M. H. Hekal and F. S. M. Abu El-Azm
Vol 000
3325, 3141 (NH), 1718, 1684, 1660 (C═O). 1H-NMR
(DMSO-d6) δ (ppm): 10.49 (s, 1H, NH, exchangeable
with D2O), 9.79 (s, 1H, NH, exchangeable with D2O),
8.02–7.16 (m, 12H arom.), 4.25–3.95 (dd, 2H, CH2,
J = 22.2 Hz), 2.28 (s, 3H, CH3). MS m/z (%): 449
(M+; 4.54), 431 (46.47), 384 (7.17), 247 (64.05), 219
(37.05), 191 (31.98), 165 (87.90), 115 (44.93), 40 (100).
Anal. Calcd. for C23H19N3O5S (449.48): C, 61.46; H,
4.26; N, 9.35; S, 7.13. Found: C, 61.31; H, 4.33; N, 9.22;
acetate (1 g) in glacial acetic acid (20 mL) was refluxed
for 10 h. The deposited solid on hot was filtered off,
washed with ethanol, dried, and recrystallized from
dioxane to give 8 as pale yellow crystals, yield 56%, mp
290–292°C. IR (υ/cmꢀ1): 3310 (NH), 1686 (C═O), 1625
1
(C═N). H-NMR (DMSO-d6) δ (ppm): 10.9 (s, 1H, NH,
exchangeable with D2O), 9.04–7.43 (m, 8H arom.), 6.61
(s, 1H, C4─H). MS m/z (%): 302 (M+; 5.22), 277 (46.7),
234 (19.8), 190 (85.1), 179 (52), 115 (83.3), 90 (63.7),
77 (48). Anal. Calcd. for C17H10N4O2 (302.29): C, 67.55;
H, 3.33; N, 18.53. Found: C, 67.45; H, 3.29; N, 18.50.
S, 6.96.
N-Cyclohexyl-2-(1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)
benzamide 7d.
Recrystallized from petroleum ether
Method 2.
A mixture of compound 4 (2.63 g,
80–100°C as white crystals, mp 90–92°C. IR (υ/cmꢀ1):
3326 (NH), 2930, 2853 (aliph. CH2), 1723, 1677 (C═O).
1H-NMR (CDCl3) δ (ppm): 8.23–7.23 (m, 8H arom.),
5.85 (s, 1H, NH, exchangeable with D2O), 4.35–4.12
(dd, 2H, CH2, J = 22 Hz), 3.66 (m, 1H, CHcyclohexane),
1.65–1.07 (m, 10H, CH2cyclohexane). MS m/z (%): 362
(M+; 8.60), 264 (100), 263 (37.25), 236 (89.37), 208
(18.75), 90 (46.17), 77 (11.88). Anal. Calcd. for
C22H22N2O3 (362.42): C, 72.91; H, 6.12; N, 7.73.
10 mmol), semicarbazide hydrochloride (1.11 g,
10 mmol), and anhydrous sodium acetate (1 g) was
exposed to MW at 800 W for 3 min. After cooling, the
reaction mixture was treated with boiling water and the
solid formed was filtered, dried, and recrystallized from
dioxane to give 8 as pale yellow crystals, yield 85%
(identity mp mixed mp, TLC, and IR).
Synthesis of 6H-isoquinolino[2,3-a]quinazoline-5,12-dione
9. Method 1.
A mixture of compound 4 (2.63 g,
Found: C, 73.00; H, 5.95; N, 7.66.
10 mmol) and ammonium acetate (10 g) was fused in an
oil bath at 170°C for 1 h. The deposited solid on hot was
filtered off, washed with water for several times, dried,
and recrystallized from DMF to give 9 as yellow crystals,
yield 78%, mp > 320°C. IR (υ/cmꢀ1): 3148 (NH), 1674
2-(1,3-Dioxo-3,4-dihydroisoquinolin-2(1H)-yl)-N-phenylbenzamide
7e. Recrystallized from dioxane as pale yellow crystals,
mp 251–253°C. IR (υ/cmꢀ1): 3276 (NH), 1721, 1674
1
(C═O). H-NMR (DMSO-d6) δ (ppm): 10.17 (s, 1H, NH,
exchangeable with D2O), 8.07–6.61 (m, 13H arom.),
4.34–4.02 (dd, 2H, CH2, J = 22.5 Hz). Anal. Calcd. for
C22H16N2O3 (356.37): C, 74.15; H, 4.53; N, 7.86. Found:
C, 74.03; H, 4.42; N, 7.79.
2-(1,3-Dioxo-3,4-dihydroisoquinolin-2(1H)-yl)-N-(2-mercaptophenyl)
1
(C═O). H-NMR (DMSO-d6) δ (ppm): 11.83 (s, 1H, NH,
exchangeable with D2O), 9.27–7.31 (m, 8H arom.), 6.21
(s, 1H, C7─H). Anal. Calcd. for C16H10N2O2 (262.26): C,
73.27; H, 3.84; N, 10.68. Found: C, 73.31; H, 3.81; N,
10.65.
benzamide 7f.
Recrystallized from ethanol as yellow
Method 2.
A mixture of compound 4 (2.63 g,
crystals, mp 124–126°C. IR (υ/cmꢀ1): 3358 (NH), 1721,
1682 (C═O). 1H-NMR (DMSO-d6) δ (ppm): 10.38 (s,
1H, NH, exchangeable with D2O), 8.08–6.42 (m, 12H
arom.), 5.53 (s, 1H, SH, exchangeable with D2O),
4.33–4.055 (dd, 2H, CH2, J = 22.5 Hz). Anal. Calcd. for
C22H16N2O3S (388.44): C, 68.02; H, 4.15; N, 7.21; S,
10 mmol) and ammonium acetate (10 g) was exposed to
MW at 900 W for 4 min. After cooling, the reaction
mixture was treated with boiling water and the solid
formed was filtered, dried, and recrystallized from DMF
to give 9 as pale yellow crystals, yield 93% (identity mp
mixed pm, TLC, and IR).
8.25. Found: C, 67.94; H, 4.01; N, 7.18; S, 8.23.
Pharmacological activity. Cytotoxicity assay.
The
2-(1,3-Dioxo-3,4-dihydroisoquinolin-2(1H)-yl)-N-(4-sulfamoylphenyl)
benzamide 7g. Recrystallized from dioxane as pale yellow
cytotoxic activity of 13 compounds was tested against
three human tumor cell lines, namely, hepatocellular
carcinoma (liver) HePG-2, colon cancer HCT-116, and
mammary gland (breast) MCF-7. The cell lines were
obtained from the ATCC via the Holding Company for
Biological Products and Vaccines (Cairo, Egypt).
5-Fluorouracil was used as a standard anticancer drug
for comparison. The reagents used were RPMI-1640
medium, MTT, DMSO, and 5-fluorouracil (Sigma Co.,
St. Louis, MO, USA) and fetal bovine serum (GIBCO,
Paisley, UK).
crystals, mp 322–324°C. IR (υ/cmꢀ1): 3371, 3303, 3259
1
(NH, NH2), 1719, 1670 (C═O). H-NMR (DMSO-d6) δ
(ppm): 10.70 (s, 1H, NH, exchangeable with D2O), 8.04–
7.40 (m, 12H arom.), 7.20 (s, 2H, NH2, exchangeable
with D2O), 4.34–4.16 (dd, 2H, CH2, J = 21 Hz). MS
m/z (%): 435 (M+; 1.73), 421 (1.52), 364 (8.99), 278
(19.40), 265 (89.64), 237 (100), 125 (96.12), 90 (86.95).
Anal. Calcd. for C22H17N3O5S (435.45): C, 60.68; H,
3.93; N, 9.65; S, 7.36. Found: C, 60.55; H, 4.09; N, 9.47;
S, 7.22.
The different cell lines [34,35] mentioned in the
preceding texts were used to determine the inhibitory
effects of compounds on cell growth by using the MTT
assay. This colorimetric assay is based on the conversion
Synthesis of 9H-isoquinolino[2,3-a][1,2,4]triazolo[1,5-c]
quinazoline-2,9(1H)-dione 8. Method 1.
A mixture of
(2.63 g, 10 mmol), semicarbazide
hydrochloride (1.11 g, 10 mmol), and anhydrous sodium
compound
4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet