Discovering some novel tetrahydroquinoline derivatives bearing the biologically active sulfonamide moiety as a new class of antitumor agents

Article abstract of DOI:10.1016/j.ejmech.2010.01.022

The present article describes the synthesis of some novel 4-(2-amino-3-cyano-4-(substituted-aryl)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesulfonamide (23-41) starting with 4-(3-oxo-cyclohex-1-enylamino)benzenesulfonamide (3). All the newly synthesized compounds were evaluated for their in vitro antitumor activity. Compounds 32, 25, 41, 35, 33, and 37 with IC₅₀ values (2.5, 3, 5, 10, 12, and 12.5 μg/mL) are more potent and efficacious than Doxorubicin (CAS-23214-92-8) as reference drug with (IC₅₀ value = 37.5 μg/mL). Also, compounds 28, 30, 31, and 34 (with IC₅₀ values = 25 μg/mL) are nearly as active as Doxorubicin.

Full text of DOI:10.1016/j.ejmech.2010.01.022

European Journal of Medicinal Chemistry 45 (2010) 1849–1853
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Discovering some novel tetrahydroquinoline derivatives bearing the biologically
active sulfonamide moiety as a new class of antitumor agents
,
d
Saleh I. Alqasoumi a, Areej M. Al-Taweel a, Ahmed M. Alafeefy b, Mostafa M. Ghorab c , Eman Noaman
*
a Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
b Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
c Medicinal, Aromatic and Poisonous Plants Research Center (MAPPRC), College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
d Radiation Biology Department, National Center for Radiation Research and Technology, Atomic Energy Authority, Nasr City, Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
The present article describes the synthesis of some novel 4-(2-amino-3-cyano-4-(substituted-aryl)-5-
oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesulfonamide (23–41) starting with 4-(3-oxo-cyclohex-
1-enylamino)benzenesulfonamide (3). All the newly synthesized compounds were evaluated for their in
vitro antitumor activity. Compounds 32, 25, 41, 35, 33, and 37 with IC50 values (2.5, 3, 5, 10, 12, and
Received 23 June 2009
Received in revised form
5 January 2010
Accepted 11 January 2010
Available online 20 January 2010
12.5
(IC50 value ¼ 37.5
active as Doxorubicin.
m
g/mL) are more potent and efficacious than Doxorubicin (CAS-23214-92-8) as reference drug with
m
g/mL). Also, compounds 28, 30, 31, and 34 (with IC50 values ¼ 25 g/mL) are nearly as
m
Keywords:
Ó 2010 Elsevier Masson SAS. All rights reserved.
Antitumor activity
Tetrahydroquinoline
Sulfonamide
Synthesis
1. Introduction
quinoline-3-carbonitrile as efficient Src kinase inhibitors, and as
part of our research effort to explore the new antitumor hetero-
cyclic compounds [17–24], we synthesized a novel series of tetra-
hydroquinoline-3-carbonitriles 23–41, bearing the biologically
active sulfonamide moiety at 1-position with substituted-aryl at
the 4-position and free amino group at the 2-position as analogues
of compounds I and II.
Protein tyrosine kinases (TKs) play an important role in cell
growth and differentiation. These enzymes catalyze the transfer of
a phosphate group from ATP to a tyrosine residue on an appropriate
substrate, thereby bringing about cell signaling events. Several
nonreceptor TKs have been identified, among them the Src family
of cytoplasmic protein TKs [1]. The TK Src has been implicated in
several disease states, including cancer [2,3], osteoporosis [4], and
stroke [5]. Therefore, inhibition of Src kinase could prove useful in
the treatment of these and other diseases. A number of Src family
kinase inhibitors have been reported in the literature, including
4-anilinoquinazolines [6], pyrazolo [3,4-d]- pyrimidines [7], pyr-
rolo[2,3-d]pyrimidines [8], pyrido[2,3-d ]pyrimidin-7(8H)-ones
[9],1,6-naphthyridin-2(1H)-ones [10], and aminopyrido[2,3-d]pyr-
imidin-7-yl ureas [11]. A series of 4-anilino-3-quinolinecarbonitrile
compounds has been reported to be potent inhibitors of EGFr [12],
Src [13] and MEK [14] kinases. While earlier synthetic efforts were
directed at 4-anilino-6,7-dialkoxy-3-quinolinecarbonitrile Src
kinase inhibitors, such as compound I [15], recent efforts have
focused on 4-anilino-7-thienyl-3-quinolinecarbonitriles (e.g., II) as
potent Src kinase inhibitors [16]. Given the obvious importance of
O
Ar
Cl
Cl
O
CN
Cl
Cl
O
N
N
HN
N
NH2
HN
O
CN
CN
O
O
N
S
N
N
SO2NH2
I
II
23-41
2. Results and discussion
2.1. Chemistry
The present work reports the possible utility of 4-(3-oxo-
cyclohex-1-enylamino)-benzenesulfonamide 3 in the synthesis of
4-(quinolin-1-yl)benzenesulfonamide derivatives 23–41. Enami-
none 3 was obtained by condensation of cyclohexan-1,3-dione 1
* Corresponding author. Tel.: þ966 534292860; fax: þ966 (01) 4670560.
E-mail address: mmsghorab@yahoo.com (M.M. Ghorab).
0223-5234/$ – see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.01.022

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S.I. Alqasoumi et al. / European Journal of Medicinal Chemistry 45 (2010) 1849–1853
with sulfanilamide 2 in ethanol (Scheme 1). The structure of
compound 3 was confirmed by elemental analysis and spectral
data. The IR spectrum of compound 3 revealed the presence of
bands for NH, NH2 at 3354, 3263 cmꢀ1, C]O at 1611 cmꢀ1, SO2 at
1360, 1184 cmꢀ1. Also, the 1H NMR spectrum in DMSO-d6 indicated
the presence of signal at 9.0 ppm which could be assigned to NH of
the enaminone 3.
compounds 23–41 is illustrated in terms of initial condensation of the
appropriate aldehyde with malononitrile affording the activated
arylidenemalononitriles4–22, followed byaddition of the enaminone
3 to arylidenemalononitriles 4–22. The IR spectra of compounds 23–
41 showed bands at 3472–3185 cmꢀ1 due to (NH2), 2227–2120 cmꢀ1
(ChN), 1647–1611 cmꢀ1 (C]O), 1383–1140 cmꢀ1 (SO2).
Treating the enaminone, 3, with arylidenemalononitriles, 4–22,
in the presence of catalytic amount of triethylamine as a base
catalyst, yielded the corresponding tetrahydroquinolines 23–41 via
the formation of the intermediate Michael type products, followed
by intramolecular cyclization (Scheme 1).
The N-Aryl-substituted benzenesulfonamide decreased the
nucleophilicity of the enaminone 3 towards 2-arylidenemalono-
nitriles 4–22. The base catalyst triethylamine was required to
generate the anion of the enaminone 3, thus facilitating the addi-
tion to the unsaturated nitriles 4–22.
2.2. Antitumor activity
Doxorubicin, the reference 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 concentration was
plotted to obtain the survival curve of Ehrlich Ascites Carcinoma
(EAC) cells. The response parameter calculated was IC50 value
(Table 1), which corresponds to the compound concentration
causing 50% mortality in net cells.
Compounds 23–41 were unambiguously synthesized by another
route involving one-pot condensation of the aldehyde, malononitrile
and enaminone 3 in a molar ratio of (1:1:1) in refluxing ethanol
containing triethylamine as catalyst. In this case, formation of
2.2.1. Structure–activity relationship
The parent target molecule, containing both tetrahydroquino-
line and sulfonamide moieties, was synthesized with amino group
O
NH2
O
NH
EtOH
+
O
SO2NH2
2
1
SO2NH2
3
3
Ar
CN
CN
EtOH
TEA
CN
CN
ArCHO
O
4-22
Ar
N
O
Ar
CN
NH2
CN
C N
NH
SO2NH2
SO2NH2
23-41
23: Ar= -C6H5
33: Ar= -C6H2.(OCH3)3.2,4,5.
34: Ar= -C6H3.Cl2.2,4.
35: Ar= -C6H3.OC2H5-3, OCH3-4.
36: Ar= -C10H6.OH-2.
37: Ar= -C10H6.OCH3-2.
38: Ar= -C10H6.OCH3-4.
39: Ar= 2-furyl.
24: Ar= -C6H4.CH3-4.
25: Ar= -C6H4.OH-4.
26: Ar= CH=CH-C6H5.
27: Ar= -C6H4.OCH3-2.
28: Ar= -C6H4.OCH3-4..
29: Ar= piperonyl.
30: Ar= vanillyl.
31: Ar= -C6H4.NO2-3.
32: Ar= -C6H4.NO2-4.
40: Ar= 2-furyl,CH3-5.
41: Ar= 2-thienyl.
Scheme 1.

S.I. Alqasoumi et al. / European Journal of Medicinal Chemistry 45 (2010) 1849–1853
1851
Table 1
In vitro cytotoxic activity of the newly synthesized compounds 23–41.
3. Conclusions
b
The present data showed that, compounds combining tetrahy-
droquinoline and benzenesulfonamide moieties, exhibited prom-
ising in vitro cytotoxic activity against EAC cells, especially
compounds 32 and 25 containing substituted phenyl with either
NO2 or OH groups in position 4. Compounds 32, 25, 41, 35, 33 and
37 exhibited the highest in vitro cytotoxic activity when compared
with the other tested compounds and doxorubicin as a reference
drug. Also, compounds 28, 30, 31 and 34 are nearly as active as
doxorubicin.
Compd. No.
Non-viable cells (%)a
Concentration ( g/mL)
IC50 (mg/mL)
m
100
50
60
40
50
100
40
0
25
10
Doxorubicin
100
40
100
100
45
39
30
30
95
10
0
20
10
30
90
2
0
30
0
37.5
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
>100c
50
3
>100c
>100c
25
0
100
95
100
71
100
100
95
100
15
90
10
90
73
95
100
65
70
5
50
0
75
25
25
2.5
12
25
10
4. Experimental
50
50
80
72
50
60
0
62
10
0
0
42
85
40
40
50
0
40
10
0
4.1. Chemistry
Melting points (ꢁC, uncorrected) were determined in open
capillaries on a Gallenkamp melting point apparatus (Sanyo
Gallenkamp, Southborough, UK). Precoated silica gel plates (silica
gel 0.25 mm, 60G F254; Merck, Germany) were used for thin
layer chromatography, 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. Infra red
spectra were recorded in KBr discs using IR-470 Shimadzu
spectrometer (Shimadzu, Tokyo, Japan). 1H NMR spectra (in
DMSO-d6) were recorded on Bruker AC-300 Ultra Shield NMR
>100c
12.5
70
80
90
10
70
30
5
>100c
>100c
5
45
100
40
88
10
80
2
70
a
Ehrlich Ascites Carcinoma (EAC) cells.
b
IC50 value: Corresponds to the compound concentration causing 50% mortality
in net cells.
c
Compounds with IC50 > 100 mg/mL are considered to be inactive.
spectrometer (Bruker, Flawil, Switzerland,
dppm) at 300 MHz,
at position 2, and cyano group at position 3 in addition to several
substituents at position 4, in order to study the structure–activity
relationship of the newly synthesized compounds 23–41. From
these results, it was found that substitution with either 4-nitro-
phenyl 32, 4-hydroxyphenyl 25, 2-thienyl 41, 3-ethoxy-4-methox-
yphenyl 35, trimethoxyphenyl 33 and 2-methoxynaphthyl 37 at
using TMS as internal Standard and peak multiplicities are
designed as follows: s, singlet; d, doublet; t, triplet; m, multiplet.
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).
position 4 (with IC50 values ¼ 2.5, 3, 5, 10, 12, and 12.5
mg/mL)
showed a significant cytotoxic activity which was even higher than
that of reference drug Doxorubicin (CAS-23214-92-8) with IC50
4.1.1. 4-(3-Oxo-cyclohex-1-enylamino)benzenesulfonamide (3)
A mixture of cyclohexane-1,3-dione 1 (1.12 g, 0.01 mol) and
sulfanilamide 2 (1.72 g, 0.01 mol) in ethanol (30 mL) was refluxed
for 3 h. The reaction mixture was cooled and then poured onto cold
water the obtained solid was crystallized from ethanol to give 3.
Yield, 92%; m.p. 236–238 ꢁC; IR (KBr, cmꢀ1): 3354, 3263 (NH, NH2),
3032 (CH arom.), 1611 (C]O), 1360, 1184 (SO2). 1H NMR: 1.05–1.9
[m, 6H, 3CH2 cyclo.], 5.5 [s, 1H, CH], 7.0–7.8 [m, 6H, Ar-H þ SO2NH2],
9.0 [s, 1H, NH]. Anal.Calcd. for C12H14N2O3S: C, 54.12; H, 5.30; N,
10.52. Found: C, 54.32; H, 5.53; N, 10.33.
value ¼ 37.5
mg/mL. The substitution in para position was found to
enhance the cytotoxic activity rather than in ortho or meta posi-
tions. These findings were clearly observed as the presence of 4-
nitrophenyl 32 (IC50 value ¼ 2.5
(IC50 value ¼ 3 g/mL) led to an increase in the antitumor activity
where the percentage of non-viable cells were 85% and 90%
respectively, at a concentration of 10 g/mL. Compound 32 having
mg/mL), and 4-hydroxyphenyl 25
m
m
p-nitrophenyl at position 4 is more active than compound 31
bearing m-nitrophenyl at the same position. Also, the presence of
methoxy group at ortho-position 37 with (IC50 value ¼ 12.5
m
g/mL)
4.1.2. 4-[2-Amino-3-cyano-4-(substituted-aryl)-5-oxo-5,6,7,8-
tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (23–41)
4.1.2.1. Method (A). A mixture of compound 3 (2.66 g, 0.01 mol)
and the corresponding 2-arylidenemalononitrile derivatives 4–22
(0.01 mol) in ethanol (20 mL) containing 3 drops of triethylamine,
was refluxed for 6 h. The reaction mixture was filtered while hot
and the solid obtained was crystallized from dioxane to give 32–41,
respectively.
is more active than compound 36 containing hydroxy group at the
same position. On the other hand, it was found that compound 41
carrying 2-thienyl at position 4 enhances the cytotoxic activity
rather the 2-furyl 39. In addition compound having trimethoxy
group 33 is more potent than compounds carrying only one
methoxy group 27 and 28.
It was very interesting to observe that compound 28 with 4-
methoxyphenyl at position 4, compound 30 with 4-hydroxy-3-
methoxyphenyl, compound 31 with 3-nitrophenyl and compound
4.1.2.2. Method (B). A solution of enaminone 3 (2.66 g, 0.01 mol),
the appropriate aldehyde (0.01 mol) and malononitrile (0.66 g,
0.01 mol) in absolute ethanol (30 mL) containing 3 drops of trie-
thylamine, was refluxed for 5 h. The solid obtained after concen-
tration and cooling, was filtered and crystallized from dioxane to
give 23–41, respectively (M.P., mixed M.P.).
34 with 2,4- dichlorophenyl (IC50 values ¼ 25
mg/mL) are nearly as
active as Doxorubicin as positive control, while compounds 24, 29,
and 38 exhibited
a moderate activity but less active than
Doxorubicin.
It is clear from the present data that, the comparison of the cyto-
toxicity of tetrahydroquinoline derivatives against Ehrlich Ascites
Carcinoma (EAC) cells (Table 1) has showed that the cell killing
potency follows the order 32 > 25 > 41 >33 > 37 > Doxorubicin. The
presence of a cyano group at position 3 [12,25] in these compounds is
supposed to enhance their antitumor activity.
4.1.3. 4-[2-Amino-3-cyano-4-phenyl-5-oxo-5,6,7,8-
tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (23)
Yield, 90%; m.p. 246–248 ꢁC; IR: 3354, 3263 (NH2), 3029 (CH
arom.), 2224 (ChN), 1613 (C]O), 1390, 1140 (SO2). 1H NMR: 1.5–1.9

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S.I. Alqasoumi et al. / European Journal of Medicinal Chemistry 45 (2010) 1849–1853
[m, 6H, 3CH2 cyclo.], 4.1 [s, 1H, CH], 5.3 [s, 2H, NH2], 7.2–7.8 [m, 11H,
Ar-H þ SO2NH2]. MS, m/z (%): 420[Mþ] (2), 73 (100). Anal.Calcd. for
C22H20N4O3S: C, 62.84; H, 4.79; N,13.32. Found: C, 62.48; H, 4.55; N,
13.61.
Ar-H þ SO2NH2], 9.0 [s, 1H, OH]. Anal.Calcd. for C23H22N4O5S: C,
59.22; H, 4.75; N, 12.01. Found: C, 59.50; H, 4.52; N, 12.32.
4.1.11. 4-[2-Amino-3-cyano-4-(3-nitrophenyl)-5-oxo-5,6,7,8-
tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (31)
4.1.4. 4-[2-Amino-3-cyano-4-p-tolyl-5-oxo-5,6,7,8-
tetrahydroquinolin-1(4H)yl]benzenesulfonamide (24)
Yield, 83%; m.p. 210–212 ꢁC; IR: 3420, 3350, 3290 (NH2), 3029
(CH arom.), 2950, 2860 (CH aliph.), 2173 (ChN), 1647 (C]O), 1375,
1193 (SO2). 1H NMR: 1.6–2.2 [m, 6H, 3CH2 cyclo.], 4.4 [s, 1H, CH], 5.5
[s, 2H, NH2], 7.1–7.8 [m, 10H, Ar-H þ SO2NH2]. MS m/z (%): 465[Mþ]
(8.7), 207 (100). Anal.Calcd. for C22H19N5O5S: C, 56.77; H, 4.11; N,
15.05. Found: C, 56.48; H, 4.42; N, 15.37.
Yield, 82%; m.p. 291–293 ꢁC; IR: 3458, 3344, 3220 (NH2), 3020
(CH arom.), 2940, 2850 (CH aliph.), 2169 (ChN) 1634 (C]O), 1378,
1165 (SO2). 1H NMR: 1.6–1.8 [m, 6H, 3CH2 cyclo.], 2.2 [s, 3H, CH3],
4.0 [s, 1H, CH], 5.4 [s, 2H, NH2], 7.1–8.0 [m, 10H, Ar-H þ SO2NH2].
Anal.Calcd. for C23H22N4O3S: C, 63.58; H, 5.10; N, 12.89. Found: C,
63.37; H, 5.34; N, 12.63.
4.1.12. 4-[2-Amino-3-cyano-4-(4-nitrophenyl)-5-oxo-5,6,7,8-
tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (32)
Yield, 82%; m.p. 287–288 ꢁC; IR: 3472, 3361, (NH2), 3070 (CH
arom.), 2978, 2947 (CH aliph.), 2184 (ChN), 1647 (C]O), 1375, 1193
(SO2). 1H NMR: 1.8–2.2 [m, 6H, 3CH2 cyclo.], 4.6 [s, 1H, CH], 5.6 [s,
2H, NH2], 7.5–8.0 [m, 10H, Ar-H þ SO2NH2]. Anal.Calcd. for
C22H19N5O5S: C, 56.77; H, 4.11; N, 15.05. Found: C, 56.82; H, 4.30; N,
15.19.
4.1.5. 4-[2-Amino-3-cyano-4-p-hydroxyphenyl-5-oxo-5,6,7,8-
tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (25)
Yield, 87%; m.p. 288–289 ꢁC; IR: 3458 (OH), 3325, 3253 (NH2),
2925, 2853 (CH aliph.), 2180 (ChN) 1643 (C]O), 1375, 1163 (SO2).
1H NMR: 1.4–1.9 [m, 6H, 3CH2 cyclo.], 4.3 [s, 1H, CH], 5.5 [s, 2H,
NH2], 7.3–7.9 [m, 10H, Ar-H þ SO2NH2], 10.8 [s, 1H, OH]. MS m/z (%):
436 [Mþ] (7.5), 73 (100). Anal.Calcd. for C22H20N4O4S: C, 60.54; H,
4.62; N, 12.84. Found: C, 60.22; H, 4.35; N, 12.58.
4.1.13. 4-[2-Amino-3-cyano-4-(2,4,5-trimethoxyphenyl)-5-oxo-
5,6,7,8-tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (33)
Yield, 86%; m.p. 149–151 ꢁC; IR: 3390, 3358 (NH2), 3083 (CH
arom.), 2997, 2953 (CH aliph.), 2219 (ChN) 1613 (C]O), 1341, 1193
(SO2). 1H NMR: 1.9–2.2 [m, 6H, 3CH2 cyclo.], 3.7, 3.92, 3.94 [3s, 9H,
3OCH3], 5.5 [s, 1H, CH], 6.7 [s, 2H, NH2], 7.2–8.1 [m, 8H, Ar-
H þ SO2NH2]. Anal.Calcd. for C25H26N4O6S: C, 58.81; H, 5.13; N,
10.97. Found: C, 58.54; H, 5.45; N, 11.25.
4.1.6. 4-[2-Amino-3-cyano-4-styryl-5-oxo-5,6,7,8-
tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (26)
Yield, 79%; m.p. 177–179 ꢁC; IR: 3353, 3262, (NH2), 3022 (CH
arom.), 2940, 2860 (CH aliph.), 2227 (ChN) 1611 (C]O), 1360, 1140
(SO2). 1H NMR: 1.9–2.4 [m, 6H, 3CH2 cyclo.], 4.0 [s, 1H, CH], 5.5 [s,
2H, NH2], 7.3–7.8 [m,11H, Ar-H þ SO2NH2], 8.0, 8.2 [2d, 2H, CH]CH,
J ¼ 7.4, 7.2 Hz]. Anal.Calcd. for C24H22N4O3S: C, 64.56; H, 4.97; N,
12.55. Found: C, 64.36; H, 4.71; N, 12.23.
4.1.14. 4-[2-Amino-3-cyano-4-(2,4-dichlorophenyl)-5-oxo-5,6,7,8-
tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (34)
4.1.7. 4-[2-Amino-3-cyano-4-(2-methoxyphenyl)-5-oxo-5,6,7,8-
tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (27)
Yield, 76%; m.p. 255–257 ꢁC; IR: 3446, 3341, 3276 (NH2), 3035
(CH arom.), 2175 (ChN) 1653 (C]O),1371,1187 (SO2). 1H NMR: 1.9–
2.2 [m, 6H, 3CH2 cyclo.], 3.7 [s, 3H, OCH3], 4.4 [s, 1H, CH], 5.4 [s, 2H,
NH2], 7.2–7.9 [m, 10H, Ar-H þ SO2NH2]. Anal.Calcd. for
C23H22N4O4S: C, 61.32; H, 4.92; N, 12.44. Found: C, 61.65; H, 4.74; N,
12.64.
Yield, 90%; m.p. 291–293 ꢁC; IR: 3464, 3347 (NH2), 3064 (CH
arom.), 2957, 2860 (CH aliph.), 2171 (ChN) 1634 (C]O), 1374, 1189
(SO2). 1H NMR: 1.8–2.2 [m, 6H, 3CH2 cyclo.], 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: C, 53.99; H, 3.71; N,
11.45. Found: C, 54.31; H, 3.95; N, 11.79.
4.1.15. 4-[2-Amino-3-cyano-4-(3-ethoxy-4-methoxyphenyl)-5-
oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (35)
Yield, 79%; m.p. 213–215 ꢁC; IR: 3360, 3349, 3290 (NH2), 3089
(CH arom.), 2965, 2850 (CH aliph.), 2176 (ChN) 1654 (C]O), 1373,
1167 (SO2). 1H NMR: 1.0 [t, 3H, CH3],1.6–2.2 [m, 6H, 3CH2 cyclo.], 3.6
[s, 3H, OCH3], 4.3 [s, 1H, CH], 4.6 [q, 2H, CH2], 5.6 [s, 2H, NH2], 7.2–
8.1 [m, 9H, Ar-H þ SO2NH2]. Anal.Calcd. for C25H26N4O5S: C, 60.71;
H, 5.30; N, 11.33. Found: C, 60.47; H, 4.98; N, 11.56.
4.1.8. 4-[2-Amino-3-cyano-4-(4-methoxyphenyl)-5-oxo-5,6,7,8-
tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (28)
Yield, 81%; m.p. 260–262 ꢁC; IR: 3434, 3352, 3264 (NH2), 3063
(CH arom.), 2940, 2850 (CH aliph.), 2176 (ChN) 1644 (C]O), 1372,
1172 (SO2). 1H NMR: 1.6–2.2 [m, 6H, 3CH2 cyclo.], 3.5 [s, 3H, OCH3],
4.3 [s, 1H, CH], 5.4 [s, 2H, NH2], 7.1–8.0 [m, 10H, Ar-H þ SO2NH2].
Anal.Calcd. for C23H22N4O4S: C, 61.32; H, 4.92; N, 12.44. Found: C,
61.66; H, 4.69; N, 12.71.
4.1.16. 4-[2-Amino-3-cyano-4-(2-hydroxy-1-naphthyl)-5-oxo-
5,6,7,8-tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (36)
Yield, 69%; m.p. >300 ꢁC; IR: 3419 (OH), 3335, 3234 (NH2), 3064
(CH arom.), 2950, 2840 (CH aliph.), 2210 (ChN) 1638 (C]O), 1361,
1158 (SO2). 1H NMR: 1.7–2.2 [m, 6H, 3CH2 cyclo.], 4.4 [s, 1H, CH], 5.4
[s, 2H, NH2], 7.2–7.9 [m, 12H, Ar-H þ SO2NH2], 10.8 [s, 1H, OH]. MS
m/z (%): 486 [Mþ] (44.8), 73 (100). Anal.Calcd. for C26H22N4O4S: C,
64.18; H, 4.56; N, 11.52. Found: C, 64.49; H, 4.23; N, 11.19.
4.1.9. 4-[2-Amino-4-(benzo[d][1,3]dioxol-5-yl)-3-cyano-5-oxo-
5,6,7,8-tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (29)
Yield, 85%; m.p. 202–204 ꢁC; IR: 3349, 3257, 3185 (NH2), 3034
(CH arom.), 2978, 2947 (CH aliph.), 2222 (ChN), 1611 (C]O), 1375,
1181 (SO2). 1H NMR: 1.3–2.2 [m, 6H, 3CH2 cyclo.], 4.0 [s, 2H, OCH2O],
4.4 [s, 1H, CH], 5.5 [s, 2H, NH2], 7.2–8.3 [m, 9H, Ar-H þ SO2NH2].
Anal.Calcd. for C23H20N4O5S: C, 59.47; H, 4.34; N, 12.06. Found:
C, 59.61; H, 4.62; N, 12.34.
4.1.17. 4-[2-Amino-3-cyano-4-(2-methoxy-1-naphthyl)-5-oxo-
5,6,7,8-tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (37)
Yield, 66%; m.p. 228–230 ꢁC; IR: 3339, 3255, 3186 (NH2), 3106
(CH arom.), 2949, 2830 (CH aliph.), 2120 (ChN) 1611 (C]O), 1361,
1183 (SO2). 1H NMR: 1.8–2.2 [m, 6H, 3CH2 cyclo.], 3.6 [s, 3H, OCH3],
5.5 [s, 1H, CH], 7.3–7.8 [m, 14H, Ar-H þ NH2 þ SO2NH2]. Anal.Calcd.
for C27H24N4O4S: C, 64.78; H, 4.83; N,11.19. Found: C, 64.49; H, 4.57;
N, 10.87.
4.1.10. 4-[2-Amino-3-cyano-4-(4-hydroxy-3-methoxyphenyl)-5-
oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (30)
Yield, 69%; m.p. 274–276 ꢁC; IR: 3471 (OH), 3360, 3194 (NH2),
3070 (CH arom.), 2978, 2947 (CH aliph.), 2148 (ChN), 1647 (C]O),
1375, 1193 (SO2). 1H NMR: 1.8–2.2 [m, 6H, 3CH2 cyclo.], 3.6 [s, 3H,
OCH3], 4.6 [s, 1H, CH], 5.6 [s, 2H, NH2], 7.3–8.0 [m, 9H,

S.I. Alqasoumi et al. / European Journal of Medicinal Chemistry 45 (2010) 1849–1853
1853
4.1.18. 4-[2-Amino-3-cyano-4-(4-methoxy-1-naphthyl)-5-oxo-
5,6,7,8-tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (38)
Yield, 71%; m.p. >300 ꢁC; IR: 3441, 3350, 3239, 3188 (NH2), 3106
(CH arom.), 2949, 2830 (CH aliph.), 2214 (ChN) 1640 (C]O), 1383,
1157 (SO2). 1H NMR: 1.8–2.2 [m, 6H, 3CH2 cyclo.], 3.5 [s, 3H, OCH3],
5.5 [s, 1H, CH], 7.2–8.4 [m, 14H, Ar-H þ NH2 þ SO2NH2]. Anal.Calcd.
for C27H24N4O4S: C, 64.78; H, 4.83; N,11.19. Found: C, 64.53; H, 4.62;
N, 11.26.
In a set of sterile test tubes 0.8 ml RBMI-1640 media containing
(glutamine, fetal calf serum as nutrient, streptomycin and peni-
cillin), 0.1 mL of each of the tested compounds (corresponding to
100, 50, 25, 10 mg) were mixed then 0.1 mL of tumor cell suspension
(2 ꢃ106) was added. The test tubes were incubated at 37 ꢁC for 2 h.
Trypan blue exclusion test was carried out to calculate the
percentage of non-viable cells after 2 h of incubation [27]. The
results of in vitro cytotoxic activity experiments are presented in
Table 1.
4.1.19. 4-[2-Amino-3-cyano-4-(2-furyl)-5-oxo-5,6,7,8-
tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (39)
References
Yield, 84%; m.p. 198–199 ꢁC; IR: 3354, 3262 (NH2), 3034 (CH
arom.), 2950, 2840 (CH aliph.), 2224 (ChN), 1611 (C]O), 1360, 1184
(SO2). 1H NMR: 1.6–2.2 [m, 6H, 3CH2 cyclo.], 4.4 [s, 1H, CH], 5.4 [s,
2H, NH2], 7.2–8.2 [m, 9H, Ar-H þ SO2NH2]; MS m/z (%): 410 [Mþ]
(2.1), 207 (100). Anal.Calcd. for C20H18N4O4S: C, 58.53 H, 4.42; N,
13.65. Found: C, 58.87; H, 4.11; N, 13.98.
[1] D.H. Boschelli, F. Boschelli, Drugs Future 25 (2000) 717–736.
[2] J.D. Bjorge, A. Jakymiw, D.J. Fujita, Oncogene 19 (2000) 5620–5635.
[3] R.B. Irby, T.J. Yeatman, Oncogene 19 (2000) 5636–5642.
[4] M. Missbach, E. Altmann, M. Susa, Curr. Opin. Drug Discov. Dev. 3 (2000)
541–548.
[5] R. Paul, Z.G. Zhang, B.P. Eliceiri, Q. Jiang, A.D. Boccia, R.L. Zhang, M. Chopp,
D.A. Cheresh, Nat. Med. 7 (2001) 222–227.
[6] M.R. Myers, N.N. Setzer, A.P. Spada, A.L. Zulli, C.-Y.J. Hsu, A. Zilberstein,
S.E. Johnson, L.E. Hook, M.V. Jacoski, Bioorg. Med. Chem. Lett.
417–420.
[7] J.H. Hanke, J.P. Gardner, R.L. Dow, P.S. Changelian, W.H. Brissette, E.J. Weringer,
B.A. Pollok, P.A. Connelly, J. Biol. Chem. 271 (1996) 695–701.
[8] M. Missbach, E. Altmann, L. Widler, M. Susa, E. Buchdunger, H. Mett, T. Meyer,
J. Green, Bioorg. Med. Chem. Lett. 10 (2000) 945–949.
[9] S.R. Klutchko, J.M. Hamby, D.H. Boschelli, Z.P. Wu, A.J. Kraker, A.M. Amar,
B.G. Hartl, C. Shen, W.D. Klohs, R.W. Steinkampf, D.L. Driscoll, J.M. Nelson,
W.L. Elliott, B.J. Roberts, C.L. Stoner, P.W. Vincent, D. Dykes, R.L. Panek, G.H. Lu,
T.C. Major, T.K. Dahring, H. Hallak, L.A. Bradford, H.D.H. Showalter,
A.M. Doherty, J. Med. Chem. 41 (1998) 3276–3292.
7 (1997)
4.1.20. 4-[2-Amino-3-cyano-4-(5-methyl-2-furyl)-5-oxo-5,6,7,8-
tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (40)
Yield, 89%; m.p. 296–298 ꢁC; IR: 3355, 3263 (NH2), 3034 (CH
arom.), 2923, 2860 (CH aliph.), 2207 (ChN) 1611 (C]O), 1360, 1184
(SO2). 1H NMR: 1.8–2.2 [m, 6H, 3CH2 cyclo.], 2.5 [s, 3H, CH3], 5.4 [s,
1H, CH], 7.2–7.8 [m, 10H, Ar-H þ NH2 þ SO2NH2]. Anal.Calcd. for
C21H20N4O4S: C, 59.42 H, 4.75; N, 13.20. Found: C, 59.10; H, 5.09; N,
12.88.
[10] A.M. Thompson, G.W. Rewcastle, S.L. Boushelle, B.G. Hartl, A.J. Kraker, G.H. Lu,
B.L. Batley, R.L. Panek, H.D.H. Showalter, W.A. Denny, J. Med. Chem. 43 (2000)
3134–3147.
[11] M.C. Schroeder, J.M. Hamby, C.J.C. Connolly, P.J. Grohar, R.T. Winters,
M.R. Barvian, C.W. Morre, S.L. Boushelle, S.M. Crean, A.J. Kraker, D.L. Driscoll,
P.W. Vincent, W.L. Elliott, G.H. Lu, B.L. Batley, T.K. Dahring, T.C. Major,
R.L. Panek, A.M. Doherty, H.D.H. Showalter, J. Med. Chem. 44 (2001)
1911–1915.
[12] A. Wissner, D.M. Berger, D.H. Boschelli, M.B. Floyd, L.M. Greenberger,
B.C. Gruber, B.D. Johnson, N. Mamuya, R. Nilakantan, M.F. Reich, R. Shen,
H.R. Tsou, E. Upeslacis, Y.F. Wang, B. Wu, F. Ye, N. Zhang, J. Med. Chem. 43 (17)
(2000) 3244–3256.
4.1.21. 4-[2-Amino-3-cyano-4-(2-thienyl)-5-oxo-5,6,7,8-
tetrahydroquinolin-1(4H)-yl]benzenesulfonamide (41)
Yield, 83%; m.p. 234–236 ꢁC; IR: 3354, 3262 (NH2), 3033 (CH
arom.), 2950, 2840 (CH aliph.), 2223 (ChN) 1612 (C]O), 1360, 1184
(SO2). 1H NMR: 1.7–2.2 [m, 6H, 3CH2 cyclo.], 4.6 [s, 1H, CH], 5.6 [s,
2H, NH2] 7.2–8.1 [m, 9H, Ar-H þ SO2NH2]. MS m/z (%): 425 [Mþ ꢀ 1]
(1.5), 73 (100). Anal.Calcd. for C20H18N4O3S2: C, 56.32 H, 4.25; N,
13.14. Found: C, 56.07; H, 4.53; N, 12.80.
[13] D.H. Boschelli, D.Y. Wang, F. Ye, B. Wu, N. Zhang, M. Dutia, D.W. Powell,
A. Wissner, K. Arndt, J.M. Weber, F. Boschelli, J. Med. Chem. 44 (2001)
822–833.
4.2. Biological testing
[14] N. Zhang, B. Wu, D. Powell, A. Wissner, M.B. Floyd, E.D. Kovacs, L. Toral-Barza,
C. Kohler, Bioorg. Med. Chem. Lett. 10 (2000) 2825–2828.
4.2.1. Animals, chemicals and facilities
Ehrlich ascites carcinoma (EAC) cells were maintained in female
Swiss albino mice weighing 25–30 g (the holding company for
biological products and vaccines, VACSERA, Cairo, Egypt) were
housed at a constant temperature (24 ꢂ 2 ꢁC) with alternating 12-h
light and dark cycles and fed standard laboratory food (Milad CO.,
Cairo, Egypt) and water ad libitum. All chemicals and reagents were
of the highest grade commercially available. Facilities including
animal house, biochemical equipments have been made available
by the National Center for Radiation Research and Technology
(NCRRT), Atomic Energy Authority (AEA), Cairo, Egypt. Animal care
and handling was done according to the guidelines set by the world
health organization, Geneva, Switzerland and approved from the
committee for animals care at NCRRT, AEA.
[15] D.H. Boschelli, F. Ye, D.Y. Wang, M. Dutia, S. Johnson, B. Wu, K. Miller,
D.W. Powell, K. Arndt, C. Discafani, C. Etienne, J. Gibbons, J. Grod, J. Lucas,
J.M. Weber, F. Boschelli, J. Med. Chem. 44 (2001) 3965–3977.
[16] D.H. Boschelli, D.Y. Wang, F. Ye, A. Yamashita, N. Zhang, D.W. Powell,
J.M. Weber, F. Boschelli, Bioorg. Med. Chem. Lett. 12 (2002) 211–214.
[17] M.M. Ghorab, F.A. Ragab, E. Noaman, H.I. Heiba, E.M. El-Hossary, Arzneimittel-
Forsch./Drug Res. 58 (1) (2007) 35–41.
[18] M.M. Ghorab, F.A. Ragab, E. Noaman, H.I. Heiba, E.M. El-Hossary, Arzneimittel-
Forsch./Drug Res. 57 (12) (2007) 795–803.
[19] M.M. Ghorab, N.M. Taha, M.A. Radwan, N.E. Amin, M.A. Shehab, M.I. Faker,
Phosphorus Sulfur Silicon Rel. Elem. 183 (12) (2008) 2891–2905.
[20] M.M. Ghorab, M.A. Radwan, N.M. Taha, N.E. Amin, M.A. Shehab, M.I. Faker,
Phosphorus Sulfur Silicon Rel. Elem. 183 (12) (2008) 2906–2917.
[21] M.M. Ghorab, N.E. Amin, M.S. El-Gaby, N.M. Taha, M.A. Shehab, M.I. Faker,
Phosphorus Sulfur Silicon Rel. Elem. 183 (12) (2008) 2918–2928.
[22] M.M. Ghorab, M.S. El-Gaby, N.E. Amin, N.M. Taha, M.A. Shehab, M.I. Faker,
Phosphorus Sulfur Silicon Rel. Elem. 183 (12) (2008) 2929–2942.
[23] D.A. Abou El Ella, M.M. Ghorab, E. Noaman, H.I. Heiba, A.I. Khalil, Bioorg Med.
Chem. 16 (5) (2008) 2391–2402.
[24] M.M. Ghorab, D.A. Abou El Ella, E. Noaman, H.I. Heiba, A.I. Khalil, Phosphorus
Sulfur Silicon Rel. Elem. 183 (1) (2008) 90–104.
[25] L. Shewchuk, A. Hassell, B. Wisely, W. Rocque, W. Holmes, J. Veal, L.F. Kuyper, J.
Med. Chem. 43 (1) (2000) 133–138.
[26] P. Uma Devi, F.E. Solomon, A.C. Sharada, Pharm. Biol. 37 (3) (1999) 231–236.
[27] D.J. Brusick, In carcinogenesis and mutagenesis testing. in: J.F. Douglas (Ed.),
Cytogenetic Assays. Aberrations and SCE Techniques. Human Press Inc., Clif-
ton, New Jersey, 1984, pp. 265–276.
4.2.2. Antitumor activity [26]
Ehrlich Ascites Carcinoma (EAC) cells were obtained by needle
aspiration of ascetic fluid from preinoculated mice; under aseptic
conditions. Tumor cells suspension (2.5 ꢃ106 per mL) was prepared
in RBMI-1640 media. Tested compounds were prepared with
various dilutions by dissolving: 100, 50, 25 & 10
compounds in DMSO (1 mL).
mg of the tested