Y.-H. Yang et al. / European Journal of Medicinal Chemistry 44 (2009) 1808–1812
1811
7.5.3. Data for 2,20-di-[[[3-methyl-4-(2,2,2-trifluoroethyl)]prid-2-
Table 1
Structure and anti-tumor activity of bis-benzimidazoles against SKOV-3, HeLa, and
BGC-823 tumor cell lines
yl]methylenethio]-5,50-bis-1H,10H-benzimidazole (10)
Yield: 80%; m.p.: 177–180 ꢁC; 1H NMR (300 MHz, DMSO-d6,
ppm): 12.68 (1H, br s, Bz-NH), 8.31 (1H, d, J ¼ 5.7, Py-6-H), 7.40–7.80
(3H, m, Bz-4-H, Bz-6-H, Bz-7-H), 7.09 (1H, d, J ¼ 5.7, Py-5-H), 4.90
(2H, q, J ¼ 8.7, OCH2CF3), 4.75 (2H, s, SCH2), 2.26 (3H, s, Py-3-CH3);
ESI-MS (m/z): 705.6 [M þ H]þ; IR (KBr, cmꢂ1): 3430, 2936, 1626,
1580,1474,1431,1384,1282,1256,1170,1110, 979, 857, 803, 663, 578.
7.5.4. Data for 2,20-di-[[(3-methoxy-4-chloro)prid-2-
Compound
Substituents
Pyridyl
IC50
SKOV-3
0.00134
(
m
M)a
yl]methylenethio]-5,50-bis-1H,10H-benzimidazole (11)
Yield: 69%; m.p.: 124–127 ꢁC; 1H NMR (300 MHz, DMSO-d6,
ppm): 12.66 (1H, br s, Bz-NH), 8.25 (1H, d, J ¼ 5.2, Py-6-H), 7.66 (1H,
s, Bz-4-H), 7.55 (1H, d, J ¼ 5.2, Py-5-H), 7.49 (1H, d, J ¼ 8.3, Bz-7-H),
7.41 (1H, d, J ¼ 8.5, Bz-6-H), 4.80 (2H, s, SCH2), 3.92 (3H, s, Py-3-
OCH3); ESI-MS (m/z): 609.3 [M þ H]þ; IR (KBr, cmꢂ1): 3438, 1626,
1564, 1461, 1401, 1384, 1281, 1233, 1082, 897, 818, 664.
R
HeLa
–
1.6
>50
>50
18.3
45.4
>50
>50
7.1
>50
32.4
>50
BGC-823
Taxol
Cisplatin
8
9
10
11
12
13
14
15
16
17
–
–
1.3
Pyrid-2-yl
Pyrid-2-yl
Pyrid-2-yl
Pyrid-2-yl
Pyrid-2-yl
Pyrid-2-yl
Pyrid-2-yl
Pyrid-3-yl
Pyrid-4-yl
Pyrid-3-yl
3,5-CH3, 4-OCH3
3,4-OCH3
3-CH3, 4-OCH2CF3
3-OCH3, 4-Cl
3-CH3, 4-OCH3
3-CH3, 4-OCH2CH3
H
H
2.95
>50
22.96
>50
>50
>50
38.60
8.73
2.81
>50
>50
>50
>50
>50
>50
16.4
>50
11.0
>50
7.5.5. Data for 2,20-di-[[(3-methyl-4-methoxy)prid-2-
yl]methylenethio]-5,50-bis-1H,10H-benzimidazole (12)
Yield: 79%; m.p.: 159–162 ꢁC; 1H NMR (300 MHz, DMSO-d6,
ppm): 12.67 (1H, br s, Bz-NH), 8.26 (1H, d, J ¼ 5.6, Py-6-H), 7.67 (1H,
s, Bz-4-H), 7.50 (1H, d, J ¼ 8.3, Bz-7-H), 7.42 (1H, dd, J ¼ 8.3, J ¼ 1.0,
Bz-6-H), 6.96 (1H, d, J ¼ 5.7, Py-5-H), 4.71 (2H, s, SCH2), 3.85 (3H, s,
OCH3), 2.21 (3H, s, Py-3-CH3); ESI-MS (m/z): 569.5 [M þ H]þ; IR
(KBr, cmꢂ1): 3439, 1625, 1584, 1467, 1431, 1384, 1297, 1097, 807, 600.
H
6-Cl
>50
a
The drug concentrations that inhibited cell growth by 50% (IC50) were deter-
mined from semilogarithmic dose-response plots.
(5.0 ml, 82.7 mmol), and ethanol (30 ml) dropwise. The solution
was heated to reflux for 4 h and monitored by TLC. The mixture was
evaporated under reduced pressure. Water (50 ml) was added to
the residue, and conc. HCl was added to adjust the pH to about 3.
The solution was filterated to yield the solid and dried. The yield of
compound 7 was 4.0 g (78%), with an m.p. >400 ꢁC. GC–MS (m/z):
[M]þ 298; 1H NMR (300 MHz, DMSO-d6, ppm): 12.61 (d, 2H, 1-NH
and 2-SH), 7.40 (dd, J ¼ 8.3, J ¼ 1.6, 1H, Bz-6-H), 7.29 (s, 1H, Bz-4-H),
7.21 (d, J ¼ 8.3, 1H, Bz-7-H).
7.5.6. Data for 2,20-di-[[(3-methyl-4-ethoxy)prid-2-
yl]methylenethio]-5,50-bis-1H,10H-benzimidazole (13)
Yield: 75%; m.p.: 125–128 ꢁC; 1H NMR (300 MHz, DMSO-d6,
ppm): 12.68 (1H, br s, Bz-NH), 8.24 (1H, d, J ¼ 5.6, Py-6-H), 7.69 (1H,
s, Bz-4-H), 7.52 (1H, d, J ¼ 8.3, Bz-7-H), 7.44 (1H, dd, J ¼ 8.3, J ¼ 1.2,
Bz-6-H), 6.94 (1H, d, J ¼ 5.7, Py-5-H), 4.71 (2H, s, SCH2), 4.11 (2H, q,
J ¼ 6.9, OCH2CH3), 2.21 (3H, s, Py-3-CH3), 1.35 (3H, t, J ¼ 6.9,
OCH2CH3); ESI-MS (m/z): 597.4 [M þ H]þ; IR (KBr, cmꢂ1): 3439,
1625, 1583, 1467, 1384, 1299, 1279, 1092, 809.
7.5. General process for the synthesis of compounds 8–17
7.5.7. Data for 2,20-di-[(prid-2-yl)methylenethio]-5,50-bis-1H,10H-
benzimidazole (14)
After a mixture of compound 7 (1.0 g, 3.36 mmol), ethanol
(30 ml), sodium hydroxide (1.0 g, 24.0 mmol), and water (10 ml)
was stirred for 30 min, substituted chloromethylpyridine hydro-
chloride (6.90 mmol) was added and heated to reflux for 8 h. The
mixture was evaporated under reduced pressure. Water (50 ml)
was added to the residue, and glacial acetic acid was added to
adjust the pH to about 5. The solution was filterated to yield the
solid and dried. Compounds 8–17 were purified by gel column
chromatography (fluent CHCl3:CH3OH ¼ 90:1).
Yield: 81%; m.p.: 91–94 ꢁC; 1H NMR (300 MHz, DMSO-d6, ppm):
12.68 (1H, br s, Bz-NH), 8.52 (1H, d, J ¼ 4.7, Py-6-H), 7.75 (1H, t,
J ¼ 7.5, Py-4-H), 7.60–7.72 (1H, m, Bz-4-H), 7.54 (1H, d, J ¼ 7.7, Py-3-
H), 7.40–7.60 (2H, m, Bz-6-H, Bz-7-H), 7.29 (1H, dd, J ¼ 7.2, J ¼ 5.1,
Py-5-H), 4.69 (2H, s, SCH2); ESI-MS (m/z): 481.4 [M þ H]þ; IR (KBr,
cmꢂ1): 3427, 1623, 1593, 1475, 1435, 1384, 1341, 1276, 1004, 804,
748, 585.
Compounds 8–17 were characterized as follows.
7.5.8. Data for 2,20-di-[(prid-3-yl)methylenethio]-5,50-bis-1H,10H-
benzimidazole (15)
7.5.1. Data for 2,20-di-[[(3,5-dimethyl-4-methoxy)prid-2-
yl]methylenethio]-5,50-bis-1H,10H-benzimidazole (8)
Yield: 74%; m.p.: 103–106 ꢁC; 1H NMR (300 MHz, DMSO-d6,
ppm): 12.70 (1H, br s, Bz-NH), 8.66 (1H, d, J ¼ 1.6, Py-2-H), 8.43 (1H,
dd, J ¼ 4.8, J ¼ 1.1, Py-6-H), 7.87 (1H, dt, J ¼ 7.8, J ¼ 1.6, Py-4-H), 7.67
(1H, s, Bz-4-H), 7.51 (1H, d, J ¼ 8.3, Bz-7-H), 7.43 (1H, dd, J ¼ 8.4,
J ¼ 0.8, Bz-6-H), 7.33 (1H, dd, J ¼ 7.8, J ¼ 4.8, Py-5-H), 4.59 (2H, s,
SCH2); ESI-MS (m/z): 481.4 [M þ H]þ; IR (KBr, cmꢂ1): 3423, 1623,
1479, 1430, 1384, 1343, 1278, 1126, 1030, 975, 803, 709, 668.
Yield: 80%; m.p.: 109–112 ꢁC; 1H NMR (300 MHz, DMSO-d6,
ppm): 12.68 (1H, br s, Bz-NH), 8.19 (1H, s, Py-6-H), 7.67 (1H, s, Bz-4-
H), 7.50 (1H, d, J ¼ 8.3, Bz-7-H), 7.42 (1H, dd, J ¼ 8.3, J ¼ 1.5, Bz-6-H),
4.71 (2H, s, SCH2), 3.72 (3H, s, OCH3), 2.30 (3H, s, Py-3-CH3), 2.21
(3H, s, Py-5-CH3); ESI-MS (m/z): 597.2 [M þ H]þ; IR (KBr, cmꢂ1):
3439, 1624, 1569, 1475, 1433, 1384, 1273, 1078, 1000, 805.
7.5.9. Data for 2,20-di-[(prid-4-yl)methylenethio]-5,50-bis-1H,10H-
benzimidazole (16)
7.5.2. Data for 2,20-di-[[(3,4-dimethoxy)prid-2-yl]methylenethio]-
5,50-bis-1H,10H-benzimidazole (9)
Yield: 87%; m.p.: 126–129 ꢁC; 1H NMR (300 MHz, DMSO-d6,
ppm): 12.69 (1H, br s, Bz-NH), 8.45 (2H, m, J ¼ 4.5, Py-2-H and Py-6-
H), 7.54 (1H, s, Bz-4-H), 7.45 (2H, m, Py-3-H and Py-5-H), 7.36 (1H,
d, J ¼ 8.3, Bz-7-H), 7.22 (1H, dd, J ¼ 8.3, J ¼ 1.4, Bz-6-H), 4.52 (2H, s,
SCH2); ESI-MS (m/z): 481.4 [M þ H]þ; IR (KBr, cmꢂ1): 3424, 3077,
1605, 1561, 1498, 1417, 1385, 1338, 1279, 1227, 1068, 1004, 977, 803,
754, 714, 665.
Yield: 89%; m.p.: 202–205 ꢁC; 1H NMR (300 MHz, DMSO-d6,
ppm): 12.68 (1H, br s, Bz-NH), 8.17 (1H, d, J ¼ 5.7, Py-6-H), 7.40–7.70
(3H, m, Bz-4-H, Bz-7-H, Bz-6-H), 7.09 (1H, d, J ¼ 5.7, Py-5-H), 4.69
(2H, s, SCH2), 3.89 (3H, s, OCH3), 3.82 (3H, s, OCH3); ESI-MS (m/z):
601.1 [M þ H]þ; IR (KBr, cmꢂ1): 3441, 1626, 1587, 1489, 1428, 1384,
1302, 1281, 1227, 1071, 995, 788.