In vitro cytotoxic evaluation of some new heterocyclic sulfonamide derivatives

Article abstract of DOI:10.1002/jhet.619

Sulfonamide-bearing compounds posses many types of biological activities and have been recently reported to show substantial antitumor activity in vitro and/or in vivo. There are a variety of mechanisms for the anticancer activity, and the most prominent

Full text of DOI:10.1002/jhet.619

May 2011
In Vitro Cytotoxic Evaluation of Some New Heterocyclic
Sulfonamide Derivatives
563
Mostafa M. Ghorab,a* Mansour S. Al-Said,a and Ebaa M. El-Hossaryb
aMedicinal, Aromatic and Poisonous Plants Research Center (MAPPRC), College of Pharmacy,
King Saud University, Riyadh 11451, Saudi Arabia
bDepartment of Drug Radiation Research, National Center for Radiation Research and Technology,
Atomic Energy Authority, Cairo, Egypt
*E-mail: mmsghorab@yahoo.com
Received June 20, 2010
DOI 10.1002/jhet.619
Published online 22 February 2011 in Wiley Online Library (wileyonlinelibrary.com).
Sulfonamide-bearing compounds posses many types of biological activities and have been recently
reported to show substantial antitumor activity in vitro and/or in vivo. There are a variety of mecha-
nisms for the anticancer activity, and the most prominent mechanism is the inhibition of carbonic anhy-
drase isozymes. This work reports the synthesis of some new quinoline, pyrimido[4,5-b]quinoline and
3,1-oxazinoquinoline derivatives bearing a sulfonamide moiety. All the newly synthesized compounds
were evaluated for their in vitro anticancer activity against Ehrlich ascites carcinoma cells. Compounds
10, 13, and 26 were the most active compounds with IC50 values of 6.1 lM, 6.8 lM, and 6.4 lM,
respectively, and exhibited better activities than the reference drug doxorubicin (IC50 ¼ 68.1 lM).
J. Heterocyclic Chem., 48, 563 (2011).
INTRODUCTION
activity [17–19]. In the light of these facts, and as a
continuation of our previous reported work [20,21], we
planned to synthesize a novel series of quinoline and
pyrimido[4,5-b]quinoline derivatives bearing a sulfona-
mide moiety, to study their structure activity relationship
and hoping that the new compounds might show signifi-
cant anticancer activity.
Sulfonamides posses many types of biological activ-
ities and many of them are widely used in therapy as
antibacterial [1], hypoglycemic [2], diuretic [3,4], anti-
carbonic anhydrase [3,5], and antithyroid agents [6].
Recently, a host of structurally novel sulfonamide deriv-
atives have been reported to show substantial antitumor
activity in vitro and/or in vivo [7–11].
It has been known that aryl/heteroaryl sulfonamides
may act as antitumor agents through a variety of mecha-
nisms such as cell cycle perturbation in the G1 phase, dis-
ruption of microtubule assembly, angiogenesis inhibition,
and functional suppression of the transcriptional activator
NF-Y. Moreover, following an extensive evaluation,
numerous sulfonamides were found to act as carbonic
anhydrase (CA) inhibitors [12–15]. The most prominent
mechanism was the inhibition of CA isozymes [16].
On the other hand, quinoline derivatives are important
biologically active compounds showing anticancer
RESULTS AND DISCUSSION
Chemistry. Several compounds were designed with
the aim of exploring their antitumor activity (Schemes
1–4). Enaminone 3 was obtained from condensation of
1,3-cyclohexandione 1 with sulfanilamide 2. The struc-
ture of compound 3 was supported by elemental analysis
and spectral data. IR spectrum of compound 3 revealed
the presence of bands at 3354, 3263, and 3210 cmꢀ1
(NH, NH2), at 2940, 2870 cmꢀ1 (CH aliph.), and 1612
1
cmꢀ1 (C¼¼O). Also, the H-NMR spectrum in DMSO-d6
C
V
2011 HeteroCorporation

564
M. M. Ghorab, M. S. Al-Said, and E. M. El-Hossary
Vol 48
Scheme 1
indicated the presence of a signal at 9.0 ppm which
could be assigned to NH of enaminone 3. Treatment of
enaminone 3 with 2,4-dichlorobenzylidenemalononitrile
4 in the presence of a catalytic amount of triethylamine
resulted in cycloaddition affording compound 6, via the
formation of the intermediate Michael type product 5,
followed by intramolecular cyclization (Scheme 1).
Compound 6 was unambiguously synthesized by
another route involving one-pot condensation of the 2,4-
dichlorobenzaldehyde, malononitrile, and enaminone 3
in a molar ratio (1:1:1) in refluxing ethanol containing
triethylamine as catalyst. In this case, formation of com-
pound 6 illustrated in terms of initial condensation of
the aldehyde with malononitrile affording the activated
arylidenemalononitrile 4, followed by addition of the
enaminone 3 to the arylidenemalononitrile 4. IR spec-
trum of compound 6 revealed bands at 3464, 3347 cmꢀ1
(NH2), 2171 cmꢀ1 (CBN), 1634 cmꢀ1 (C¼¼O), 1374,
1189 cmꢀ1 (SO2). The mass spectrum of 6 revealed a
molecular ion peak m/z at 489 (Mþ, 1.8%), with a base
peak m/z at 73 (100), (Scheme 1).
Refluxing compound 6 in formic acid caused cyclization
via elimination of two moles of water to give the pyri-
midoquinoline derivative 8. Its IR spectrum showed the
absence of CBN band, which confirms the cyclization
and the formation of pyrimido[4,5-b]quinoline system.
Reaction of compound 6 with acetic anhydride and/or
trifluoroacetic anhydride for 5 min furnished the monoacyl
derivative 9 and 12, respectively. On the other hand, when
compound 6 was reacted with acetic anhydride for long
time (20 h), the corresponding diacetyl derivative 10 was
obtained instead of the cyclic system pyrimidoquinoline
derivative 11 on the basis of elemental analysis and IR
spectrum which showed the presence of (CBN) band. On
the other hand, when compound 6 was reacted with tri-
fluoroacetic anhydride for long time (20 h), the correspond-
ing cyclic system pyrimidoquinoline derivative 13 was
obtained instead of 14 on the basis of elemental analysis
and IR spectrum which showed the disappearance of CBN
band (Scheme 3). IR spectra of compounds 9, 10, and 12
revealed the presence of CBN band. 1H-NMR spectrum of
10 showed a signal at 2.4 ppm for two acetyl groups.
Interaction of compound 6 with formamide caused
cyclization to give the pyrimidoquinoline derivative 7
(Scheme 2). Its IR spectrum exhibited the absence of
CBN band, which confirms the cyclization and the
formation of the pyrimido[4,5-b]quinoline system.
The reactivity of compound 6 toward some carbonyl
compounds in different conditions was also discussed.
Thus, reaction of compound 6 with aromatic aldehydes in
acetic acid yielded Schiff’s bases 15–38. The structures
of compounds 15–38 were confirmed by elemental
Journal of Heterocyclic Chemistry
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In Vitro Cytotoxic Evaluation of Some New Heterocyclic Sulfonamide Derivatives
565
Scheme 2
1
analyses, IR, H-NMR, and mass spectral data (Scheme
In vitro anticancer activity. Doxorubicin, the refer-
ence drug, used in this study is one of the most effective
antitumor agents used to produce regressions in acute
leukemia’s, Hodgkin’s disease, and other lymphomas.
The relationship between survival ratio and drug con-
centration was plotted to obtain the survival curve of
Ehrlich ascites carcinoma cells (EAC). The response
parameter calculated was IC50 value (Table 1), which
corresponds to the compound concentration causing
50% mortality in net cells.
4). IR spectra of compounds 15–38 exhibited the pres-
1
ence of CBN band. Also, H-NMR spectra of compounds
15–38 revealed the presence of signal for N¼¼CH.
From the literature survey, it was found that ZnCl2 is
an effective catalyst in organic reactions for the prepara-
tion of 3,1-oxazine derivatives. The use of anhydrous
AlCl3, CuCl, CuCl2, TiCl4, and p-toluenesulfonic acid
was much less effective [22]. Thus, interaction of com-
pound 6 with 3-hydroxybenzaldehyde in dimethylforma-
mide containing anhydrous ZnCl2 yielded the corre-
sponding 3,1-oxazinoquinoline derivative 40. Its IR
spectrum exhibited the absence of CBN band and the
presence of characteristic bands at 3365, 3270, and 3220
cmꢀ1 (NH, NH2), and 1640 cmꢀ1 (C¼¼O). 1H-NMR
spectrum of 40 revealed signals at 4.5 ppm for (CH pyr-
idine), 6.1 ppm for (CH oxazine) and 8.1, 8.2 ppm for
two NH groups. Its mass spectrum exhibited a molecular
ion peak m/z at 611 with a base peak at 44 (100).
From these results (Table 1), it can be seen that the
diacetyl quinoline derivative 10 (IC50 ¼ 6.1 lM), pyri-
midoquinoline derivative 13 having trifluoromethyl at
position-2 (IC50 ¼ 6.8 lM), compounds 7, 8, 9, 20, 22,
25, 26, 28, 29, 31, 33, 34, and 36 IC50 (19.3, 16, 23.5,
16.8, 16.5, 10.4, 6.4, 9.2, 8.9, 9.5, 22, 20.6, and 11.2
lM) showed significant cytotoxic activities which were
even higher than that of the reference drug doxorubicin
(IC50 ¼ 68.1 lM).
The formation of 3,1-oxazinoquinoline derivative 40
can be explained by (Scheme 4). The attack of the amino
group of 6 onto the carbonyl carbon atom of 3-hydroxy-
benzaldehyde, gave intermediate 39 and the product 40
was obtained through subsequent cyclization by attack of
the oxygen atom onto the nitrile group of 6 [23].
Also, the diacetyl quinoline derivative 10 (IC50 ¼ 6.1
lM) is the most active compound compared with the
other tested compounds and the reference drug Doxoru-
bicin. In the meantime, the diacetyl quinoline derivative
10 is more active than the monoacetyl quinloine deriva-
tive 9 (IC50 ¼ 23.5 lM).
Journal of Heterocyclic Chemistry
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566
M. M. Ghorab, M. S. Al-Said, and E. M. El-Hossary
Vol 48
Scheme 3
60G F254; Merck, Germany) were used for thin-layer chroma-
tography, dichloromethane/methanol (9.5:0.5) mixture was
used as a developing solvent system, and the spots were
visualized by ultraviolet light and/or iodine. Infrared spectra
were recorded in KBr disks using IR-470 Shimadzu spectrom-
eter (Shimadzu, Tokyo, Japan). 1H-NMR spectra (in DMSO-
d6) were recorded on Bruker AC-300 Ultra Shield NMR spec-
trometer (Bruker, Flawil, Switzerland, d ppm) at 300 MHz,
using TMS as internal Standard and peak multiplicities are
designed as follows: s, singlet; d, doublet; t, triplet; m, multip-
Additionally, compound 26 bearing 3-nitrophenyl at
position-2 (IC50 ¼ 6.4 lM) is the most potent compound
in the Schiff’s bases series and exhibited a higher activity
than the 2-nitrophenyl derivative, 25 (IC50 ¼ 10.4 lM).
The pyrimidoquinoline derivative 13 having trifluoro-
methyl at position-2 (IC50 ¼ 6.8 lM) revealed higher
activity than the pyrimidoquinoline derivative 7 contain-
ing the amino group at position-4 (IC50 ¼ 19.3 lM).
It was found that Schiff’s base 34 carrying 2-furyl-5-
methyl at position-2 (IC50 ¼ 20.6 lM) exhibited higher
activity than the unsubstituted furan 33 at the same posi-
tion (IC50 ¼ 22 lM).
let. Electron impact mass spectra were recorded on
a
Shimadzu GC-MS-QP 5000 instrument (Shimadzu, Tokyo,
Japan). Elemental analyses were performed on Carlo Erba
1108 Elemental Analyzer (Heraeus, Hanau, Germany).
On the other hand, it is clear from the results that the
quinoline derivative 6 and Schiff’s bases 16, 23, and 38
(IC50 ¼ 51.1, 50.6, 50.7, and 53.6 lM) are nearly as active
as doxorubicin. Substituting Schiff’s bases with phenyl 15,
4-tolyl 17, 4-methoxyphenyl 19, 4-methoxynaphthyl 32,
and/or 3-pyridyl 37 exhibited a moderate activity but less
than the reference drug doxorubicin. Finally, compounds
21, 24, 27, and 35 showed no activity.
4-(3-Oxocyclohex-1-enylamino)benzenesulfonamide
3. A
mixture of 1,3-cyclohexanedione 1 (1.12 g, 0.01 mol) and
sulfanilamide 2 (1.72 g, 0.01 mol) in ethanol (30 mL) was
refluxed for 5 h. The reaction mixture was cooled and then
poured onto cold water and the obtained solid was crystallized
from ethanol to give 3. Yield, 92%; m.p. 236–238ꢁC; IR (KBr,
cmꢀ1): 3354, 3263, 3210 (NH, NH2), 3032 (CH arom.), 2940,
2870 (CH aliph.), 1612 (C¼¼O), 1360, 1184 (SO2). 1H-NMR
(DMSO-d6) d: 1.05–1.9 (m, 6H, 3CH2), 5.5 (s, 1H, CH), 7.0–
7.8 (m, 6H, Ar-H þ SO2NH2), 9.0 (s, 1H, NH). Anal. Calcd.
for C12H14N2O3S (266.32): C, 54.12; H, 5.30; N, 10.52.
Found: C, 54.32; H, 5.53; N, 10.33.
EXPERIMENTAL
4-(2-Amino-3-cyano-4-(2,4-dichlorophenyl)-5-oxo-5,6,7,8-
tetrahydroquinolin-1(4H)-yl)benzenesulfonamide 6.
Chemistry. Melting points (ꢁC, uncorrected) were deter-
mined in open capillaries on a Gallenkemp melting point
apparatus (Sanyo Gallenkemp, Southborough, UK) and were
uncorrected. Precoated silica gel plates (silica gel 0.25 mm,
Method
A. A mixture of enaminone (2.66 g, 0.01 mol) and
3
2,4-dichlorobenzylidinemalononitrile 4 (2.23 g, 0.01 mol) in
ethanol (20 mL) containing three drops of triethylamine was
Journal of Heterocyclic Chemistry
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In Vitro Cytotoxic Evaluation of Some New Heterocyclic Sulfonamide Derivatives
567
Scheme 4
refluxed for 6 h. The reaction mixture was filtered while
hot, and the solid obtained was crystallized from dioxane to
give 6.
Method B. A solution of enaminone 3 (2.66 g, 0.01 mol),
2,4-dichlorobenzaldehyde (1.75 g, 0.01 mol), and malononitrile
(0.66 g, 0.01 mol) in absolute ethanol (30 mL) containing
three drops of triethylamine was refluxed for 6 h. The obtained
solid after concentration was filtered and crystallized from
ethanol to give 6.
and then poured onto cold water, and the obtained solid was
crystallized from dioxane to give 7. Yield, 86%; m.p. >
320ꢁC; IR (KBr, cmꢀ1): 3270, 3188 (NH2), 3064 (CH arom.),
2957, 2880 (CH aliph.), 1640 (C¼¼O), 1590 (C¼¼N), 1380,
1
1158 (SO2), 798 (CACl). H-NMR (DMSO-d6) d: 1.3–2.6 (m,
6H, 3CH2), 4.4 (s, 1H, CH), 6.7 (s, 2H, NH2), 6.9–7.8 (m, 9H,
Ar-H þ SO2NH2). MS m/z (%): 516 [Mþ] (4.1), 43 (100).
Anal. Calcd. for C23H19Cl2N5O3S (516.40): C, 53.49; H, 3.71;
N, 13.56. Found: C, 53.73; H, 3.52; N, 13.88.
Yield, 90%; m.p. 291–293ꢁC; IR (KBr, cmꢀ1): 3464, 3347
(NH2), 3064 (CH arom.), 2957, 2860 (CH aliph.), 2171
(CBN), 1634 (C¼¼O), 1374, 1189 (SO2), 706 (CACl). 1H-
NMR (DMSO-d6) d: 1.8–2.2 (m, 6H, 3CH2), 4.9 (s, 1H, CH),
5.4 (s, 2H, NH2), 7.1–7.9 (m, 9H, Ar-H þ SO2NH2). MS m/z
(%): 489 [Mþ] (1.8), 73 (100). Anal. Calcd. for
C22H18Cl2N4O3S (489.37): C, 53.99; H, 3.71; N, 11.45. Found:
C, 53.31; H, 3.95; N, 11.79.
4-(4-Amino-5-(2,4-dichlorophenyl)-6-oxo-6,7,8,9-tetrahy-
dropyrimido[4,5-b]quinolin-10(5H)-yl)benzenesulfonamide
7. A solution of compound 6 (4.89 g, 0.01 mol) in formamide
(20 mL) was refluxed for 6 h, the reaction mixture was cooled
4-(5-(2,4-Dichlorophenyl)-4,6-dioxo-3,4,6,7,8,9-hexahydro-
pyrimido[4,5-b]quinolin-10(5H)-yl)benzenesulfonamide 8. A
solution of compound 6 (4.89 g, 0.01 mol) in formic acid (20
mL) was refluxed for 5 h, the reaction mixture was cooled and
then poured onto cold water, and the obtained solid was crys-
tallized from dioxane to give 8. Yield, 79%; m.p. 220–222ꢁC;
IR (KBr, cmꢀ1): 3300, 3271 (NH, NH2), 3095 (CH arom.),
2955, 2860 (CH aliph.), 1710, 1654 (2C¼¼O), 1625 (C¼¼N),
1370, 1164 (SO2), 796 (CACl). 1H-NMR (DMSO-d6) d: 1.4–
2.6 (m, 6H, 3CH2), 4.7 (s, 1H, CH), 7.1–7.9 (m, 10H, Ar-H þ
CH pyrimidine þ SO2NH2), 8.4 (s, 1H, NH). MS m/z (%):
517 [Mþ] (2.3), 44 (100). Anal. Calcd. for C23H18Cl2N4O4S
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568
M. M. Ghorab, M. S. Al-Said, and E. M. El-Hossary
Vol 48
Table 1
In Vitro cytotoxic activity of the newly synthesized compounds 6–40.
Nonviable cells (%)
Concentration (lg/mL)
a
Compound number
100
50
25
10
IC50 (lg/mL)
IC50 (lM)
6
7
8
9
10
12
13
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
95
80
65
70
100
60
95
6
95
95
100
60
100
50
80
6
50
60
80
40
90
5
90
25
80
20
20
40
70
7
40
50
40
30
85
0
80
25
40
20
2
25
10
51.1
19.3
16
23.5
6.1
100
100
100
10
95
95
100
80
100
60
8.3
12.5
3.5
>100b
4
50
–
6.8
86.6
50.6
72.7
61.7
82.3
16.8
–
30
43
37.5
50
30
50
0
80
10
10
>100b
10
31
90
90
80
80
30
80
90
10
95
90
10
95
95
90
80
10
75
60
80
95
68
60
40
20
75
80
10
80
90
5
50
30
10
70
80
10
80
80
0
16.5
50.7
–
10.4
6.4
45
85
>100b
6.5
100
60
100
100
30
4
>100b
6
–
9.2
6
8.9
–
9.5
91.3
22
>100b
6.3
60
99
95
80
50
60
60
0
60
0
95
95
20
80
80
90
95
100
40
40
0
12.5
12
>100b
6.5
43
20.6
–
70
20
40
20
30
70
20
30
20
24
11.2
74.3
53.6
98.1
68.1
37
38
40
31
60
Doxorubicin
37
a IC50 value: corresponds to the compound concentration causing 50% mortality in net cells.
b Compounds with IC50 ꢂ 100 lg/mL are considered to be inactive.
(517.38): C, 53.39; H, 3.51; N, 10.83. Found: C, 53.64; H,
3.80; N, 10.52.
excess acetic anhydride was removed under reduced pressure.
The obtained solid was crystallized from dioxane to give 10.
Yield, 76%; m.p. 300–302ꢁC; IR (KBr, cmꢀ1): 3300, 3245
(NH2), 2931, 2860 (CH aliph.), 2212 (CBN), 1781, 1733,
1656 (3C¼¼O), 1370, 1163 (SO2), 715 (CACl). 1H-NMR
(DMSO-d6) d: 1.6–2.6 (m, 6H, 3CH2), 2.4 (s, 6H, 2COCH3),
5.3 (s, 1H, CH), 7.3–8.0 (m, 9H, Ar-H þ SO2NH2). Anal.
Calcd. for C26H22Cl2N4O5S (573.45): C, 54.46; H, 3.87; N,
9.77. Found: C, 54.66; H, 3.57; N, 9.42.
N-(3-cyano-4-(2,4-dichlorophenyl)-5-oxo-1-(4-sulfamoyl-
phenyl)-1,4,5,6,7,8-hexahydroquinolin-2-yl)-2,2,2-trifluoroa-
cetamide 12. A solution of compound 6 (4.89 g, 0.01 mol) in
trifluoroacetic anhydride (20 mL) was refluxed for 5 min, the
reaction mixture was then concentrated, and the solid separated
was crystallized from dioxane to give 12. Yield, 66%; m.p.
140–142ꢁC; IR (KBr, cmꢀ1): 3320, 3266, 3105 (NH, NH2),
2955, 2880 (CH aliph.), 2184 (CBN), 1660, 1628 (2C¼¼O),
1373, 1165 (SO2), 733 (CACl). 1H-NMR (DMSO-d6) d: 1.6–
2.6 (m, 6H, 3CH2), 4.7 (s, 1H, CH), 7.2–8.1 (m, 9H, Ar-H þ
N-(3-cyano-4-(2,4-dichlorophenyl)-5-oxo-1-(4-sulfamoylphenyl)-
1,4,5,6,7,8-hexahydroquinolin-2-yl)acetamide 9. A solution of
compound 6 (4.89 g, 0.01 mol) in acetic anhydride (20 mL)
was refluxed for 5 min. The reaction mixture was then concen-
trated, and the solid separated was crystallized from acetic
acid to give 9. Yield, 88%; m.p. 266–268ꢁC; IR (KBr, cmꢀ1):
3433, 3347, 3290 (NH, NH2), 3080 (CH arom.), 2956, 2870
(CH aliph.), 2167 (CBN), 1718, 1645 (2C¼¼O), 1372, 1167
(SO2), 707 (CACl). 1H-NMR (DMSO-d6) d: 1.6–2.4 (m, 6H,
3CH2), 2.1 (s, 3H, COCH3), 5.0 (s, 1H, CH), 7.3–7.9 (m, 9H,
Ar-H þ SO2NH2), 11.9 (s, 1H, NH). Anal. Calcd. for
C24H20Cl2N4O4S (531.41): C, 54.24; H, 3.79; N, 10.54. Found:
C, 54.53; H, 3.51; N,10.79.
N-acetyl-N-(3-cyano-4-(2,4-dichlorophenyl)-5-oxo-1-(4-sul-
famoylphenyl)-1,4,5,6,7,8-hexahydroquinolin-2-yl)acetamide
10. A solution of compound 6 (4.89 g, 0.01 mol) in acetic
anhydride (20 mL) was refluxed for 20 h. After cooling, the
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In Vitro Cytotoxic Evaluation of Some New Heterocyclic Sulfonamide Derivatives
569
SO2NH2), 8.8 (s, 1H, NH). MS m/z (%): 585 [Mþ] (2.6), 64
(100). Anal. Calcd. for C24H17Cl2F3N4O4S (585.38): C, 49.24;
H, 2.93; N, 9.57. Found: C, 49.60; H, 2.69; N, 9.34.
N¼¼CH). Anal. Calcd. for C30H24Cl2N4O4S (606.09): C, 59.31;
H, 3.98; N, 9.22. Found: C, 59.64; H, 3.71; N, 9.54.
4-(3-Cyano-4-(2,4-dichlorophenyl)-2-(4-methoxybenzylide-
neamino)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesulfo-
namide 19. Yield, 83%; m.p. 277–279ꢁC; IR (KBr, cmꢀ1):
3380, 3310 (NH2), 2960, 2870 (CH aliph.), 2210 (CBN), 1660
4-(4,6-Dioxo-5-[2,4–dichloropheny]-3,5,6,7,8,9-hexahydro-
4H-2-trifluoromethyl-pyrimido[4,5-b]quinolin-10-yl)benzene-
sulfonamide 13. A solution of compound 6 (4.89 g, 0.01 mol)
in trifluoroacetic anhydride (20 mL) was refluxed for 20 h. Af-
ter cooling, the excess trifluoroacetic anhydride was removed
under reduced pressure. The obtained solid was crystallized
from dioxane to give 13. Yield, 64%; m.p. 305–307ꢁC; IR
(KBr, cmꢀ1): 3410, 3367, 3273 (NH, NH2), 2958, 2860 (CH
aliph.), 1669, 1653 (2C¼¼O), 1627 (C¼¼N), 1372, 1166 (SO2),
796 (CACl). 1H-NMR (DMSO-d6) d: 1.7–2.4 (m, 6H, 3CH2),
4.9 (s, 1H, CH), 7.0–7.9 (m, 9H Ar-H þ SO2NH2), 11.7
(s, 1H, NH). MS m/z (%): 585 [Mþ] (2.1), 46 (100). Anal.
Calcd. for C24H17Cl2F3N4O4S (585.38): C, 49.24; H, 2.93; N,
9.57. Found: C, 49.63; H, 3.14; N, 9.79.
1
(C¼¼O), 1620 (C¼¼N), 1380, 1180 (SO2), 796 (CCl). H-NMR
(DMSO-d6) d: 1.6–2.4 (m, 6H, 3CH2), 3.7 (s, 3H, OCH3), 5.2
(s, 1H, CH), 7.1–7.9 (m, 13H, Ar-H þ SO2NH2), 9.8 (s, 1H,
N¼¼CH). Anal. Calcd. for C30H24Cl2N4O4S (606.09): C, 59.31;
H, 3.98; N, 9.22. Found: C, 59.50; H, 3.68; N, 8.90.
4-(3-Cyano-4-(2,4-dichlorophenyl)-2-(2-hydroxybenzylidene-
amino)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesul-
fonamide 20. Yield, 81%; m.p. 298–300ꢁC; IR (KBr, cmꢀ1):
3366 (OH), 3272, 3105 (NH2), 2957, 2929, 2865 (CH aliph.),
2171 (CBN), 1650 (C¼¼O), 1628 (C¼¼N), 1372, 1185 (SO2),
796 (CACl). 1H-NMR (DMSO-d6) d: 1.6–2.4 (m, 6H, 3CH2),
5.3 (s, 1H, CH), 7.1–7.8 (m, 13H, Ar-H þ SO2NH2), 8.5 (s,
1H, N¼¼CH), 10.8 (s, 1H, OH). MS m/z (%): 593 [Mþ] (3.7),
56 (100). Anal. Calcd. for C29H22Cl2N4O4S (592.07): C,
58.69; H, 3.74; N, 9.44. Found: C, 58.45; H, 3.99; N, 9.15.
4-(3-Cyano-4-(2,4-dichlorophenyl)-2-(4-hydroxybenzylidene-
amino)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesulfo-
namide 21. Yield, 77%; m.p. 281–283ꢁC; IR (KBr, cmꢀ1):
3420 (OH), 3366, 3273 (NH2), 3100 (CH arom.), 2958, 2860
(CH aliph.), 2181 (CBN), 1651 (C¼¼O), 1628 (C¼¼N), 1372,
4-(2-(Substitutedbenzylideneamino)-3-cyano-4-(2,4-dichlor-
ophenyl)5-oxo-5,6,7,8,-tetrahydroquinolin-1(4H)-yl)benzene-
sulfonamide) 15-38. A mixture of compound 6 (4.89 g, 0.01
mol) and the corresponding aromatic aldehyde (0.01 mol) in
acetic acid (20 mL) was refluxed for 5 h, the reaction mixture
was cooled and then poured onto cold water. The obtained
solid was crystallized from dioxane to give 15–38.
4-(2-(Benzylideneamino)-3-cyano-4-(2,4-dichlorophenyl)-5-
oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesulfonamide
15. Yield, 86%; m.p. 315–317ꢁC; IR (KBr, cmꢀ1): 3366, 3275
(NH2), 3100 (CH arom.), 2958, 2920 (CH aliph.), 2171
(CBN), 1651 (C¼¼O), 1626 (C¼¼N), 1372, 1185 (SO2), 796
(CACl). 1H-NMR (DMSO-d6) d: 1.7–2.4 (m, 6H, 3CH2), 5.1
(s, 1H, CH), 7.0–7.9 (m, 14H, Ar-H þ SO2NH2), 9.1 (s, 1H,
N¼¼CH]. MS m/z (%): 577 [Mþ] (4.9), 64 (100). Anal. Calcd.
for C29H22Cl2N4O3S (576.08): C, 60.32; H, 3.84; N, 9.70.
Found: C, 60.67; H, 3.59; N, 9.46.
4-(3-Cyano-4-(2,4-dichlorophenyl)-5-oxo-2-(2-phenylethyli-
deneamino)-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesulfo-
namide 16. Yield, 88%; m.p. 311–313ꢁC; IR (KBr, cmꢀ1):
3365, 3273 (NH2), 3102 (CH arom.), 2958, 2920 (CH aliph.),
2257 (CBN), 1651 (C¼¼O), 1626 (C¼¼N), 1372, 1185 (SO2),
796 (CACl). 1H-NMR (DMSO-d6) d: 1.7–2.6 (m, 6H, 3CH2),
4.6 (s, 1H, CH), 5.2 (d, 2H, CH2, J ¼ 8.1 Hz), 7.3–8.0 (m,
14H Ar-H þ SO2NH2), 7.6 (t, 1H, N¼¼CH]. Anal. Calcd. for
C30H24Cl2N4O3S (590.09): C, 60.92; H, 4.09; N, 9.47. Found:
C, 60.74; H, 4.33; N, 9.68.
4-(3-Cyano-4-(2,4-dichlorophenyl)-2-(4-methylbenzylidenea-
mino)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesulfo-
namide 17. Yield, 87%; m.p. 308–310ꢁC; IR (KBr, cmꢀ1):
3365, 3272(NH2), 3104 (CH arom.), 2959, 2929 (CH aliph.),
2170 (CBN), 1651 (C¼¼O), 1627(C¼¼N), 1371, 1185 (SO2),
796 (CACl). 1H-NMR (DMSO-d6) d: 1.4–2.5 (m, 6H, 3CH2),
2.4 (s, 3H, CH3), 5.1 (s, 1H, CH), 7.2–8.0 (m, 13H, Ar-H þ
SO2NH2), 12.0 (s, 1H, N¼¼CH). Anal. Calcd. for
C30H24Cl2N4O3S (590.09): C, 60.92; H, 4.09; N, 9.47. Found:
C, 61.25; H, 3.84; N, 9.10.
1
1185 (SO2), 795 (CACl). H-NMR (DMSO-d6) d: 1.6–2.4 (m,
6H, 3CH2), 5.4 (s, 1H, CH), 7.3–8.0 (m, 13H, Ar-H þ
SO2NH2), 8.4 (s, 1H, N¼¼CH), 10.4 (s, 1H,OH). MS m/z (%):
593 [Mþ] (1.25), 47 (100). Anal. Calcd. for C29H22Cl2N4O4S
(592.07): C, 58.69; H, 3.74; N, 9.44. Found: C, 58.98; H,
3.51; N, 9.65.
4-(3-Cyano-4-(2,4-dichlorophenyl)-5-oxo-2-((E)-3-phenylally-
lideneamino)-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesul-
fonamide 22. Yield, 69%; m.p. 144–146ꢁC; IR (KBr, cmꢀ1):
3360, 3280 (NH2), 3056 (CH arom.), 2960, 2870 (CH aliph.),
2182 (CBN), 1653 (C¼¼O), 1590 (C¼¼N), 1371, 1165 (SO2),
751 (CACl). 1H-NMR (DMSO-d6) d: 1.4–2.6 (m, 6H, 3CH2),
5.1 (d, 1H, CH-4), 5.2–5.5 (m, 1H, CH), 6.9 (d, 1H, CHAPh,
J ¼ 7.8 Hz), 7.0–7.9 (m, 14H, Ar-H þ SO2NH2), 9.7 (d, 1H,
N¼¼CH, J ¼ 7.6 Hz). Anal. Calcd. for C31H24Cl2N4O3S
(602.09): C, 61.69; H, 4.01; N, 9.28. Found: C, 61.85; H,
3.77; N, 8.95.
4-(2-(2-Chlorobenzylideneamino)-3-cyano-4-(2,4-dichloro-
phenyl)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesul-
fonamide 23. Yield, 70%; m.p. 273–275ꢁC; IR (KBr, cmꢀ1):
3366, 3273 (NH2), 3103 (CH arom.), 2958, 2929 (CH aliph.),
2171 (CBN), 1696 (C¼¼O), 1627 (C¼¼N), 1372, 1185 (SO2),
795 (CACl). 1H-NMR (DMSO-d6) d: 1.6–2.4 (m, 6H, 3CH2),
4.9 (s, 1H, CH), 7.3–7.9 (m, 13H, Ar-H þ SO2NH2), 9.9
(s, 1H, N¼¼CH). MS m/z (%): 611 [Mþ] (2.3), 46 (100). Anal.
Calcd. for C29H21Cl3N4O3S (610.04): C, 56.92; H, 3.46; N,
9.16. Found: C, 57.25; H, 3.76; N, 8.80.
4-(3-Cyano-4-(2,4-dichlorophenyl)-2-(4-hydroxy-3-methoxy-
benzylideneamino)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)-
benzenesulfonamide 24. Yield, 78%; m.p. 260–262ꢁC; IR
(KBr, cmꢀ1): 3410 (OH), 3365, 3273 (NH2), 3100 (CH
arom.), 2956, 2860, (CH aliph.), 2181 (CBN), 1651 (C¼¼O),
1590 (C¼¼N), 1371, 1165 (SO2), 796 (CACl). 1H-NMR
(DMSO-d6) d: 1.6–2.4 (m, 6H, 3CH2), 3.8 (s, 3H, OCH3), 5.1
(s, 1H, CH), 6.9–7.9 (m, 12H, Ar-H þ SO2NH2), 9.7 (s, 1H,
4-(3-Cyano-4-(2,4-dichlorophenyl)-2-(2-methoxybenzylidene-
amino)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesulfo-
namide 18. Yield, 79%; m.p. 235–237ꢁC; IR (KBr, cmꢀ1):
3363, 3180 (NH2), 2955, 2880 (CH aliph.), 2182 (CBN), 1651
1
(C¼¼O), 1591 (C¼¼N), 1371, 1164 (SO2), 796 (CCl). H-NMR
(DMSO-d6) d: 1.4–2.5 (m, 6H, 3CH2), 3.8 (s, 3H, OCH3), 5.1
(s, 1H, CH), 6.9–7.9 (m, 13H, Ar-H þ SO2NH2), 10.4 (s, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

570
M. M. Ghorab, M. S. Al-Said, and E. M. El-Hossary
Vol 48
N¼¼CH), 11.8 (s, 1H, OH). Anal. Calcd. for C30H24Cl2N4O5S
(623.51): C, 57.79; H, 3.88; N, 8.99. Found: C, 57.51; H,
3.58; N, 8.69.
(s, 1H, OH). MS m/z (%): 643 [Mþ] (2.3), 64 (100). Anal.
Calcd. for C33H24Cl2N4O4S (643.54): C, 61.59; H, 3.76; N,
8.71. Found: C, 61.28; H, 3.92; N, 8.46.
4-(3-Cyano-4-(2,4-dichlorophenyl)-2-(2-nitrobenzylidenea-
mino)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesulfo-
namide 25. Yield, 65%; m.p. 297–299ꢁC; IR (KBr, cmꢀ1):
3366, 3273 (NH2), 3100 (CH arom.), 2958, 2928 (CH aliph.),
2170 (CBN), 1651 (C¼¼O), 1628 (C¼¼N), 1372, 1185 (SO2),
796 (CACl). 1H-NMR (DMSO-d6) d: 1.6–2.4 (m, 6H, 3CH2),
5.1 (s, 1H, CH), 7.0–7.9 (m, 13H, Ar-H þ SO2NH2), 9.2
(s, 1H, N¼¼CH). MS m/z (%): 622 [Mþ] (0.93), 46 (100).
Anal. Calcd. for C29H21Cl2N5O5S (622.48): C, 55.96; H, 3.40;
N, 11.25. Found: C, 56.31; H, 3.72; N, 11.58.
4-(3-Cyano-4-(2,4-dichlorophenyl)-2-((2-methoxynaphthalen-
1-yl)methyleneamino)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-
yl)benzenesulfonamide 31. Yield, 66%; m.p. 108–110ꢁC; IR
(KBr, cmꢀ1): 3300, 3255 (NH2), 3085 (CH arom.), 2944, 2885
(CH aliph.), 2182 (CBN), 1665 (C¼¼O), 1619 (C¼¼N), 1369,
1152 (SO2), 796 (CACl). 1H-NMR (DMSO-d6) d: 1.6–2.4
(m, 6H, 3CH2), 3.9 (s, 3H, OCH3), 5.1 (s, 1H, CH), 7.3–8.2
(m, 15H, Ar-H þ SO2NH2), 10.8 (s, 1H, N¼¼CH). Anal. Calcd.
for C34H26Cl2N4O4S (657.57): C, 62.10; H, 3.99; N, 8.52.
Found: C, 61.85; H, 4.25; N, 8.70.
4-(3-Cyano-4-(2,4-dichlorophenyl)-2-((4-methoxynaphthalen-
1-yl)methyleneamino)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-
yl)benzenesulfonamide 32. Yield, 71%; m.p. 142–144ꢁC; IR
(KBr, cmꢀ1): 3335, 3300 (NH2), 3090 (CH arom.), 2940, 2870
(CH aliph.), 2181 (CBN), 1676 (C¼¼O), 1647 (C¼¼N), 1370,
1190 (SO2), 766 (CACl). 1H-NMR (DMSO-d6) d: 1.6–2.4
(m, 6H, 3CH2), 3.9 (s, 3H, OCH3), 5.0 (s, 1H, CH), 7.0–8.3
(m, 15H, Ar-H þ SO2NH2), 10.1 (s, 1H, N¼¼CH). Anal. Calcd.
for C34H26Cl2N4O4S (657.57): C, 62.10; H, 3.99; N, 8.52.
Found: C, 62.47; H, 4.28; N, 8.77.
4-(3-Cyano-4-(2,4-dichlorophenyl)-2-(3-nitrobenzylidenea-
mino)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesulfo-
namide 26. Yield, 73%; m.p. 259–261ꢁC; IR (KBr, cmꢀ1):
3365, 3273 (NH2), 3092 (CH arom.), 2957, 2860 (CH aliph.),
2182 (CBN), 1648 (C¼¼O), 1591 (C¼¼N), 1371, 1165 (SO2),
796 (CACl). 1H-NMR (DMSO-d6) d: 1.7–2.3 (m, 6H, 3CH2),
5.4 (s, 1H, CH), 6.9–8.0 (m, 13H, Ar-H þ SO2NH2), 9.8 (s,
1H, N¼¼CH). MS m/z (%): 622 [Mþ] (0.82), 47 (100). Anal.
Calcd. for C29H21Cl2N5O5S (622.48): C, 55.96; H, 3.40; N,
11.25. Found: C, 55.74; H, 3.11; N, 10.93.
4-(2-(Benzo[d][1,3]dioxol-5-ylmethyleneamino)-3-cyano-4-
(2,4-dichlorophenyl)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-
yl)benzenesulfonamide 27.. Yield, 80%; m.p. 279–281ꢁC; IR
(KBr, cmꢀ1): 3367, 3273 (NH2), 3102 (CH arom.), 2957, 2880
(CH aliph.), 2171 (CBN), 1651 (C¼¼O), 1628 (C¼¼N), 1372,
4-(3-Cyano-4-(2,4-dichlorophenyl)-2-(furan-2-ylmethylenea-
mino)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesulfo-
namide 33. Yield, 78%; m.p. 268–270ꢁC; IR (KBr, cmꢀ1):
3366, 3272 (NH2), 3079 (CH arom.), 2956, 2866 (CH aliph.),
2181 (CBN), 1651 (C¼¼O), 1627 (C¼¼N), 1371, 1165 (SO2),
795 (CACl). 1H-NMR (DMSO-d6) d: 1.6–2.4 (m, 6H, 3CH2),
5.1 (s, 1H, CH), 7.1–8.2 (m, 12H, Ar-H þ SO2NH2), 9.8
(s, 1H, N¼¼CH). MS m/z (%): 567 [Mþ] (4.4), 48 (100). Anal.
Calcd. for C27H20Cl2N4O4S (567.44): C, 57.15; H, 3.55; N,
9.87. Found: C, 57.44; H, 3.81; N, 10.16.
1
1185 (SO2), 796 (CACl). H-NMR (DMSO-d6) d: 1.7–2.4 (m,
6H, 3CH2), 5.1 (s, 1H, CH), 6.1 (s, 2H, OACH2AO), 7.1–7.9
(m, 12H, Ar-H þ SO2NH2), 9.8 (s, 1H, N¼¼CH). Anal. Calcd.
for C30H22Cl2N4O5S (621.49): C, 57.98; H, 3.57; N, 9.01.
Found: C, 57.76; H, 3.88; N, 9.34.
4-(3-Cyano-2-(2,4-dichlorobenzylideneamino)-4-(2,4-dichlor-
ophenyl)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesul-
fonamide 28. Yield, 82%; m.p. 75–77ꢁC; IR (KBr, cmꢀ1):
3421, 3280 (NH2), 3087 (CH arom.), 2970, 2870 (CH aliph.),
2183 (CBN), 1686 (C¼¼O), 1636 (C¼¼N), 1373, 1198 (SO2),
4-(3-Cyano-4-(2,4-dichlorophenyl)-2-((5-methylfuran-2-yl)-
methylene amino)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)-
benzenesulfonamide 34.. Yield, 81%; m.p. 264–266ꢁC; IR
(KBr, cmꢀ1): 3367, 3273 (NH2), 3100 (CH arom.), 2957, 2866
(CH aliph.), 2181 (CBN), 1699 (C¼¼O), 1628 (C¼¼N), 1321,
1166 (SO2), 796 (CACl). 1H-NMR (DMSO-d6) d: 1.6–2.4
(m, 6H, 3CH2), 2.3 (s, 3H, CH3), 5.1 (s, 1H, CH), 6.3 (d, 2H,
CH furan, J ¼ 8.3 Hz), 7.3–7.9 (m, 9H, Ar-H þ SO2NH2),
11.9 (s, 1H, N¼¼CH). Anal. Calcd. for C28H22Cl2N4O4S
(581.47): C, 57.84; H, 3.81; N, 9.64. Found: C, 58.09; H,
3.57; N, 9.92.
4-(3-Cyano-4-(2,4-dichlorophenyl)-2-(thiophene-2-ylmethyle-
neamino)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzene-
sulfonamide 35. Yield, 77%; m.p. 262–264ꢁC; IR (KBr,
cmꢀ1): 3365, 3272 (NH2), 3099 (CH arom.), 2957, 2880 (CH
aliph.), 2181 (CBN), 1651 (C¼¼O), 1591 (C¼¼N), 1371, 1165
(SO2), 796 (CACl). 1H-NMR (DMSO-d6) d: 1.6–2.4 (m, 6H,
3CH2), 5.2 (s, 1H, CH), 7.0–8.1 (m, 13H, Ar-H þ SO2NH2 þ
N¼¼CH). MS m/z (%): 583 [Mþ] (4.1), 45 (100). Anal. Calcd.
for C27H20Cl2N4O3S2 (583.51): C, 55.58; H, 3.45; N, 9.60.
Found: C, 55.92; H, 3.67; N, 9.39.
1
759 (CACl). H-NMR (DMSO-d6) d: 1.7A2.4 (m, 6H, 3CH2),
5.2 (s, 1H, CH), 6.9–8.0 (m, 12H, Ar-H þ SO2NH2), 9.8 (s,
1H, N¼¼CH). MS m/z (%): 646 [Mþ] (4.5), 46 (100). Anal.
Calcd. for C29H20Cl4N4O3S (646.37): C, 53.89; H, 3.12; N,
8.67. Found: C, 53.61; H, 3.49; N, 8.90.
4-(3-Cyano-4-(2,4-dichlorophenyl)-5-oxo-2-(2,4,5-trimethox-
ybenzylideneamino)-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benze-
nesulfonamide 29. Yield, 76%; m.p. 200–202ꢁC; IR (KBr,
cmꢀ1): 3468, 3351 (NH2), 2929, 2890 (CH aliph.), 2182
(CBN), 1648 (C¼¼O), 1590 (C¼¼N), 1373, 1190 (SO2), 758
(CCl). 1H-NMR (DMSO-d6) d: 1.6–2.5 (m, 6H, 3CH2), 3.6,
3.8, 3.9 (3s, 9H, 3OCH3), 5.0 (s, 1H, CH), 7.1–8.1 (m, 11H,
Ar-H þ SO2NH2), 9.3 (s, 1H, N¼¼CH). Anal. Calcd. for
C32H28Cl2N4O6S (667.56): C, 57.57; H, 4.23; N, 8.39. Found:
C, 57.29; H, 4.55; N, 8.64.
4-(3-Cyano-4-(2,4-dichlorophenyl)-2-((2-hydroxynaphthalen-
1-yl)methyleneamino)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-
yl)benzenesulfonamide 30. Yield, 78%; m.p. 201–203ꢁC; IR
(KBr, cmꢀ1): 3410 (OH), 3368, 3310 (NH2), 3090 (CH
arom.), 2928, 2860 (CH aliph.), 2181 (CBN), 1636 (C¼¼O),
1593 (C¼¼N), 1372, 1163 (SO2), 796 (CACl). 1H-NMR
(DMSO-d6) d: 1.6–2.4 (m, 6H, 3CH2), 4.6 (s, 1H, CH), 7.0–
8.1 (m, 15H, Ar-H þ SO2NH2), 8.9 (s, 1H, N¼¼CH), 9.7
4-(3-Cyano-4-(2,4-dichlorophenyl)-2-(pyridine-2-ylmethyle-
neamino)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzene-
sulfonamide 36. Yield, 73%; m.p. 200–202ꢁC; IR (KBr,
cmꢀ1): 3361, 3310 (NH2), 3092 (CH arom.), 2954, 2860 (CH
aliph.), 2182 (CBN), 1652 (C¼¼O), 1590 (C¼¼N), 1371, 1165
(SO2), 795 (CACl). 1H-NMR (DMSO-d6) d: 1.6–2.3 (m, 6H,
3CH2), 4.9 (s, 1H, CH), 6.9–8.6 (m, 14H, Ar-H þ SO2NH2 þ
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2011
In Vitro Cytotoxic Evaluation of Some New Heterocyclic Sulfonamide Derivatives
571
N¼¼CH). MS m/z (%): 578 [Mþ] (2.7), 44 (100). Anal. Calcd.
for C28H21Cl2N5O3S (578.47): C, 58.14; H, 3.66; N, 12.11.
Found: C, 57.91; H, 3.91; N, 12.36.
health organization, Genneva, Switherland and approved from
the committee for animals care at NCRRT, AEA.
EAC cells were obtained by needle aspiration of ascetic
fluid from preinoculated mice, under aseptic conditions. Tumor
cells suspension (2.5 ꢃ 106 per mL) was prepared in RBMI-
1640 media. Tested compounds were prepared with various
dilutions by dissolving: 100, 50, 25, and 10 lg of the tested
compounds in DMSO (1 mL).
In a set of sterile test tubes 0.8 mL RBMI-1640 media con-
taining (glutamine, fetal calf serum as nutrient, streptomycin,
and penicillin), 0.1 mL of each of the tested compounds
(corresponding to 100, 50, 25, and 10 lg) were mixed then
0.1 mL of tumor cell suspension (2 ꢃ 106) was added. The
test tubes were incubated at 37ꢁC for 2 h. Trypan blue exclu-
sion test was carried out to calculate the percentage of nonvi-
able cells after 2 h of incubation [22]. The results of in vitro
cytotoxic activity experiments are presented in Table 1.
4-(3-Cyano-4-(2,4-dichlorophenyl)-2-(pyridine-3-ylmethyle-
neamino)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzene-
sulfonamide 37. Yield, 76%; m.p. 299–301ꢁC; IR (KBr, cmꢀ1):
3365, 3272 (NH2), 3103 (CH arom.), 2958, 2929 (CH aliph.),
2171 (CBN), 1697 (C¼¼O), 1627 (C¼¼N), 1372, 1185 (SO2),
796 (CACl). 1H-NMR (DMSO-d6) d: 1.8–2.4 (m, 6H, 3CH2),
5.0 (s, 1H, CH), 6.9–9.3 (m, 14H, Ar-H þ SO2NH2
þ
N¼¼CH). MS m/z (%): 578 [Mþ] (3.3), 46 (100). Anal. Calcd.
for C28H21Cl2N5O3S (578.47): C, 58.14; H, 3.66; N, 12.11.
Found: C, 58.46; H, 3.39; N, 11.86.
4-(3-Cyano-4-(2,4-dichlorophenyl)-2-(pyridine-4-ylmethyle-
neamino)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzene-
sulfonamide 38. Yield, 69%; m.p. 304–306ꢁC; IR (KBr, cmꢀ1):
3365, 3272 (NH2), 3103 (CH arom.), 2958, 2929 (CH aliph.),
2171 (CBN), 1651 (C¼¼O), 1627 (C¼¼N), 1372, 1185 (SO2),
795 (CACl). 1H-NMR (DMSO-d6) d: 1.6–2.4 (m, 6H, 3CH2),
REFERENCES AND NOTES
4.8 (s, 1H, CH), 6.9–8.8 (m, 14H, Ar-H þ SO2NH2
þ
N¼¼CH). MS m/z (%): 578 [Mþ] (4.2), 46 (100). Anal. Calcd.
for C28H21Cl2N5O3S (578.47): C, 58.14; H, 3.66; N, 12.11.
Found: C, 57.96; H, 3.94; N, 11.83.
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4-(5-(2,4-Dichlorophenyl)-2-(3-hydroxyphenyl)-4-imino-6-
oxo-1,2,6,7,8,9-hexahydro-4H-[1,3]oxazino[4,5-b]quinolin-10
(5H)-yl)benzenesulfonamide 40. A solution of dimethylforma-
mide (20 mL) and anhydrous zinc chloride (1.36 g, 0.01 mol)
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benzaldehyede (1.12 g, 0.01 mol). The reaction mixture was
heated at reflux for 4 h. After completion of the reaction as
indicated by TLC, the cooled reaction mixture was quenched
with water (20 mL) and the precipitate was separated by filtra-
tion. The filtration residue was dispersed into water and titrated
to pH 12–13 by 20% sodium hydroxide. After filtration, the
product was isolated by column chromatography (200–300
mesh silica gel, ethyl acetate-petroleum ether ¼ 1:2). Yield,
72%; m.p. >320ꢁC; IR (KBr, cmꢀ1): 3430 (OH), 3365, 3270
(NH, NH2), 1640 (C¼¼O), 1590 (C¼¼N), 1371, 1161 (SO2), 711
(CACl). 1H-NMR (DMSO-d6) d: 1.4–2.4 (m, 6H, 3CH2), 4.5
(s, 1H, CH), 5.5 (d, 1H, CHAO, J ¼ 7.7 Hz), 6.8 (s, 1H,
¼¼NH), 7.0–7.9 (m, 13H, Ar-H þ SO2NH2), 8.1 (s, 1H, NH),
12.2 (s, 1H, OH). 13C-NMR (DMSO) d: 21.9, 28.4, 31.2, 36.2,
70.8, 82.9, 111.8, 112.0, 114.3, 115.6, 120.1, 127.1, 129.3,
129.9, 130.2, 130.7, 132.8, 134.6, 139.7, 141.6, 144.6, 152.8,
156.1, 159.7, 163.9, 198.4. Anal. Calcd. for C29H24Cl2N4O5S
(611.50): C, 56.96; H, 3.96; N, 9.16. Found: C, 57.21; H, 4.29;
N, 8.86.
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for Radiation Research and Technology (NCRRT), Atomic
Energy Authority (AEA), Cairo, Egypt. Animal care and han-
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet