O.M. Abdelhafez, et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
piperidine), 3.39 (3H, s, OCH3), 3.99 (2H, s, CH2-N) 6.19 (1H, d, H-4
furan), 6.66 (1H, d, H-3 benzofuran), 6.88 (1H, d, H-3 furan), 6.98 (1H,
d, H-2 benzofuran), 7.23–7.34 (2H, d, CH = CH, J = 5.0 Hz), , 9.52
(1H, s, OH, D2O exchangeable). 13C NMR (DMSO‑d6, δ, ppm): 13.99
(CH3), 27.67 (CH2-piperidine), 44.51, 52.84, 60.51, 98.85, 102.19,
109.23, 110.87, 112.43, 126.53, 131.53, 144.20, 150.76, 153.62,
156.37, 159.62, 164.70, 198.21 (C]O).
193.38 (C]S).
4.2.10. 4-(6-hydroxy-4-methoxy-7-(piperidin-1-ylmethyl)benzofuran-5-
yl)-6-(5-methylfuran-2-yl)pyrimidine-2(1H)-thione (17b)
Yield: 84%; mp: 194–196 ˚C; Anal. calcd. for C24H25N3O4S (451.54):
C, 63.84; H, 5.58; N, 9.31; S, 7.10. Found: C, 63.71; H, 5.39; N, 9.24; S,
7.00. 1H NMR (DMSO‑d6, δ, ppm): 1.45 (3H, s, CH3-furan), 2.24–2.43
(10H, m, CH2-piperidine), 3.73 (1H, s, NH, D2O exchangeable), 4.07
(3H, s, OCH3), 4.34 (2H, s, CH2-N), 6.06 (1H, s, H-5 pyrimidine), 6.72
(1H, d, H-4 furan), 7.18 (1H, d, H-3 furan), 7.39 (1H, s, H-3 benzo-
furan), 7.82 (1H, d, H-2 benzofuran), 10.91 (1H, s, OH, D2O ex-
changeable). 13C NMR (DMSO‑d6, δ, ppm): 14.17 (CH3), 24.01 (CH2-
piperidine), 43.84, 55.01, 59.51 (OCH3), 96.35, 98.52, 101.02, 111.86,
116.19, 129.19, 153.70, 155.37, 160.87, 163.37, 165.54, 170.37,
173.70, 176.54, 183.04 (C]S).
4.2.6. (E)-1-(6-hydroxy-4-methoxy-7-((4-methylpiperazin-1-yl)methyl)
benzofuran-5-yl)-3-(5-methylfuran-2-yl)prop-2-en-1-one (15c)
Yield: 80%; mp: 140–142 ˚C; Anal. calcd. for C23H26N2O5 (410.46):
C, 67.30; H, 6.38; N, 6.82. Found: C, 67.41; H, 6.48; N, 6.94. 1H NMR
(DMSO‑d6, δ, ppm): 2.22–2.32 (14H, m, CH3-furan, N-CH3 and CH2-
piprazine), 3.19 (3H, s, OCH3), 4.00 (2H, s, CH2-N), 6.39 (1H, d, H-4
furan), 6.88 (1H, d, H-3 benzofuran), 6.98 (1H, d, H-3 furan), 7.11 (1H,
d, H-2 benzofuran), 7.32–7.64 (2H, d, CH = CH, J = 4.0 Hz), 9.58 (1H,
s, OH, D2O exchangeable). 13C NMR (DMSO‑d6, δ, ppm): 14.03 (CH3),
43.51 (N-CH3), 50.84, 57.18, 61.35, 109.50, 110.52, 111.67, 111.89,
114.54, 120.26, 123.36, 145.03, 150.67, 151.66, 154.27, 155.37,
158.70, 177.70, 190.04 (C]O).
4.2.11. 4-(6-Hydroxy-4-methoxy-7-((4-methylpiperazin-1-yl)
methyl)
benzofuran-5-yl)-6-(5-methylfuran-2-yl)pyrimidine-2(1H)-thione (17c)
Yield: 85%; mp: above 300 ˚C; Anal. calcd. for C24H26N4O4S
(466.55): C, 61.78; H, 5.62; N, 12.01; S, 6.87. Found: C, 61.82; H, 5.73;
N, 12.30; S, 6.99. 1H NMR (DMSO‑d6, δ, ppm): 2.00 (3H, s, CH3-
furan), 2.14–2.45 (13H, m, CH2-piperazine, N-CH3 and CH2-N), 4.13
(1H, s, NH, D2O exchangeable), 4.27 (3H, s, OCH3), 6.09 (1H, s, H-5
pyrimidine), 6.94 (1H, d, H-4 furan), 7.26 (1H, d, H-3 furan), 7.35 (1H,
s, H-3 benzofuran), 8.12 (1H, d, H-2 benzofuran), 11.81 (1H, s, OH,
D2O exchangeable). 13C NMR (DMSO‑d6, δ, ppm): 13.17 (CH3), 48.84
(N-CH3), 53.68, 54.35, 64.68, 73.02, 95.35, 98.35, 122.86, 124.69,
125.53, 130.03, 134.36, 137.36, 141.70, 150.87, 156.70, 161.70,
167.04, 170.20, 179.21, 193.88 (C]S).
4.2.7. (E)-1-(6-Hydroxy-4-methoxy-7-(morpholinomethyl)benzofuran-5-
yl)-3-(5-methylfuran-2-yl)prop-2-en-1-one (15d)
Yield: 82%; mp: 1–1 ˚C; Anal. calcd. for C22H23NO6 (397.42): C,
66.49; H, 5.83; N, 3.52. Found: C, 66.56; H, 5.91; N, 3.68. 1H NMR
(DMSO‑d6, δ, ppm): 2.00–2.12 (11H, m, CH3-furan, CH2-morpholine),
4.39 (3H, s, OCH3), 4.49 (2H, s, CH2-N), 6.21 (1H, d, H-4 furan), 6.36
(1H, d, H-3 benzofuran), 6.84 (1H, d, H-3 furan), 6.95 (1H, d, H-2
benzofuran), 7.13–7.34 (2H, d, CH = CH, J = 5.0 Hz) , 10.52 (1H, s,
OH, D2O exchangeable). 13C NMR (DMSO‑d6, δ, ppm): 16.39 (CH3),
45.63 (CeN), 54.84, 55.31, 64.36, 98.91, 103.35, 110.23, 110.98,
114.56, 125.61, 133.42, 145.32, 152.67, 153.62, 153.97, 159.62,
165.11, 195.12 (C]O).
4.2.12. 4-(6-Hydroxy-4-methoxy-7-(morpholinomethyl)benzofuran-5-yl)-
6-(5-methylfuran-2-yl)pyrimidine-2(1H)-thione (17d)
Yield: 87%; mp: above 300 ˚C; Anal. calcd. for C23H23N3O5S
(453.51): C, 60.91; H, 5.11; N, 9.27; S, 7.07. Found: C, 60.99; H, 5.24;
N, 9.39; S, 7.19. 1H NMR (DMSO‑d6, δ, ppm): 1.55 (3H, s, CH3-furan),
2.29–2.53 (10H, m, CH2-morphline and CH2-N), 3.65 (1H, s, NH, D2O
exchangeable), 4.01 (3H, s, OCH3), 6.12 (1H, s, H-5 pyrimidine), 6.52
(1H, d, H-4 furan), 7.29 (1H, d, H-3 furan), 7.39 (1H, s, H-3 benzo-
furan), 7.74 (1H, d, H-2 benzofuran), 10.11 (1H, s, OH, D2O ex-
changeable). 13C NMR (DMSO‑d6, δ, ppm): 13.84 (CH3), 49.84, 56.51,
58.85 (OCH3), 68.51 (CH2-morpholine), 86.85, 94.85, 102.19, 110.36,
111.19, 112.19, 147.03, 154.03, 156.20, 165.37, 166.37, 169.04,
171.20, 182.21 (C]S).
General procedure for the preparation of different pyrimidines (16,
17a-d).
To a mixture of the selected chalcones (15a-d) (0.001 mol), urea
and/or thiourea (0.004 mol) in ethanol (25 ml), a solution of potassium
hydroxide (0.2 g) in water (2 ml) was added and the reaction mixture
was refluxed for 6 h, the alcohol was evaporated under vacuum till
dryness and the residue was acidified with dil.HCl. The formed solid
was filtered off, and crystallized from methanol to give the title com-
pounds.
4.2.8. 4-(7-Bromo-6-hydroxy-4-methoxybenzofuran-5-yl)-6-(5-
methylfuran-2-yl)pyrimidin-2(1H)-one (16)
4.2.13. Preparation of 2-amino-6-(7-bromo-6-hydroxy-4-methoxybenzofuran-
5-yl)-4-(5-methylfuran-2-yl)nicotinonitrile (18)
Yield: 87%; mp: 90–91 ˚C; Anal. calcd. for C18H13BrN2O5 (417.21):
C, 51.82; H, 3.14; N, 6.71. Found: C, 51.71; H, 3.01; N, 6.59.1H NMR
(DMSO‑d6, δ, ppm): 2.29 (3H, s, CH3-furan), 4.17 (3H, s, OCH3), 4.43
(1H, s, H-5 pyrimidine), 5.91 (1H, d, H-4 furan), 6.14 (1H, s, NH, D2O
exchangeable), 6.55 (1H, d, H-3 furan), 6.93 (1H, s, H-3 benzofuran),
8.41 (1H, d, H-2 benzofuran), 10.42 (1H, s, OH, D2O exchangeable).
13C NMR (DMSO‑d6, δ, ppm): 13.72 (CH3), 56.16 (OCH3), 84.64 (C-
Br), 109.19, 110.88, 113.97, 114.51, 119.21, 119.51, 146.28, 147.91,
151.87, 152.73, 155.03 (C]O), 156.98, 163.38, 165.27.
To the chalcone 15a (0.0025 mol) in ethanol (30 ml), malononitrile
(0.165 g , 0.0025 mol) and ammonium acetate (1.5 g, 0.002 mol) were
added. The reaction mixture was refluxed for 10–14 h. The obtained
solid was filtered off, washed with absolute ethanol and crystallized
from methanol.
Yield: 80%; mp: 80–82˚C; Anal. calcd. for C20H14BrN3O4 (440.25):
C, 54.56; H, 3.21; N, 9.54. Found: C, 54.72; H, 3.36; N, 9.71. 1H NMR
(DMSO‑d6, δ, ppm): 2.24 (3H, s, CH3-furan), 3.73 (2H, s, NH2, D2O
exchangeable), 4.07 (3H, s, OCH3), 5.22 (1H, d, H-4 furan), 6.31 (1H, d,
H-3 furan), 7.18 (1H, d, H-3 benzofuran), 7.39 (1H, s, CH-pyridine),
8.05 (1H, d, H-2 benzofuran), 10.92 (1H, s, OH, D2O exchangeable).
13C NMR (DMSO‑d6, δ, ppm): 14.51 (CH3), 60.06 (OCH3), 72.68,
93.22, 107.24, 110.46, 111.43, 112.71, 114.14, 115.43, 120.07 (CN),
143.95, 147.54, 149.89, 151.98, 152.75, 153.50, 155.25, 156.98,
162.68.
4.2.9. 4-(7-Bromo-6-hydroxy-4-methoxybenzofuran-5-yl)-6-(5-
methylfuran-2-yl)pyrimidine-2(1H)-thione (17a)
Yield: 86%; mp: 114–115 ˚C; Anal. calcd. for C18H13BrN2O4S
(433.28): C, 49.90; H, 3.02; N, 6.47; S, 7.40. Found: C, 49.94; H, 3.21;
N, 6.55; S, 7.57. 1H NMR (DMSO‑d6, δ, ppm): 2.11 (3H, s, CH3-furan),
3.53 (1H, s, NH, D2O exchangeable), 4.00 (3H, s, OCH3), 4.92 (1H, s, H-
5 pyrimidine), 5.96 (1H, d, H-4 furan), 6.39 (1H, d, H-3 furan), 7.12
(1H, s, H-3 benzofuran), 7.88 (1H, d, H-2 benzofuran), 11.29 (1H, s,
4.3. Biology
OH, D2O exchangeable). 13C NMR (DMSO‑d6, δ, ppm): 14.12 (CH3)
,
61.06 (OCH3), 110.19, 111.67, 111.86, 114.69, 119.21, 120.69,
123.36, 124.53, 131.70, 144.16, 145.70, 149.87, 155.03, 156.98,
4.3.1. Cell culture and cell proliferative assay
The human breast cancer MCF-7 cells were purchased from ATCC.
9