Synthesis of new pyrazole, triazole, and thiazolidine-pyrimido [4, 5-b] quinoline derivatives with potential antitumor activity

Article abstract of DOI:10.1007/s12272-012-0306-5

2-Hydrazinyltetrahydropyrimido [4, 5-b] quinolin-4(3H)-one (3) was prepared by desulfurization reaction of S- and N-dimethyl derivatives 2 with hydrazine hydrate. Reactions of (3) with malonitrile, carbondisulfide, potassium thiocyanate, phthalic anhydrid

Full text of DOI:10.1007/s12272-012-0306-5

Arch Pharm Res Vol 35, No 3, 437-445, 2012
DOI 10.1007/s12272-012-0306-5
Synthesis of New Pyrazole, Triazole, and Thiazolidine-Pyrimido
[4, 5-b] quinoline Derivatives with Potential Antitumor Activity
Ameen Ali Abu-Hashem1,2 and Ahmed S. Aly1
2
1Photochemistry Department (Heterocyclic Unit), National Research Center, 12622, Dokki, Giza, Egypt and Chemistry
Department, Faculty of Science, Jazan University, 2097 Jazan, Saudi Arabia
(Received June 8, 2011/Revised August 8, 2011/Accepted August 16, 2011)
2-Hydrazinyltetrahydropyrimido [4, 5-b] quinolin-4(3H)-one (
tion reaction of S- and N-dimethyl derivatives with hydrazine hydrate. Reactions of (
malonitrile, carbondisulfide, potassium thiocyanate, phthalic anhydride and aromatic alde-
hydes afforded 3, 5-di aminopyrazolopyrimido [4, 5-b] quinoline ( ), triazolotetrahydropyrim-
ido [4, 5-b] quinoline ( ), aminotriazolopyrimido [4, 5-b] quinoline ( ), aminophthalimidopyri-
mido [4, 5-b] quinoline ( ) and N-arylidene hydrazinepyrimido [4, 5-b] quinoline 8a-d, respec-
tively Furthermore, 8a-d reacted with mercaptoacetic acid gave the thiazolidinonepyrimido
3
) was prepared by desulfuriza-
2
3
) with
4
5
6
7
.
[4, 5-b] quinoline 9a-d, which afforded the thiazolotriazolopyrimido [4, 5-b] quinolinone 10a-d
upon treatment with ethanolic potassium hydroxide. The newly synthesized compounds were
characterized by elemental analyses, IR, 1H-NMR, 13C-NMR and mass spectrometer. The
investigated compounds were screened for their cytotoxicity. Compounds
potent antitumor activity.
4, 6 and 5 exhibited
Key words: Pyrazole, Triazole, Thiazolidinone, Pyrimido [4, 5-b] quinoline, Antitumor activity
matory and analgesic (El-Gazzar et al., 2009a, 2009b)
activities. Our research group has been interested in
INTRODUCTION
Cancer is a major worldwide health problem and developing a synthetic strategy for polyfunctionalized
previous researches have shown that pyrimidoquino- heterocycles (El-Gazzar et al., 2009a, 2009b) and in
line derivatives are among the potential cures for can- developing products with antitumor activity (Abu-
cer. Pyrimidoquinoline derivatives are of importance Hashem et al., 2010; Abu-Hashem et al., 2011; Gouda
due to their biological activities; especially, Pyrimido et al., 2011).
[4,5-b]quinoline derivatives have received much atten-
tion over the years due to their interesting pharmaco-
logical properties, including antimicrobial (El-Sayed
et al., 2004; Selvi et al., 2006; El-Gazzar et al., 2009c),
anti-inflammatory (El-Gazzar et al., 2009a, 2009b,
MATERIALS AND METHODS
General
All melting points are in oC and were determined on
2009c), anti-allergy (Althuis et al., 1979), antifolates Gallenkamp electric melting point apparatus. The IR
(Perner et al., 2003), anti-HIV infections (Dorjsuren et spectra were recorded potassium bromide (KBr) on a
1
al., 2006), antimalarial (Joshi et al., 2005; Joshi and Perkin–Elmer 1430 spectrometer. The H-NMR and
Viswanathan, 2006), antitumor (Singh et al., 1998; Ali 13C-NMR spectra (
δ
, ppm) were recorded on JEOL-
et al., 2007, 2008a, 2008b), antibacterial (Taguchi et ECA 500 and JEOL JNM-LA-400 FT NMR Spectrom-
al., 1992; Chen et al., 2001), antioxidant, anti-inflam- eters, and chemical shifts were expressed as
values
δ
against TMS as an internal standard. Mass spectra
were recorded on GCMS-QP 1000 EX (Shimadzu) (Gas
Chromatography-Mass spectrometer). Microanalytical
data were obtained at the Microanalytical Center at
Cairo University and National Research Center,
Egypt. The pharmacological evaluations were carried
Correspondence to: Ameen Ali Abu-Hashem, National Research
Center, Photochemistry Department, 12622, Dokki, Giza, Egypt
Tel: 2-12-521-1700, 966-59-136-3915, Fax: 2-2-3337-0931, 966-7-
324-5212
E-mail: aminaliabuhashem@yahoo.com
437

438
A. A. Abu-Hashem and A. S. Aly
out in the pharmacological unit, Department of Phar-
macognosy, Faculty of Pharmacy, Mansoura University,
Egypt.
(E)-2-(3, 5-diamino-1H-pyrazol-1-yl)-9-(4-methoxy-
benzylidene)-5-(4-methoxy phenyl)-3-methyl-6,
7, 8, 9-tetrahydropyrimido [4, 5-b] quinolin-4
(3H)-one (4)
A mixture of (3) (4.69 g, 10 mmol) and malononitrile
(0.66 g, 10 mmol) in absolute ethanol (35 mL) con-
taining a few drops of piperidine was refluxed for 7 h.
(E)-9-(4-methoxybenzylidene)-5-(4-methoxyphe-
nyl)-3-methyl-2-(methylthio)-6, 7, 8, 9-tetra hydro-
pyrimido [4, 5-b] quinolin-4 (3H)-one (2)
Ethanolic sodium ethoxide solution (10 mmol The separated solid was filtered, dried and recrystal-
sodium metal in 40 mL absolute ethanol) was added lized from ethanol. Yield 80%; m.p. 270-272oC; IR
each of
was continued for 30 min and the mixture was allowed 1H-NMR (DMSO-d6):
to cool to room temperature, and methyl iodide (2.82 2.25 (t, 2H, = 12.52 Hz, CH2), 2.75 (t, 2H,
1 (4.56 g, 10 mmol) under boiling. The heating (KBr): ν
/cm−1 = 3350 (NH2), 1680 (CO), 1630 (C=N).
δ
/ppm = 1.64-1.70 (m, 2H, CH2),
J
J
= 12.55
mL, 20 mmol) was added. The mixture was stirred Hz, CH2), 3.79, 3.81 (2s, 6H, 2OCH3), 4.23 (s, 3H, N-
under reflux for 5 h, then cooled to room temperature CH3), 6.351 (s, 1H, pyrazol H-4), 6.10, 6.60 (2brs, 4H,
and poured into cold water (100 mL). The solid pro- 2NH2, D2O exchangeable), 7.12-7.70 (m, 8H, Ar-H),
duct that precipitated was filtered off, washed with 8.10 (s, 1H, methine-H). MS (70 ev, %) m/z 537 (M+ +
water and crystallized from benzen to yield (
2
ν
) golden 2, 20.4), 536 (M+ + 1, 25.5), 535 (M+, 80), 505 (15), 469
/cm−1
(90), 454 (30), 439 (12), 425 (18), 319 (21), 201 (40),
δ/ppm = 133 (100). Anal. calcd for C30H29N7O3 (535.6): C, 67.27;
crystals. Yield 85%; m.p. 175-177oC; IR (KBr):
=
1
1695 (CO), 1620 (C=N). H-NMR (CDCl3):
1.66-1.70 (m, 2H, CH2), 2.27 (t, 2H,
J = 12.51 Hz, CH2), H, 5.46; N, 18.31%. Found: C, 67.20; H, 5.40; N,
2.65 (s, 3H, SCH3), 2.76 (t, 2H, = 12.55 Hz, CH2), 3.81, 18.26%.
J
3.84 (2s, 6H, 2OCH3), 4.22 (s, 3H, N-CH3), 7.11-7.66 (m,
8H, Ar-H), 8.12 (s, 1H, methine-H). MS (70 ev, %) m/z
487 (M+ + 2, 10.4), 486 (M+ + 1, 35.7), 485 (M+, 90).
Anal. calcd for C28H27N3O3S (485.6): C, 69.25; H, 5.60;
N, 8.65%. Found: C, 69.10; H, 5.55; N, 8.50%.
11-(4-methoxybenzylidene)-7-(4-methoxyphenyl)-
5-methyl-2-thioxo-8, 9, 10, 11-tetrahydro [1, 3,4]
triazolo [2', 3'- 2, 3] pyrimido [4, 5-b] quinolin-
6-one (5)
A mixture of (3) (4.69 g, 10 mmol) in ethanolic
potassium hydroxide solution (10 mmol in 30 mL
ethanol and 5 mL water) and CS2 (10 mmol) was
refluxed for 8 h. The reaction mixture was cooled,
(E)-2-hydrazinyl-9-(4-methoxybenzylidene)-5-(4-
methoxyphenyl)-3-methyl-6, 7, 8, 9-tetrahydro-
pyrimido [4, 5-b] quinolin-4 (3H)-one (3)
A suspension of (2) (4.85 g, 10 mmol) in hydrazine diluted with cold water (30 mL) and acidified with
hydrate (30 mL) was stirred under gentle reflux for 12 acetic acid. The solid was filtered, dried and recry-
h and the reaction mixture was allowed to cool to stallized from ethanol. Yield 80%; m.p. 210-212oC. IR
room temperature. The separated solid was filtered, (KBr):
washed with ethanol, dried as yellow crystals and NMR (DMSO-d6):
recrystallized from DMF. Yield 83%; m.p. 245-247oC; 2.25 (t, 2H,
= 12.50 Hz, CH2), 2.74 (t, 2H,
IR (KBr):
/cm−1 = 3205 (NH), 1675 (CO), 1625 (C=N). Hz, CH2), 3.80, 3.82 (2s, 6H, 2OCH3), 4.24 (s, 3H, N-
1H-NMR (DMSO-d6):
/ppm = 1.65-1.71 (m, 2H, CH2), CH3), 7.11-7.72 (m, 8H, Ar-H), 8.12 (s, 1H, methine-
2.26 (t, 2H, = 12.51 Hz, CH2), 2.74 (t, 2H, J = 12.56 H), 9.20 (brs., NH, D2O exchangeable). MS (70 ev, %)
ν
/cm−1 = 3320 (NH), 1684 (CO), 1635 (C=N). 1H-
δ
/ppm = 1.65-1.71 (m, 2H, CH2),
J
J
= 12.56
ν
δ
J
Hz, CH2), 3.78, 3.82 (2s, 6H, 2OCH3), 4.20 (s, 3H, N- m/z 513 (M+ + 2, 15.1), 512 (M+ + 1, 22.2), 511 (M+,
CH3), 7.10-7.68 (m, 8H, Ar-H), 8.11 (s, 1H, methine-H), 87). Anal. calcd for C28H25N5O3S (511.6): C, 65.74; H,
9.10, 11.30 (2brs, 3H, NH2 and NH D2O exchangeable). 4.93; N, 13.69%. Found: C, 65.60; H, 4.85; N, 13.60%.
13C-NMR (DMSO-d6):
δ/ppm = 28.4, 29.7, 30.8, 33.9,
55.8 (3C, CH2; 1C, CH3; 2C, OCH3), 114.2, 114.8, 119.7,
129.6, 130.0, 130.2, 130.3, 130.6, 133.4, 134.00, 152.5,
152.9, 155.9, 156.1, 158.2, 159.8 (Ar-C), 163.5 (CO,
amide). MS (70 ev, %) m/z 471 (M+ + 2, 14.5), 470 (M+
+ 1, 45.5), 469 (M+, 96). Anal. calcd for C27H27N5O3
2-amino-11-(4-methoxybenzylidene)-7-(4-meth-
oxyphenyl)-5-methyl-8, 9, 10, 11-tetrahydro [1,
3, 4] triazolo [2', 3' -2, 3] pyrimido [4, 5-b] quin-
olin-6-one (6)
A mixture of (3) (4.69 g, 10 mmol) and potassium
(469.5): C, 69.07; H, 5.80; N, 14.92%. Found: C, 69.10; thiocyanate (0.97 g, 10 mmol) was heated under reflux
H, 5.75; N, 14.82%.
in acetic acid for 10 h. The precipitate was collected by
filtration, dried and crystallized from dioxane as
yellow powder. Yield 83%; m.p. 310-212oC; IR (KBr):
ν
/cm−1 = 3355 (NH2), 1680 (CO), 1633 (C=N). 1H-NMR

Pyrimidoquinoline Derivatives & Antitumor Activities
439
(DMSO-d6):
δ/ppm = 1.67-1.73 (m, 2H, CH2), 2.26 (t, CH3), 7.11-7.85 (m, 13H, Ar-H), 8.10 (s, 1H, azomethine-
2H, = 12.51 Hz, CH2), 2.75 (t, 2H,
J
J = 12.55 Hz, CH2), H), 8.25 (s, 1H, methine-H), 10.10 (brs., 1H, NH, D2O ex-
3.81, 3.84 (2s, 6H, 2OCH3), 4.25 (s, 3H, N-CH3), 6.60 changeable). MS (70 ev, %) m/z 559 (M+ + 2, 6.9), 558
(brs., 2H, NH2, D2O exchangeable), 7.12-7.74 (m, 8H, (M+ + 1, 4.5), 557 (M+, 100). Anal. calcd for C34H31N5O3
Ar-H), 8.11 (s, 1H, methine-H). 13C-NMR (DMSO-d6): (557.6): C, 73.23; H, 5.6; N, 12.56%. Found: C, 73.15;
δ
/ppm = 23.9, 28.4, 30.2, 30.8, 55.8 (3C, CH2; 1C, CH3; H, 5.55; N, 12.60%.
2C, OCH3), 114.2, 114.8, 128.1, 129.6, 130.1, 130.2,
130.3, 131.1, 137.1, 143.1, 149.2, 153.1, 155.2, 155.9, (9E)-9-(4-methoxybenzylidene)-2-(2-(4-methoxy-
157.8, 159.6 (Ar-C), 163.6 (CO, amide). MS (70 ev, %) benzylidene) hydrazinyl)-5-(4-methoxyphenyl)-
m/z 496 (M+ + 2, 12.4), 495 (M+ + 1, 28.8), 494 (M+, 3-methyl-6, 7, 8, 9-tetrahydropyrimido [4, 5-b]
80.0). Anal. calcd for C28H26N6O3 (494.5): C, 68.00; H, quinolin-4 (3
5.30; N, 16.99%. Found: C, 68.20; H, 5.38; N, 16.85%.
H
)-one (8b)
Yellow powder, yield 81%; m.p. 312-314oC (ethanol);
IR (KBr):
/cm−1 = 3275 (NH), 1677 (CO), 1652 (C=N).
1H-NMR (DMSO-d6):
/ppm = 1.69-1.75 (m, 2H, CH2),
2.30 (t, 2H, = 12.51 Hz, CH2), 2.80 (t, 2H, = 12.55
ν
δ
(E)-2-(9-(4-methoxybenzylidene)-5-(4-methoxy-
phenyl)-3-methyl-4-oxo-3, 4, 6, 7, 8, 9-hexahy-
dropyrimido [4, 5-b] quinolin-2-ylamino) isoin-
doline-1, 3-Dione (7)
J
J
Hz, CH2), 3.82, 3.85, 3.90 (3s, 9H, 3OCH3), 4.24 (s, 3H,
N-CH3), 7.10-7.87 (m, 12H, Ar-H), 8.12 (s, 1H, azo-
A mixture of compound (3) (4.69 g, 10 mmol) and methine-H), 8.30 (s, 1H, methine-H), 10.30 (brs., 1H,
phthalic anhydride (10 mmol) in methanol (40 mL) NH, D2O exchangeable). MS (70 ev, %) m/z 589 (M+ +
was refluxed for 6 h. The solid obtained was filtered, 2, 16.2), 588 (M+ + 1, 14.7), 587 (M+, 90). Anal. calcd
dried and recrystallized from dioxane. Yield 80%; m.p. for C35H33N5O4 (587.6): C, 71.53; H, 5.66; N, 11.92%.
285-287oC. IR (KBr):
(CO-N-CO), 1680 (CO), 1645 (C=N). 1H-NMR (DMSO-
d6): /ppm = 1.69-1.75 (m, 2H, CH2), 2.27 (t, 2H,
12.52 Hz, CH2), 2.77 (t, 2H, = 12.56 Hz, CH2), 3.82, methoxybenzylidene)-5-(4-methoxyphenyl)-3-
3.85 (2s, 6H, 2OCH3), 4.24 (s, 3H, N-CH3), 7.12-7.88 methyl-6, 7, 8, 9-tetrahydropyrimido [4, 5-b]
(m, 12H, Ar-H), 8.11 (s, 1H, methine-H), 9.10 (brs., 1H, quinolin-4 (3 )-one 8c
NH, D2O exchangeable). MS (70 ev, %) m/z 601 (M+ + White powder, yield 80%; m.p. 212-214oC (methanol);
2, 1.9), 600 (M+ + 1, 2.5), 599 (M+, 95), 585 (14), 479 IR (KBr): /cm−1 = 3350-2650 (brs., OH, NH), 1677 (CO),
(16), 361 (26), 216 (35), 201 (29), 187 (27), 133 (100). 1652 (C=N). H-NMR (DMSO-d6):
Anal. calcd for C35H29N5O5 (599.6): C, 70.11; H, 4.87; (m, 2H, CH2), 2.28 (t, 2H, = 12.52 Hz, CH2), 2.78 (t,
= 12.57 Hz, CH2), 3.81, 3.84 (2s, 6H, 2OCH3),
ν
/cm−1 = 3310 (NH), 1790, 1735 Found: C, 71.5; H, 5.55; N, 11.85%.
δ
J
=
(9E)-2-(2-(4-hydroxybenzylidene)hydrazinyl)-9-(4-
J
H
(
)
ν
1
δ/ppm = 1.66-1.74
J
N, 11.68%. Found: C, 70.23; H, 4.77; N, 11.60%.
2H, J
4.23 (s, 3H, N-CH3), 7.12-7.87 (m, 12H, Ar-H), 8.14 (s,
1H, azomethine-H), 8.34 (s, 1H, methine-H), 9.30 (brs.,
1H, OH, D2O exchangeable), 10.40 (brs., 1H, NH, D2O
exchangeable). MS (70 ev, %) m/z 575 (M+ + 2, 9.8), 574
(M+ + 1, 18.5), 573 (M+, 80). Anal. calcd for C34H31N5O4
(573.6): C, 71.19; H, 5.45; N, 12.21%. Found: C, 71.12;
(9E)-2-(2-(p-sub)-benzylidenehydrazinyl)-9-(4-
methoxybenzylidene)-5-(4-methoxyphenyl)-3-
methyl-6, 7, 8, 9-tetrahydropyrimido [4, 5-b] qui-
nolin-4 (3H)-one (8a-d)
General procedure
A mixture of compound (3) (4.69 g, 10 mmol) in H, 5.41; N, 12.14%.
absolute ethanol (45 mL) and the appropriate aromatic
aldehyde (10 mmol) was refluxed for 6 h, concentrated (9E)-2-(2-(4-chlorobenzylidene) hydrazinyl)-9-(4-
to half the volume and left to cool. The precipitates so methoxybenzylidene)-5-(4-methoxyphenyl)-3-
obtained were recrystallized to give 8a
-
d
, respectively. methyl-6, 7, 8, 9-tetrahydropyrimido [4, 5-b]
quinolin-4 (3 )-one 8d
Yellow powder, yield 82%; m.p. 292-294oC (ethanol);
benzylidene)-5-(4-methoxy phenyl)-3-methyl-6, 7, IR (KBr):
/cm−1 = 3345 (NH), 1678 (CO), 1653 (C=N).
)- 1H-NMR (DMSO-d6):
/ppm = 1.65-1.73 (m, 2H, CH2),
2.28 (t, 2H, = 12.51 Hz, CH2), 2.79 (t, 2H, = 12.55
H
(
)
(9E)-2-(2-benzylidenehydrazinyl)-9-(4-methoxy-
ν
8, 9-tetrahydropyrimido [4, 5-b] quinolin-4 (3
H
δ
one (8a)
J
J
Brown powder, yield 82%; m.p. 275-277oC (methanol); Hz, CH2), 3.80, 3.83 (2s, 6H, 2OCH3), 4.25 (s, 3H, N-
IR (KBr):
1H-NMR (DMSO-d6):
2.28 (t, 2H, = 12.52 Hz, CH2), 2.78 (t, 2H,
Hz, CH2), 3.81, 3.84 (2s, 6H, 2OCH3), 4.23 (s, 3H, N- (M+ + 1, 10.2), 592 (M+, 83). Anal. calcd for C34H30ClN5O3
ν
/cm−1 = 3270 (NH), 1675 (CO), 1650 (C=N). CH3), 7.14-7.87 (m, 12H, Ar-H), 8.14 (s, 1H, azomethine-
/ppm = 1.68-1.74 (m, 2H, CH2), H), 8.34 (s, 1H, methine-H), 10.31 (brs., NH, D2O ex-
= 12.57 changeable). MS (70 ev, %) m/z 594 (M+ + 2, 11.6), 593
δ
J
J

440
A. A. Abu-Hashem and A. S. Aly
(592.1): C, 68.97; H, 5.11; N, 11.83%. Found: C, 68.9; 2-[2-(4-Hydroxyphenyl)-4-oxo-thiazolidin-3-yl-
H, 5.1; N, 11.76%.
amino]-9-(4-methoxybenzylidene)-5-(4-methoxy-
phenyl)-3-methyl-6, 7, 8, 9-tetrahydro-3
H-pyri-
mido [4, 5-b] quinolin-4-one (9c)
9-(4-Methoxybenzylidene)-5-(4-methoxyphenyl)-
3-methyl-2-(4-oxo-2-(sub)-phenyl-thiazolidin-3-
Yellow powder, yield 80%; m.p. 170-172oC (DMF); IR
(KBr):
(2CO), 1651 (C=N). 1H-NMR (DMSO-d6):
1.70 (m, 2H, CH2), 2.27 (t, 2H, = 12.52 Hz, CH2),
A mixture of each (8a-d) (10 mmol) and mercapto- 2.76 (t, 2H, J = 12.56 Hz, CH2), 3.80, 3.82 (2s, 6H,
ν
/cm−1 = 3355-2640 (brs., OH, NH), 1679, 1720
/ppm = 1.64-
ylamino) - 6, 7, 8, 9-tetrahydro -3
5-b] quinolin-4-one (9a-d)
General procedure
H-pyrimido [4,
δ
J
acetic acid (0.015 mol) was refluxed in dry benzene (40 2OCH3), 3.85-3.95 (2d, 2H, thiazolidinone CH2), 4.23
mL) using a dean stark water separator for 4-8 hours. (s, 3H, N-CH3), 6.13 (s, 1H, thiazolidinone H-2), 7.11-
Excess benzene was evaporated under reduced pres- 7.88 (m, 12H, Ar-H), 8.20 (s, 1H, methine-H), 9.50 (brs.,
sure and the resulting residue was triturated with 1H, OH, D2O exchangeable), 10.50 (brs., 1H, NH, D2O
saturated NaHCO3 solution. The solids so obtained exchangeable). MS (70 ev, %) m/z 649 (M+ + 2, 14.8),
were filtered, then washed with H2O, dried and recry- 648 (M+ + 1, 12.4), 647 (M+, 80). Anal. calcd for
stallized to give 9a
-
d
, respectively.
C36H33N5O5S (647.7): C, 66.75; H, 5.14; N, 10.81%.
Found: C, 66.70; H, 5.10; N, 10.77%.
9-(4-Methoxybenzylidene)-5-(4-methoxyphenyl)-3-
methyl-2-(4-oxo-2-phenylthiazolidin-3-ylamino)-6,
2-[2-(4-Chloro-phenyl)-4-oxo-thiazolidin-3-ylamino]-
7, 8, 9-tetrahydro-3H-pyrimido [4, 5-b] quinolin- 9-(4-methoxybenzylidene)-5-(4-methoxyphenyl)-3-
4-one (9a)
methyl- 6, 7, 8, 9-tetrahydro-3 -pyrimido [4, 5-b]
H
White powder, yield 82%; m.p. 137-139oC (dioxane); quinolin-4-one (9d)
IR (KBr):
ν
/cm−1 = 3290 (NH), 1680, 1715 (2CO), 1651 Yellow powder, yield 85%; m.p. 120-122oC (dioxane).
(C=N). H-NMR (DMSO-d6): /ppm = 1.66-1.72 (m, IR (KBr):
/cm−1 = 3292 (NH), 1685, 1718 (2CO), 1653
2H, CH2), 2.27 (t, 2H, = 12.52 Hz, CH2), 2.75 (t, 2H, (C=N). H-NMR (DMSO-d6): /ppm = 1.66-1.72 (m,
= 12.56 Hz, CH2), 3.80, 3.82 (2s, 6H, 2OCH3), 3.85- 2H, CH2), 2.30 (t, 2H, = 12.50 Hz, CH2), 2.77 (t, 2H,
3.95 (2d, 2H, thiazolidinone CH2), 4.24 (s, 3H, N-CH3), = 12.55 Hz, CH2), 3.80, 3.82 (2s, 6H, 2OCH3), 3.84-
1
δ
ν
1
J
δ
J
J
J
6.10 (s, 1H, thiazolidinone H-2), 7.11-7.87 (m, 13H, 3.94 (2d, 2H, thiazolidinone CH2), 4.24 (s, 3H, N-CH3),
Ar-H), 8.20 (s, 1H, methine-H), 10.20 (brs., 1H, NH, 6.11 (s, 1H, thiazolidinone H-2), 7.11-7.89 (m, 12H,
D2O exchangeable). MS (70 ev, %) m/z 633 (M+ + 2, Ar-H), 8.24 (s, 1H, methine-H), 10.21 (brs, NH, D2O
14.7), 632 (M+ + 1, 17.5), 631 (M+, 90). Anal. calcd for exchangeable). 13C-NMR (DMSO-d6):
C36H33N5O4S (631.7): C, 68.44; H, 5.27; N, 11.09%. 28.3, 30.7, 32.4, 55.9 (4C, CH2; 1C, CH3; 2C, OCH3),
δ
/ppm = 23.9, 24.9,
Found: C, 68.40; H, 5.20; N, 11.11%.
69.2, 114.3, 114.8, 119.9, 122.6, 126.9, 127.1, 127.9,
128.9, 130.4, 131.5, 132.4, 133.7, 136.5, 142.1, 143.4,
9-(4-Methoxy-benzylidene)-5-(4-methoxyphenyl)- 150.2, 153.4, 155.9, 159.3 (Ar-C), 163.8, 171.6 (2CO,
2-[2-(4-methoxy-phenyl)-4-oxo-thiazolidin-3-yl- amide, thiazolidinone). MS (70 ev, %) m/z 668 (M+ + 2,
amino]-3-methyl-6, 7, 8, 9-tetrahydro-3
H
-pyrimido 24.7), 667 (M+ + 1, 30.5), 666 (M+, 85), 555 (8), 454 (12),
[4, 5-b] quinolin-4-one (9b)
439 (17), 425 (15), 319 (24), 201 (28), 187 (48), 133 (100).
Brown powder, yield 70%; m.p. 190-192oC (methanol); Anal. calcd for C36H32ClN5O4S (666.2): C, 64.90; H, 4.84;
IR (KBr):
ν
/cm−1 = 3291 (NH), 1681, 1716 (2CO), 1650 N, 10.51%. Found: C, 64.75; H, 4.80; N, 10.46%.
(C=N). H-NMR (DMSO-d6): /ppm = 1.65-1.71 (m,
2H, CH2), 2.28 (t, 2H, = 12.50 Hz, CH2), 2.77 (t, 2H,
= 12.55 Hz, CH2), 3.8, 3.82, 3.84 (3s, 9H, 3OCH3),
1
δ
J
1-(p-sub-phenyl)-4-methyl-6-(4-methoxyphenyl)-
10-(4-methoxybenzylidene)-[1,3]-thiazolo [4',3' :
5'',1'']-[1,2,4]-triazolo[3'',4'' : 2,3]-7,8,9–trihydro-
pyrimido[4,5 – b]quinolin-5-one (10a-d)
General procedure
J
3.86-3.96 (2d, 2H, thiazolidinone CH2), 4.25 (s, 3H, N-
CH3), 6.12 (s, 1H, thiazolidinone H-2), 7.12-7.86 (m,
12H, Ar-H), 8.21 (s, 1H, methine-H), 10.23 (brs, 1H,
NH, D2O exchangeable). MS (70 ev, %) m/z 663 (M+ +
A mixture of compound (9a-d) (10 mmol) in ethanolic
2, 4.6), 662 (M+ + 1, 3.5), 661 (M+, 82). Anal. calcd for potassium hydroxide (10 mmol in 40 mL ethanol) was
C37H35N5O5S (661.7): C, 67.15; H, 5.33; N, 10.58%. refluxed for 6-9 h. The reaction mixture was cooled,
Found: C, 67.10; H, 5.30; N, 10.50%.
diluted with cold water (35 mL) and acidified with
hydrochloric acid. The solid that formed was filtered,
dried and recrystallized from proper solvent to give
10a-d, respectively.

Pyrimidoquinoline Derivatives & Antitumor Activities
441
1
4-methyl-6-(4-methoxyphenyl)-10-(4-methoxybenz- IR (KBr):
ν
/cm−1 = 1680 (CO), 1640 (C=N). H-NMR
/ppm = 1.65-1.71 (m, 2H, CH2), 2.28 (t,
= 12.52 Hz, CH2), 2.76 (t, 2H, = 12.56 Hz, CH2),
ylidene)-1-phenyl-[1,3]-thiazolo[4',3' : 5'',1'']-[1,2,4]- (DMSO-d6):
triazolo[3'',4'': 2,3]-7, 8, 9–trihydropyrimido[4,5 - 2H,
δ
J
J
b]quinolin-5-one (10a)
3.80, 3.81 (2s, 6H, 2OCH3), 4.12 (s, 1H, thiazolidine H-
Yellowish powder, yield 79%; m.p. 220-222oC (dioxane). 5), 4.24 (s, 3H, N-CH3), 4.94 (s, 1H, thiazolidine H-2),
1
IR (KBr):
(DMSO-d6):
= 12.52 Hz, CH2), 2.76 (t, 2H,
ν
/cm−1 = 1678 (CO), 1645 (C=N). H-NMR 7.15-7.91 (m, 12H, Ar-H), 8.22 (s, 1H, methine-H).13C-
δ/ppm = 1.65-1.71 (m, 2H, CH2), 2.27 (t, 2H, NMR (DMSO-d6):
δ/ppm = 24.1, 24.9, 32.6, 35.7, 55.9
= 12.56 Hz, CH2), (3C, CH2; 1C, CH3; 2C, OCH3), 65.7, 79.3, 112.1, 114.1,
J
J
3.82, 3.83 (2s, 6H, 2OCH3), 4.12 (s, 1H, thiazolidine H- 114.8, 122.7, 125.6, 126.8, 127.1, 128.1, 128.9, 130.1,
5), 4.25 (s, 3H, N-CH3), 4.98 (s, 1H, thiazolidine H-2), 131.4, 132.3, 138.9, 142.5, 144.1, 148.7, 151.1, 153.6,
7.12-7.88 (m, 13H, Ar-H), 8.22 (s, 1H, methine-H). MS 154.2, 155.9, 159.8 (Ar-C), 164.5 (CO, amide). MS (70
(70 ev, %) m/z 615 (M+ + 2, 20.2), 614 (M+ + 1, 35.1), ev, %) m/z 650 (M+ + 2, 35.8), 649 (M+ + 1, 47.5), 648
613 (M+, 83). Anal. calcd for C36H31N5O3S (613.7): C, (M+, 86), 537 (9), 523 (19), 442 (14), 321 (26), 203 (33),
70.45; H, 5.09; N, 11.41%. Found: C, 70.41; H, 5.14; N, 187 (37), 133 (100). Anal. calcd for C36H30ClN5O3S
11.55%.
(648.1): C, 66.71; H, 4.67; N, 10.80%. Found: C, 66.65;
H, 4.55; N, 10.75%.
1-(4-methoxyphenyl)-4-methyl-4-(4-methoxyphen-
yl)-10-(4-methoxybenzylidene)-[1, 3]-thiazolo [4',
3': 5'', 1'']-[1, 2, 4]triazolo[3'', 4'': 2, 3]-7, 8, 9–tri-
hydropyrimido [4, 5-b] quinolin-5-one (10b)
Pharmacological studies
The human carcinoma cancer cell lines KB, CNE2,
MGC-803 and MCF-7 supplemented from The National
Brown powder, yield 81%; m.p. 232-234oC (DMF); IR Cancer Institute, Cairo University, Egypt.
(KBr):
d6): /ppm = 1.66-1.72 (m, 2H, CH2), 2.29 (t, 2H,
12.50 Hz, CH2), 2.76 (t, 2H, = 12.55 Hz, CH2), 3.81,
ν
/cm−1 = 1679 (CO), 1644 (C=N). 1H-NMR (DMSO-
δ
J
=
The method used
The in vitro cytotoxicity of the synthesized compounds
J
3.82, 3.85 (3s, 9H, 3OCH3), 4.14 (s, 1H, thiazolidine H- against different cancer cell lines was assessed with
5), 4.26 (s, 3H, N-CH3), 4.96 (s, 1H, thiazolidine H-2), the MTT assay as described previously (Mosmann,
7.14-7.90 (m, 12H, Ar-H), 8.24 (s, 1H, methine-H). MS 1983; Skehan et al., 1990). The MTT assay is based on
(70 ev, %) m/z 645 (M+ + 2, 22.4), 644 (M+ + 1, 30.3), 643 the reduction of soluble 3-(4, 5-dimethyl-2-thiazolyl)-2,
(M+, 85). Anal. calcd for C37H33N5O4S (643.7): C, 69.03; 5-diphenyl-2
H-tetrazolium bromide (MTT) into a blue-
H, 5.17; N, 10.88%. Found: C, 69.12; H, 5.21; N, 10.80%. purple formazan product, mainly by mitochondrial
reductase activity inside living cells. The cells used in
1-(4-hydroxyphenyl)-4-methyl-6-(4-methoxyphen- the cytotoxicity assay were cultured in RPMI 1640
yl)-10-(4-methoxybenzylidene)-[1, 3]-thiazolo[4',3' medium supplemented with 10% fetal calf serum.
: 5'',1'']-[1, 2, 4]-triazolo [3'',4'' : 2,3]- 7, 8, 9–tri- Cells suspended in the medium (2Y' 104/mL) were
hydropyrimido[ 4, 5-b]quinolin-5-one (10c)
White powder, yield 80%; m.p. 262-264oC (dioxane); in a 5% CO2 incubator. After 12 h, the test sample (2
IR (KBr): L) was added to the cells (2Y' 104) in 96-well plates
/cm−1 = 3350-2655 (OH), 1678 (CO), 1645
(C=N). H-NMR (DMSO-d6):
/ppm = 1.65-1.70 (m, and cultured at 37oC for 3 days. The cultured cells
2H, CH2), 2.27 (t, 2H, = 12.50 Hz, CH2), 2.76 (t, 2H, were mixed with 20 L of MTT solution and incubated
= 12.55 Hz, CH2), 3.80, 3.81 (2s, 6H, 2OCH3), 4.12 (s, for 4 h at 37oC. The supernatant was carefully removed
1H, thiazolidine H-5), 4.25 (s, 3H, N-CH3), 4.95 (s, 1H, from each well and 100 L of DMSO was added to
plated in 96-well culture plates and incubated at 37oC
ν
µ
1
δ
J
µ
J
µ
thiazolidine H-2), 7.12-7.91 (m, 12H, Ar-H), 8.23 (s, each well to dissolve the formazan crystals that were
1H, methine-H), 9.80 (brs., OH, D2O exchangeable). formed by the cellular reduction of MTT. After mixing
MS (70 ev, %) m/z 631 (M+ + 2, 25.5), 630 (M+ + 1, with a mechanical plate mixer, the absorbance of each
40.2), 629 (M+, 80). Anal. calcd for C36H31N5O4S (629.7): well was measured by a microplate reader using a test
C, 68.66; H, 4.96; N, 11.12%. Found: C, 68.55; H, 4.88; wavelength of 570 nm. The results were expressed as
N, 11.77%.
the IC50, which is the concentration of a drug inducing
50% inhibition of cell growth of treated cells when
compared to the growth of control cells. Each experi-
1-(4-chlorophenyl)-4-methyl-6-(4-methoxyphenyl)-
10-(4-methoxybenzylidene)-[1, 3]-thiazolo [4', 3': ment was performed at least 3 times. There was good
5'', 1'']-[1, 2, 4]-triazolo[3'',4'' : 2, 3]-7, 8, 9– tri- reproducibility between replicate wells with standard
hydropyrimido[4, 5- b]quinolin-5-one (10d)
errors below 10%. The results are summarized in
Yellow powder, yield 82%, m.p. 182-184oC (methanol). Table I.

442
A. A. Abu-Hashem and A. S. Aly
Table I. Cytotoxic activity of pyrimido [4, 5-b] quinoline derivatives against human tumor cells
In vitro cytotoxicity IC50 (µM)
Compounds
MCF-7a
MGC-803a
CNE2a
KBa
1
>50
>50
>50
>50
2
3
4
5
6
7
8a
8b
8c
8d
9a
9b
9c
9d
10a
10b
10c
>50
>50
19.6 ± 2.5
23.2 ± 2.4
22.1 ± 2.1
>50
>50
>50
>50
49.8 ± 1.1
47.5 ± 1.2
12.9 ± 1.4
15.3 ± 1.2
14.1 ± 1.1
35.2 ± 1.3
45.2 ± 1.1
41.8 ± 1.5
43.4 ± 1.2
38.5 ± 1.2
32.4 ± 1.4
27.1 ± 1.3
29.5 ± 1.2
25.4 ± 1.1
22.5 ± 1.6
19.3 ± 1.3
20.2 ± 1.5
17.1 ± 1.4
12.8 ± 1.3
46.8 ± 1.6
13.8 ± 1.7
16.5 ± 1.4
15.2 ± 1.5
32.1 ± 1.4
44.9 ± 1.4
39.1 ± 1.2
42.9 ± 1.3
36.2 ± 1.6
30.2 ± 1.5
24.3 ± 1.4
27.6 ± 1.8
22.5 ± 1.1
20.3 ± 1.3
17.1 ± 1.5
19.2 ± 1.2
15.8 ± 1.7
13.7 ± 1.6
16.2 ± 1.2
20.1 ± 1.3
19.4 ± 1.4
38.4 ± 1.5
>50
>50
>50
>50
>50
43.4 ± 1.2
>50
41.5 ± 1.3
35.6 ± 1.4
27.8 ± 1.5
29.4 ± 1.6
25.6 ± 1.4
24.5 ± 1.1
20.8 ± 1.4
22.6 ± 1.5
18.9 ± 1.5
12.9 ± 1.2
44.2 ± 2.4
31.4 ± 2.2
33.9 ± 2.6
29.2 ± 2.3
28.1 ± 2.4
25.7 ± 2.6
26.8 ± 2.5
24.1 ± 2.5
14.5 ± 2.2
10d
5-Fluorouracil
aKB cells are drug-sensitive human oral carcinoma cells, CNE2 cells are drug-sensitive human nasopharyngeal
carcinoma cells, MGC-803 cells are drug-sensitive human gastric carcinoma cells and MCF-7 cells are drug-sensitive
human breast adenocarcinoma cells.
trihydropyrimido [4, 5-b] quinolin-5-one 10d] showed
the highest antitumor activity (potent cytotoxicity
RESULTS AND DISCUSSION
The new rings of pyrimido [4, 5-b] quinolin-4-one against cancer cell lines). Because these compounds
derivatives seem to be effective as antitumor since the and 10d) contained different functional groups
compounds [for examples, 2-(3, 5-diamino-1 -pyrazol- and new rings for example, two amino groups with
1-yl)-9-(4-methoxybenzylidene)-5-(4-methoxy phenyl)- pyrazole ring, thioxo with triazole ring, one amino with
3-methyl-tetrahydropyrimido [4, 5-b] quinolin-4(3 )- triazole ring and 4-Cl-phenyl with thiazol-triazole ring
one , 11-(4-methoxybenzylidene)-7-(4-methoxy phenyl)- which may be potentiate the effects of these new
5-methyl-2-thioxo-tetrahydro [1, 3, 4] triazolopyrimido compounds rather than the original ones.
[4, 5-b] quinolin-6-one , 2-amino-11-(4-methoxybenzy-
lidene)-7-(4-methoxyphenyl)-5-methyl-tetrahydro [1,3,
4] triazolo pyrimido [4, 5-b] quinolin-6-one and 1-(4-
(4, 5, 6
H
H
4
5
Chemistry
6
Alkylation of 9-arylidene-5-aryl-2-thioxo-2,3,6,7,8,9-
chloro phenyl)-4-methyl-6-(4-methoxyphenyl)-10-(4- hexahydro-1H-pyrimido[4,5-b]quinolin-4-one 1 (El-
methoxybenzylidene)-[1, 3] thiazolo [1, 2, 4] triazolo- Gazzar et al., 2009a, 2009b) using methyl iodide in
Scheme 1. Synthesis of 2-hydrazinyl-tetrahydropyrimido[4, 5-b]quinolin-4-one derivatives. Reagents and conditions:
compound
2 with hydrazine hydrate reflux for 12 h, 83% yield.

Pyrimidoquinoline Derivatives & Antitumor Activities
443
Scheme 2. Synthesis of 3, 5-diamino-pyrazole, triazole, amino-triazole, amino-phthalimido-pyrimido[4, 5-b]quinoline
derivatives. Reagents and conditions: compound with many reagents, for example, malononitrile, carbon disulfide,
3
potassium thiocyanate, and phthalic anhydride, refluxed for 6-10 h, 80-83% yield.
ethanolic potassium hydroxide yielded S,N-dimethyl good yield. In the 1H-NMR spectrum of the latter com-
derivative
hydrazine hydrate afforded 2-hydrazinyl derivative
The IR spectrum of compound showed absorption nolin-2-ylamino) isoindoline-1, 3-dione
bands at with phthalic anhydride in absolute
3205 cm−1, corresponding to NH-NH2 (cf. by reaction of
experimental and Scheme 1). methanol. Mass spectra of and showed molecular
Moreover, compound was treated with malonitrile ion peaks at m/z 511 (87%), 494 (80%) and 599 (100%),
to give (E)-2-(3,5-diamino-1 -pyrazol-1-yl)-9-(4-methoxy- respectively. The structures of the final products were
benzylidene)-5-(4-methoxyphenyl)-3-methyl-6,7,8,9- established by physical and spectral methods (cf.
tetrahydropyrimido[4,5-b] quinolin-4 (3 )-one . The experimental and Scheme 2).
IR spectrum of compound revealed the absence of Treatment of with aromatic aldehydes, namely,
2
. Desulfurization of compound
2
with pound, a broad peak appears at
exchangeable). 4-Oxo-hexahydropyrimido [4, 5-b] qui-
was obtained
δ 6.60 for NH2 (D2O
3.
3
7
ν
3
5,
6
7
3
H
H
4
4
3
the NH-NH2 band and absorption bands at
ν 3350 benzaldehyde, 4-methoxybenzaldehyde, 4-hydroxy-
1
cm− , corresponding to amino of the pyrazole ring, benzaldehyde and 4-chlorobenzaldehyde, yielded the
1
and in the H-NMR spectrum, a singlet appeared at corresponding Schiff bases (9E)-2-benzylidenehydrazin-
δ
6.351 for pyrazole H-4. On the other hand, compound yl)-9-(4-methoxybenzylidene)-5-(4-methoxy-phenyl)-3-
3
reacted with carbon disulfide in the presence of methyl-6, 7, 8, 9-tetra hydropyrimido[4, 5-b] quinolin-
1
ethanolic potassium hydroxide to yield the fused 2- 4(3
mercaptotriazole derivative
. In the 1H-NMR spectrum at
for , a singlet appears at 9.20 for NH in triazole 8.25 for methylenic-proton and a broad peak at 10.10
ring (D2O exchangeable). When compound was for NH (D2O exchangeable). Compounds 8a were
reacted with potassium thiocyanate in acetic acid, reacted with mercaptoacetic acid in dry benzene to
fused 2-aminotriazole derivative was obtained in yield thiazolidinone derivatives 9a . The IR spectra
H
)-one 8a
-
d
. H-NMR spectrum showed a singlet
5
δ
δ 8.10 for azomethine proton (N=CH), a singlet at δ
5
3
-d
6
-d

444
A. A. Abu-Hashem and A. S. Aly
Scheme 3. Synthesis of N-arylidenehydrazino, thiazolidinone, thiazolo-triazolo-pyrimido[4, 5-b] quinolinone derivatives.
Reagents and conditions: aromatic aldehyde derivatives, mercaptoacetic acid and ethanolic potassium hydroxide refluxed for
4-9 h, 70-85% yield.
of compounds 9a-d showed absorption bands at
1680, 1715 cm−1 corresponding to amide carbonyl and 10d showed moderate cytotoxicity against MGC-803
carbonyl thiazolidinone ring. Compounds 9a were (IC50 16.2, 19.4, 20.1, 18.9 M) and MCF-7a (IC50 19.6,
cyclized by refluxing in ethanolic potassium hydroxide, 22.1, 23.2, 24.1 M) cancer cell lines, respectively.
ν
lines (IC50 12.9, 13.8 µM); and compounds 4, 6, 5 and
-d
µ
µ
where the nitrogen atom attack on the carbonyl group However, the rest of the compounds showed weak
was followed by elimination of water molecule, to cytotoxicity activity. Based on the structure activity
afford fused 1-(p-sub-phenyl)-4-methyl-[1,3]-thiazolo relationship (SAR), the presence of 3, 5-diaminopyra-
[4',3' : 5'',1'']-[1,2,4]-triazolo[3'',4'' : 2,3]-7,8,9–trihydro zolo; 2-amino-1, 3, 4-triazolo; 1, 3, 4-triazolo and triazolo-
pyrimido[4,5 – b]quinolin-5-one 10a-d derivatives. IR thiazolidine moieties linked to pyrimido[4,5-b]quinoline
spectrum of 10a showed absorption bands at
ν
1678 enhanced the cytotoxicity activity as in compounds
and 10d
4,
cm−1 corresponding to the amide carbonyl group and
an absence of bands corresponding to carbonyl thiazo-
lidine ring. The 1H-NMR spectrum showed a singlet at
6,
5
.
ACKNOWLEDGEMENTS
δ
4.12 corresponding to thiazolidine H-5 and a singlet
at 4.98 corresponding to thiazolidine H-2. The H-,
1
The author wishes to express his most sincere thanks
13C-NMR spectra and mass spectra supported the to Prof. Dr. Farid Abd-Elraheem Badria (Department
suggested structures (cf. experimental and Scheme 3). of Pharmacognosy, Faculty of Pharmacy and Mansoura
University 35516, Egypt) for carrying out the biologi-
cal activity tests. The present work was supported by
the Department of Photochemistry (Heterocyclic unit);
Pharmacology evaluation
In vitro cytotoxicity
The results indicated that the pyrimidoquinoline Chemical Industries Research Division, National
group introduced to the structure improved the anti- Research Centre in Cairo, Egypt.
tumor activity since the compounds without pyrimido
[4, 5-b] quinolin-4-one group displayed very weak
antitumor activity against the tumor cells. As seen in
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