1015, 911, 847, 796, 672, 645, 544; HRMS: 558.146914([M − H]−) for C25H22F6N3O5, 560.161467([M + H]+) for C25H24F6N3O5.
- 1-(3-chloro-4-fluorophenyl)-3-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)benzyl)urea (8b), white powder 0.86 g, yield 82%; m.p.: 167.8–169.1 °C; MS:528.3([M + H]+); 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.34 (d, J = 5.7 Hz, 1H), 7.77 (dd, J = 6.8, 2.4 Hz, 1H), 7.32–7.18 (m, 2H), 7.14 (d, J = 5.7 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.80 (dd, J = 8.2, 1.9 Hz, 1H), 6.63 (t, J = 5.8 Hz, 1H), 5.13 (s, 2H), 4.91 (q, J = 8.7 Hz, 2H), 4.22 (d, J = 5.7 Hz, 2H), 3.74 (s, 3H), 2.22 (s, 3H).; 13C NMR (101 MHz, DMSO-d6) δ 161.81, 155.94, 155.44, 152.33 (d, J = 240.0 Hz), 149.59, 148.04, 147.15, 138.26 (d, J = 2.8 Hz), 124.27 (q, J = 277.4 Hz), 122.05, 119.69, 119.44 (d, J = 18.9 Hz), 119.31, 118.23 (d, J = 6.5 Hz), 117.13 (d, J = 21.3 Hz), 114.26, 112.08, 108.06, 71.55, 65.08 (q, J = 34.2 Hz), 56.00, 43.09, 10.35; IR: 3313, 2944, 2883, 1641, 1564, 1500, 1477, 1420, 1390, 1308, 1258, 1209, 1164, 1131, 1008, 970, 911, 862, 800, 757, 647, 576, 445; HRMS: 526.116220([M − H]−) for C24H21ClF4N3O4, 528.130773([M + H]+) for C24H23ClF4N3O4.
- 1-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)benzyl)-3-(4-(trifluoromethyl)phenyl)urea (8c), white powder 0.78 g, yield 72%; m.p: 169.9–171.0 °C; MS:544.5([M + H]+), 566.1([M + Na]+); 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.34 (d, J = 5.7 Hz, 1H), 7.59 (q, J = 8.8 Hz, 4H), 7.14 (d, J = 5.7 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 6.82 (dd, J = 8.2, 1.9 Hz, 1H), 6.69 (t, J = 5.8 Hz, 1H), 5.14 (s, 2H), 4.91 (q, J = 8.7 Hz, 2H), 4.24 (d, J = 5.7 Hz, 2H), 3.74 (s, 3H), 2.22 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 161.81, 155.93, 155.25, 149.61, 148.03, 147.19, 144.64, 133.47, 126.37, 125.09 (q, J = 270.6 Hz), 124.26 (q, J = 277.5 Hz), 122.06, 119.73, 117.72, 114.26, 112.10, 108.05, 71.55, 65.09 (q, J = 35.0 Hz), 55.98, 43.10, 10.31; IR: 3414, 3376, 2940, 2886, 1703, 1686, 1581, 1534, 1512, 1477, 1408, 1321, 1256, 1220, 1180, 1155, 1135, 1102, 1063, 1008, 979, 862, 842, 812, 595, 554;HRMS: 542.151999 ([M − H]−) for C25H22F6N3O4, 544.166552([M + H]+)+ for C25H24F6N3O4.
- 1-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)benzyl)-3-(3-(trifluoromethyl)phenyl)urea (8d), white powder 0.83 g, yield 76%; m.p.: 153.2–154.2 °C; MS:544.2([M + H]+), 542.0([M − H]−); 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.34 (d, J = 5.7 Hz, 1H), 7.98 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 5.7 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 1.9 Hz, 1H), 6.81 (dd, J = 8.2, 1.9 Hz, 1H), 6.68 (t, J = 5.9 Hz, 1H), 5.13 (s, 2H), 4.91 (q, J = 8.7 Hz, 2H), 4.23 (d, J = 5.8 Hz, 2H), 3.74 (s, 3H), 2.22 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 161.82, 155.94, 155.46, 149.62, 148.02, 147.18, 141.80, 133.59, 130.11, 124.73 (q, J = 272.3 Hz), 124.25 (q, J = 277.4 Hz), 122.07, 121.62, 119.69, 117.68, 114.28, 114.06, 112.08, 108.02 (d, J = 4.4 Hz), 71.56, 65.10 (q, J = 34.2 Hz), 55.97 (d, J = 3.2 Hz), 43.08, 10.33; IR: 3412, 3374, 2940, 2876, 1702, 1582, 1551, 1514, 1477, 1442, 1380, 1341, 1312, 1255, 1221, 1182, 1158, 1111, 1067, 1028, 1007, 979, 891, 864, 813, 796, 702, 664, 597, 552; HRMS: 542.151999([M − H]−) for C25H22F6N3O4+, 544.161552 ([M + H]+) for C25H24F6N3O4.
- 1-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)benzyl)-3-(4-methoxyphenyl)urea (8e), white powder 0.59 g, yield 58%; m.p.: 179.5–180.3 °C; MS:566.2([M + H]+), 504.0([M − H]−); 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.29 (d, J = 8.9 Hz, 2H), 7.14 (d, J = 5.7 Hz, 1H), 6.93 (d, J = 1.9 Hz, 1H), 6.81 (dd, J = 9.0, 7.1 Hz, 3H), 6.40 (t, J = 5.9 Hz, 1H), 5.13 (s, 2H), 4.92 (q, J = 8.8 Hz, 2H), 4.20 (d, J = 5.8 Hz, 2H), 3.70 (s, 3H), 2.22 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 161.80, 155.96, 155.86, 154.40, 149.57, 148.05, 147.08, 134.08, 133.97, 124.28 (d, J = 277.9 Hz), 122.05, 119.91, 119.64, 114.33, 114.27, 112.06, 108.07, 71.58, 65.08 (q, J = 34.5 Hz), 55.99, 55.59, 43.09, 10.36; IR: 3312, 2940, 2839, 1631, 1571, 1508, 1467, 1417, 1376, 1363, 1308, 1271, 1241, 1160, 1136, 1030, 973, 862, 827, 669, 578, 524, 423; HRMS: 504.175179 ([M − H]−) for C25H25F3N3O5, 506.189732 ([M + H]+) for C25H27F3N3O5.
- 1-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)benzyl)-3-(3-nitrophenyl)urea (8f), yellow powder 0.31 g, yield 30%; m.p.: 168.9–170.5 °C; MS: 521.2([M + H]+), 519.0([M − H]−); 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.52 (t, J = 2.2 Hz, 1H), 8.33 (d, J = 5.8 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 9.1, 7.3 Hz, 1H), 7.13 (d, J = 5.9 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.96–6.92 (m, 1H), 6.85–6.71 (m, 2H), 5.13 (s, 2H), 4.91 (q, J = 8.8 Hz, 2H), 4.24 (d, J = 5.9 Hz, 2H), 3.74 (s, 3H), 2.21 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 161.83, 155.93, 155.35, 149.63, 148.59, 148.02, 147.20, 142.28, 133.51, 130.31, 124.26 (q, J = 277.8 Hz), 124.16, 122.07, 119.74, 115.95, 114.32, 112.14, 112.06, 108.05, 71.56, 65.11 (q, J = 34.4 Hz), 56.02, 43.11, 10.34; IR: 3410, 3010, 2943, 2882, 2832, 1701, 1584, 1527, 1503, 1480, 1383, 1347, 1318, 1264, 1207, 1161, 1138, 1122, 1033, 1000, 980, 868, 814, 794, 735, 671, 612, 585, 557, 445; HRMS: 519.149693 ([M − H]−) for C24H22F3N4O6, 521.164246([M + H]+) for C24H24F3N4O6.
- 1-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)benzyl)-3-(4-methoxybenzyl)urea (8g), white powder 0.39 g, yield 38%; m.p.: 153.0–154.2 °C; MS: 520.2([M + H]+), 517.9([M − H]−); 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.52 (t, J = 2.2 Hz, 1H), 8.33 (d, J = 5.8 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 9.1, 7.3 Hz, 1H), 7.13 (d, J= 5.9 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.96–6.92 (m, 1H), 6.85–6.71 (m, 2H), 5.13 (s, 2H), 4.91 (q, J = 8.8 Hz, 2H), 4.24 (d, J = 5.9 Hz, 2H), 3.74 (s, 3H), 2.21 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 161.82, 158.54, 158.46, 155.99, 149.57, 148.04, 146.99, 134.47, 133.30, 124.28 (q, J = 277.7 Hz), 122.06, 119.46, 114.26, 114.07, 111.86, 108.08, 71.61, 65.10 (q, J = 34.9 Hz), 55.92, 55.51, 43.25, 42.90, 10.36; IR: 3349, 3301, 2949, 2925, 2884, 2832, 1605, 1579, 1561, 1515, 1468, 1424, 1363, 1363, 1363, 1275, 1251, 1169, 1156, 1133, 1103, 1038, 975, 863, 816, 728, 637, 561; HRMS: 518.190829 ([M − H]−) for C26H27F3N3O5, 520.205382 ([M + H]+) for C26H29F3N3O5.
- 1-(4-ethoxybenzyl)-3-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)benzyl)urea (8h), white powder 0.57 g, yield 53%; m.p.: 148.9–149.9 °C; MS: 534.3 ([M + H]+); 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 5.7 Hz, 1H), 7.20–7.11 (m, 3H), 7.02 (d, J = 8.2 Hz, 1H), 6.90–6.81 (m, 3H), 6.75 (dd, J = 8.3, 1.9 Hz, 1H), 6.30 (td, J = 6.1, 2.3 Hz, 2H), 5.13 (s, 2H), 4.92 (q, J = 8.8 Hz, 2H), 4.15 (d, J = 5.8 Hz, 4H), 3.99 (q, J = 7.0 Hz, 2H), 3.71 (s, 3H), 2.22 (s, 3H), 1.31 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 161.82, 158.48, 157.77, 155.96, 149.54, 148.02, 146.96, 134.46, 133.16, 128.76, 124.28 (q, J= 277.7, 277.3 Hz), 122.06, 119.44, 114.56, 114.21, 111.81, 108.08, 71.57, 65.08 (q, J = 34.5 Hz), 63.39, 55.89, 43.24, 42.89, 15.11, 10.36; IR: 3331, 2978, 2927, 2883, 1609, 1579, 1556, 1516, 1471, 1423, 1390, 1275, 1249, 1148, 1025, 974, 861, 815, 753, 728, 639, 574, 548; HRMS: 532.206479 ([M − H]−) for C27H29F3N3O5, 534.221032([M + H]+) for C27H31F3N3O5.
- 1-(4-(dimethylamino)benzyl)-3-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)benzyl)urea (8i), white powder 0.73 g, yield 69%; m.p.: 159.4–161.4 °C; MS:533.9([M + H]+), 555.4([M + Na]+); 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 5.6 Hz, 1H), 7.14 (d, J = 5.7 Hz, 1H), 7.11–7.06 (m, 2H), 7.02 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.74 (dd, J = 8.2, 1.9 Hz, 1H), 6.69–6.65 (m, 2H), 6.22 (dt, J = 21.9, 5.9 Hz, 2H), 5.12 (s, 2H), 4.92 (q, J = 8.7 Hz, 2H), 4.15 (d, J = 5.9 Hz, 2H), 4.10 (d, J = 5.8 Hz, 2H), 3.71 (s, 3H), 2.85 (s, 6H), 2.22 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 161.81, 158.46, 155.98, 149.97, 149.55, 148.04, 146.96, 134.50, 128.77, 128.49, 124.28 (q, J = 277.7 Hz), 122.05, 119.44, 114.22, 112.85, 111.82, 108.08, 71.59, 65.08 (q, J = 34.3 Hz), 55.92, 43.23, 43.06, 10.36; IR: 3336, 2940, 2918, 2879, 1613, 1570, 1517, 1468, 1421, 1308, 1256, 1233, 1175, 1137, 1039, 1011, 969, 922, 854, 810, 736, 650, 564; HRMS: 531.222464 ([M − H]−) for C27H30F3N4O4, 522.237017 ([M + H]+) for C27H32F3N4O4.
- 1-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)benzyl)-1-(1-methylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (9a), white powder 0.79 g, yield 60%; m.p.: 127.3–129.4 °C; MS:657.2([M + H]+); 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 7.58–7.51 (m, 2H), 7.23 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 5.7 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.75 (dd, J = 8.2, 1.9 Hz, 1H), 5.11 (s, 2H), 4.91 (q, J = 8.7 Hz, 2H), 4.52 (s, 2H), 4.10 (tt, J = 12.0, 4.0 Hz, 1H), 3.70 (s, 3H), 2.83 (d, J = 11.6 Hz, 2H), 2.20 (d, J = 5.4 Hz, 6H), 2.06 (d, J = 10.0 Hz, 2H), 1.70 (tt, J = 12.4, 6.7 Hz, 2H), 1.55 (d, J = 14.4 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 161.81, 155.73, 149.48, 148.05, 146.93, 143.15, 140.30, 133.64, 124.26(q, J =276.1Hz), 121.50, 118.77, 120.66 (q, J = 253.5 Hz), 111.28, 108.07, 71.55, 65.11 (q, J = 34.8, 34.0 Hz), 55.95, 55.08, 53.09, 45.99, 45.70, 45.16, 39.69, 29.90, 10.36; IR: 3397, 2950, 2848, 2799, 1648, 1584, 1513, 1470, 1416, 1377, 1293, 1256, 1227, 1204, 1159, 1132, 1031, 982, 921, 847, 825, 800, 754, 536; HRMS: 655.236063 ([M − H]−) for C31H33F6N4O5, 657.250616 ([M + H]+) for C31H35F6N4O5.
- 1-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)benzyl)-1-(1-methylpiperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea (9b), white powder 0.73 g, yield 57%; m.p.: 138.4–140.5 °C; MS: 641.1([M + H]+), 321.5 ([M + 2H]2+), 639.5([M − H]−); 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 5.7 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.75 (dd, J = 8.3, 2.0 Hz, 1H), 5.10 (s, 2H), 4.91 (q, J = 8.7 Hz, 2H), 4.54 (s, 2H), 4.16–4.07 (m, 1H), 3.70 (s, 3H), 2.84 (d, J = 10.9 Hz, 2H), 2.19 (s, 6H), 2.06 (t, J = 10.0 Hz, 2H), 1.72 (q, J = 12.6, 11.8 Hz, 2H), 1.57 (d, J = 11.4 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 161.81, 155.92, 155.50, 149.49, 148.05, 146.97, 144.86, 133.47, 125.91 (q, J = 3.9 Hz), 125.08 (q, J = 270.9 Hz), 124.26 (q, J = 277.6, 277.1 Hz), 122.16 (q, J = 31.8 Hz), 122.08, 118.76, 114.21, 111.26, 108.06, 71.54, 65.11 (q, J = 34.4 Hz), 55.94, 55.06, 53.24, 45.70, 45.25, 29.88, 10.34; IR: 3387, 2943, 2846, 2802, 1650, 1584, 1513, 1468, 1416, 1378, 1313, 1250, 1224, 1162, 1131, 1063, 1030, 1016, 981, 862, 843, 811, 753, 577; HRMS: 639.241148 ([M − H]−) for C31H33F6N4O4, 641.255701([M + H]+) for C31H35F6N4O4.
- 1-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)benzyl)-3-(4-methoxyphenyl)-1-(1-methylpiperidin-4-yl)urea (9c), white powder 0.71 g, yield 59%; m.p.: 179.1–180.8; MS:603.2([M + H]+); 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 5.7 Hz, 1H), 8.12 (s, 1H), 7.33–7.26 (m, 2H), 7.14 (d, J = 5.7 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.84–6.74 (m, 3H), 5.11 (s, 2H), 4.91 (q, J = 8.7 Hz, 2H), 4.49 (s, 2H), 4.08 (tt, J = 11.3, 3.9 Hz, 1H), 3.71 (d, J = 1.9 Hz, 6H), 2.80 (d, J = 11.0 Hz, 2H), 2.21 (s, 3H), 2.17 (s, 3H), 2.06–1.95 (m, 2H), 1.67 (qd, J = 12.1, 3.9 Hz, 2H), 1.54 (d, J = 12.0 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 161.81, 156.08, 155.96, 155.07, 149.46, 148.06, 146.87, 133.99, 133.88, 124.27 (q, J = 278.0 Hz), 122.70, 122.06, 118.80, 114.19, 113.89, 111.29, 108.08, 71.57, 65.10 (q, J = 33.8 Hz), 55.96, 55.59, 55.28, 52.98, 46.03, 45.03, 30.19, 10.38; IR: 3403, 2943, 2836, 2788, 2759, 1642, 1583, 1511, 1467, 1446, 1416, 1373, 1295, 1250, 1220, 1159, 1128, 1034, 1011, 962, 860, 824, 737, 666, 576, 542, 441; HRMS: 637.241006 ([M + Cl]−) for C31H37ClF3N4O5, 603.278881 ([M + H]+) for C31H38F3N4O5.
- 1-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)benzyl)-1-(1-methylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)urea (9d), white powder 0.75 g, yield 59%; m.p.: 160.4–162.2 °C; MS: 641.2([M + H]+); 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.33 (d, J = 5.7 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.74 (dd, J = 8.2, 2.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 5.7 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 8.3, 2.0 Hz, 1H), 5.11 (s, 2H), 4.91 (q, J = 8.7 Hz, 2H), 4.54 (s, 2H), 4.11 (tt, J = 12.1, 3.9 Hz, 1H), 3.70 (s, 3H), 2.84 (d, J = 11.2 Hz, 2H), 2.20 (s, 6H), 2.05 (d, J = 13.2 Hz, 2H), 1.72 (tt, J = 12.4, 6.8 Hz, 2H), 1.57 (d, J = 11.8 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 161.81, 155.93, 155.63, 149.48, 148.06, 146.94, 141.89, 133.50, 129.78, 129.51 (q, J = 32.3, 31.7 Hz), 124.76 (d, J = 272.5 Hz), 124.26 (q, J = 278.9, 278.5 Hz), 123.84, 118.75, 118.39 (d, J = 3.9 Hz), 116.39 (d, J = 4.4 Hz), 114.22, 111.25, 108.08, 71.54, 65.10 (q, J = 34.6 Hz), 55.94, 55.05, 53.16, 46.04, 45.68, 45.21, 29.82, 10.35; IR: 3385, 2940, 2839, 2791, 2771, 2735, 1645, 1583, 1513, 1493, 1468, 1444, 1376, 1326, 1247, 1222, 1152, 1122, 1030, 1000, 972, 909, 835, 788, 749, 701, 667, 540, 458; HRMS: 639.241148 ([M − H]−) for C31H33F6N4O4, 641.255701 ([M + H]+) for C31H35F6N4O4.
- 3-(3-chloro-4-fluorophenyl)-1-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)benzyl)-1-(1-methylpiperidin-4-yl)urea (9e), white powder 0.69 g, yield 55%; m.p.: 176.2–177.7 °C; MS:625.2([M + H]+); 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 7.74 (dd, J = 6.9, 2.6 Hz, 1H), 7.41 (ddd, J = 9.2, 4.4, 2.6 Hz, 1H), 7.27 (t, J = 9.1 Hz, 1H), 7.14 (d, J = 5.7 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.75 (dd, J = 8.2, 1.9 Hz, 1H), 5.11 (s, 2H), 4.91 (q, J = 8.7 Hz, 2H), 4.51 (s, 2H), 4.08 (tt, J = 12.1, 3.9 Hz, 1H), 3.71 (s, 3H), 2.83 (d, J = 11.2 Hz, 2H), 2.20 (d, J = 2.9 Hz, 6H), 2.05 (d, J = 11.7 Hz, 2H), 1.71 (qd, J = 12.3, 3.7 Hz, 2H), 1.59–1.51 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 161.81, 155.93, 155.62, 152.83 (d, J = 240.9 Hz), 149.46, 148.06, 146.93, 138.30, 133.52, 124.27 (q, J = 277.7 Hz), 122.06, 121.79, 120.59 (d, J = 6.5 Hz), 119.01 (d, J = 18.2 Hz), 118.75, 116.71 (d, J = 21.4 Hz), 114.20, 111.26, 108.08, 71.54, 65.10 (q, J = 34.6 Hz), 55.97, 55.09, 53.16, 45.77, 45.19, 29.89, 10.37; IR: 3403, 3365, 2940, 2881, 2822, 1702, 1598, 1515, 1448, 1407, 1370, 1319, 1260, 1217, 1151, 1107, 1063, 965, 906, 842, 785, 713, 593, 509, 455; HRMS: 623.205307 ([M − H]−) for C30H33ClF4N4O4, 625.219923 ([M + H]+) for C30H35ClF4N4O4.
- 1-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)benzyl)-1-(1-methylpiperidin-4-yl)-3-(3-nitrophenyl)urea (9f), yellow powder 0.79 g, yield 64%; m.p.: 157.5–159.1 °C; MS:618.2([M + H]+); 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.47 (t, J = 2.3 Hz, 1H), 8.33 (d, J = 5.7 Hz, 1H), 7.92 (dd, J = 8.2, 2.0 Hz, 1H), 7.79 (dd, J = 8.1, 2.2 Hz, 1H), 7.51 (t, J = 8.2 Hz, 1H), 7.13 (d, J = 5.7 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 8.3, 2.0 Hz, 1H), 5.10 (s, 2H), 4.91 (q, J = 8.7 Hz, 2H), 4.55 (s, 2H), 4.10 (tt, J = 11.9, 4.0 Hz, 1H), 3.71 (s, 3H), 2.80 (d, J = 11.0 Hz, 2H), 2.20 (s, 3H), 2.16 (s, 3H), 2.00 (t, J = 11.3 Hz, 2H), 1.71 (qd, J = 12.1, 3.8 Hz, 2H), 1.61–1.52 (m, 2H); 13C NMR (101 MHz, DMSO-d6) δ 161.80, 155.93, 155.52, 149.48, 148.28, 148.06, 146.95, 142.46, 133.45, 129.97, 126.24, 124.27 (q, J = 277.6 Hz), 122.06, 118.74, 116.58, 114.26, 114.21, 111.25, 108.07, 71.54, 65.10 (q, J = 34.4 Hz), 55.97, 55.21, 53.48, 46.01, 45.24, 30.08, 10.37; IR: 3366, 2940, 2842, 2781, 1657, 1585, 1512, 1467, 1426, 1376, 1343, 1248, 1222, 1161, 1131, 1032, 1011, 967, 861, 824, 737, 667, 584, 454; HRMS: 616.238842 ([M − H]−) for C30H33F3N5O6, 618.253395 ([M + H]+) for C30H35F3N5O6.
- 3-(4-ethoxybenzyl)-1-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)benzyl)-1-(1-methylpiperidin-4-yl)urea (9g), white powder 0.41 g, yield 33%; m.p.: 119.0–121.2 °C; MS 631.3([M + H]+); 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 5.7 Hz, 1H), 7.13 (dd, J = 15.2, 7.1 Hz, 3H), 7.01 (d, J = 8.3 Hz, 1H), 6.84–6.75 (m, 4H), 6.72 (dd, J = 8.3, 2.0 Hz, 1H), 5.11 (s, 2H), 4.92 (q, J = 8.7 Hz, 2H), 4.36 (s, 2H), 4.18 (d, J = 5.6 Hz, 2H), 3.98 (q, J = 6.9 Hz, 3H), 3.63 (s, 3H), 2.79 (d, J = 11.0 Hz, 2H), 2.21 (s, 3H), 2.17 (s, 3H), 2.00 (t, J = 11.8 Hz, 2H), 1.61 (qd, J = 12.2, 3.8 Hz, 2H), 1.48 (d, J = 9.9 Hz, 2H), 1.32 (d, J = 7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 161.82, 157.98, 157.62, 155.99, 149.46, 148.06, 146.82, 134.24, 133.60, 128.63, 124.28 (q, J = 277.9 Hz), 122.08, 118.80, 114.39, 114.08, 111.14, 108.09, 71.61, 65.12 (q, J = 34.4 Hz), 63.37, 55.79, 55.18, 52.47, 45.79, 44.88, 43.52, 29.99, 15.12, 10.38; IR: 3348, 2937, 2881, 2837, 2793, 1612, 1584, 1509, 1477, 1447, 1395, 1374, 1292, 1253, 1162, 1131, 1033, 1003, 971, 916, 804, 772, 577; HRMS: 665.272306 ([M + Cl]−) for C33H41ClF3N4O5, 631.310182 ([M + H]+) for C33H42F3N4O5.
3.2. Biological Evaluation
3.2.1. Antiproliferative Activity Assays
3.2.2. Cell Cycle Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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No. | Structure | IC50(μM) | ||||
---|---|---|---|---|---|---|
A549 | MCF7 | HCT116 | PC3 | HL7702 | ||
8a | 5.30 ± 1.45 | >50 | 7.25 ± 0.87 | >50 | >50 | |
8b | 17.65 ± 5.65 | 10.98 ± 1.68 | 9.33 ± 1.38 | 29.13 ± 5.81 | >50 | |
8c | 4.88 ± 1.94 | >50 | 11.38 ± 3.28 | >50 | >50 | |
8d | 26.47 ± 5.66 | >50 | 9.44 ± 1.22 | >50 | >50 | |
8e | 29.80 ± 5.09 | >50 | 28.81 ± 3.11 | >50 | >50 | |
8f | 12.40 ± 0.60 | 13.26 ± 2.27 | 13.35 ± 2.78 | 15.87 ± 0.73 | >50 | |
8g | >50 | >50 | 7.84 ± 1.40 | >50 | >50 | |
8h | 10.93 ± 2.02 | >50 | 23.31 ± 3.12 | >50 | >50 | |
8i | 9.85 ± 4.40 | >50 | 10.88 ± 2.85 | >50 | >50 | |
9a | 17.53 ± 2.95 | 2.59 ± 0.29 | 4.41 ± 0.14 | 4.10 ± 0.19 | >50 | |
9b | 4.93 ± 0.46 | 2.56 ± 0.07 | 2.90 ± 0.16 | 3.36 ± 0.17 | >50 | |
9c | 15.76 ± 1.51 | 4.65 ± 0.73 | 12.90 ± 1.59 | 12.35 ± 1.75 | >50 | |
9d | 3.17 ± 0.22 | 2.63 ± 0.08 | 2.56 ± 0.26 | 3.62 ± 0.27 | >50 | |
9e | 5.48 ± 4.36 | 2.56 ± 0.16 | 5.82 ± 0.21 | 4.53 ± 0.33 | >50 | |
9f | 6.09 ± 0.29 | 3.18 ± 0.30 | 5.18 ± 0.33 | 7.39 ± 0.63 | >50 | |
9g | 6.04 ± 0.41 | 4.23 ± 0.47 | 2.93 ± 0.26 | 6.25 ± 0.43 | >50 | |
sorafenib | 6.16 ± 0.46 | 3.54 ± 0.19 | 3.88 ± 0.36 | 5.26 ± 0.46 | >50 |
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Hou, S.; Liang, S.; Zhang, C.; Han, Y.; Liang, J.; Hu, H.; Zhang, X.; Hu, C.; Liu, X.; Zhang, H. Design, Synthesis and Anticancer Activity of a New Series of N-aryl-N′-[4-(pyridin-2-ylmethoxy)benzyl]urea Derivatives. Molecules 2021, 26, 3496. https://doi.org/10.3390/molecules26123496
Hou S, Liang S, Zhang C, Han Y, Liang J, Hu H, Zhang X, Hu C, Liu X, Zhang H. Design, Synthesis and Anticancer Activity of a New Series of N-aryl-N′-[4-(pyridin-2-ylmethoxy)benzyl]urea Derivatives. Molecules. 2021; 26(12):3496. https://doi.org/10.3390/molecules26123496
Chicago/Turabian StyleHou, Shicheng, Shishao Liang, Chao Zhang, Yingmei Han, Jianhui Liang, Hongyu Hu, Xingeng Zhang, Chun Hu, Xiaoping Liu, and Hong Zhang. 2021. "Design, Synthesis and Anticancer Activity of a New Series of N-aryl-N′-[4-(pyridin-2-ylmethoxy)benzyl]urea Derivatives" Molecules 26, no. 12: 3496. https://doi.org/10.3390/molecules26123496