Novel quinoline bearing sulfonamide derivatives and their cytotoxic activity against MCF7 cell line

Article abstract of DOI:10.1007/s00044-017-1850-9

The present work reports the synthesis of novel 5-Oxo-5,6,7,8-tetrahydroquinoline and 2,5-dioxo-5,6,7,8-tetrahydroquinoline derivatives containing enaminone system and bearing a sulfonamide moiety. The newly synthesized compounds were designed in complian

Full text of DOI:10.1007/s00044-017-1850-9

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-017-1850-9
ORIGINAL RESEARCH
Novel quinoline bearing sulfonamide derivatives and their
cytotoxic activity against MCF7 cell line
N. S. Ahmed1,2 K. O. Badahdah1 H. M. Qassar1
●
●
Received: 14 December 2015 / Accepted: 2 March 2017
© Springer Science+Business Media New York 2017
Abstract The present work reports the synthesis of novel
5-Oxo-5,6,7,8-tetrahydroquinoline and 2,5-dioxo-5,6,7,8-
tetrahydroquinoline derivatives containing enaminone sys-
tem and bearing a sulfonamide moiety. The newly synthe-
sized compounds were designed in compliance with the
general pharmacophoric requirements for carbonic anhy-
drase inhibiting anticancer drugs, as this may play a role in
their anticancer activity. Twelve of the newly synthesized
compounds were evaluated for their in vitro anticancer
activity against human breast cancer cell line (MCF7).
Compounds 5c, 7, 10, and 12c showed IC50 values (0.048,
0.040, 0.041, 0.044 μM, respectively) comparable to that of
the reference drug doxorubicin (IC50 = 0.04 μM). On the
other hand, compounds 12a, 12d, and 16b exhibited better
activity than doxorubicin with an IC50 values (0.025, 0.036,
0.015 μM, respectively).
Introduction
Recently, researchers have been showing great
interest in the enaminone family of compounds. These
compounds possess a great potential as multipurpose syn-
thetic intermediate in organic synthesis, in heterocyclic
synthesis (Michael et al. 1999) and as they showed
a wide variety of medicinal effects such as cardiovascular
effects (García et al. 2012), anti-inflammatory (El-Hashim
et al. 2010), antiviral (El-Sabbagh and Rady 2009), anti-
tussive (El-Hashim et al. 2001), antimicrobial
(Abbas and Farghaly 2010), and anticonvulsant effects
(Edafiogho et al. 2009; Eddington et al. 2000, 2002; Jack-
son et al. 2012).
On the other hand, quinoline and its derivatives are very
much used in pharmaceuticals such as an anticancer agents
(Creaven et al. 2010; Lu et al. 2010; Gao et al. 2010; Perin
et al. 2011; Wang et al. 2012), antioxidant (Korrichi et al.
2009), antifungal (Creaven et al. 2010; Kouznetsov et al.
2012), anti-inflammatory (Ghodsi et al. 2010; Chen et al.
2011; Kumar et al. 2012), antibacterial (Garudachari et al.
2012), antimalarial (Pretorius et al. 2013), antiviral (Carta
et al. 2011; Guo et al. 2011), and for depression of schi-
zophrenia (Daniel 2007). Also, it was found that quinoline
compounds containing enaminone moiety show more
potent biological activities, especially as antiviral (Ahmed
et al. 2010; Vandurm et al. 2009), antibacterial (Jayagobi
et al. 2011), antitumor (Ghorab et al. 2009, 2010; Alqa-
soumi et al. 2009, 2010a, b; Al-Said et al. 2011), anti-
microbial (Makawana et al. 2012), and hypotensive activity
(El-Sabbagh et al. 2010).
●
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Keywords Enaminones 5,6,7,8-Tetrahydroquinolin
●
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Sulphanilamid Ultrasonic irradiation CA inhibitors
Electronic supplementary material The online version of this article
(doi:10.1007/s00044-017-1850-9) contains supplementary material,
which is available to authorized users.
* N. S. Ahmed
nesreen69eg@yahoo.com
nahmad@kau.edu.sa
1
Additionally, sulfonamides have attracted a great atten-
tion as antitumor agents since many of aryl/heteroaryl sul-
fonamides were reported to act as antitumor agents through
a variety of mechanisms, as well as the most prominent
Chemistry Department, Faculty of Science, King Abdulaziz
University, Jeddah, Saudi Arabia
2
Medicinal Chemistry Department, National Research Centre,
Dokki, Cairo, Egypt

Med Chem Res
mechanism was the inhibition of carbonic anhydrase iso-
zyme (CA) (Ghorab et al. 2009, 2010; Al-Said et al. 2011).
In this respect, we reported here the preparation of some
quinoline derivatives containing enaminone system and
bearing sulfonamide moiety, then we had tested their
in vitro growth inhibitory activities against human cultured
breast carcinoma cell lines (MCF7) in comparison to dox-
orubicin (DOX) which is one of the most effective anti-
tumor agents, hoping to obtain more active and less toxic
anticancer agents.
Fig. 1 Structural elements of CA inhibitors in the CA enzymatic
active site
Results/Discussion
A general pharmacophore (Fig. 1) for the compounds acting
as CA inhibitors has been reported by Thiry et al. (2006)
from the analysis of the CA active site and from the
structure of inhibitors described in the literature by Supuran
et al. (2003). This pharmacophore includes the structural
elements that are required to be present in the compounds in
order to act as CA inhibitors. This includes the presence of a
sulfonamide moiety which coordinates with the zinc ion of
the active site of the CA and the sulfonamide is attached to a
scaffold, which is usually a benzene ring. The side chain
might possess a hydrophilic link which is able to interact
with the hydrophilic part of the active site and a hydro-
phobic moiety which can interact with the hydrophobic part
of the CA active site (Ghorab et al. 2010). We have syn-
thesized new compounds (Schemes 1–4), and two examples
that showing their compliance with the above-mentioned
pharmacophore model is represented in Fig. 2.
based on their elemental analysis and their spectral data.
The fourier transform infrared spectroscopy (FTIR) spectra
for compound 5a revealed four bands at 3469, 3408, 3347,
and 3334 cm−1 for two NH2 groups, in addition to the
absorption band at 2177 for C≡N, besides the characteristic
1
bands for SO2 group at 1357–1190 cm−1. The H nuclear
magnetic resonance (NMR) spectrum of compound 5a in
(dimethyl sulfoxide (DMSO)-d6) showed the two methyl
groups as two singlet signals at δH 0.75 and 0.90 ppm, the
two methylene proton appeared as a pair of singlet signal at
δH 1.07 and 2.09 ppm, and C4-H proton appeared as singlet
signal at δH 4.45 ppm. Moreover, two singlet signals at δH
5.80 and 8.54 ppm for NH2 and SO2NH2 groups, respec-
tively, are exchangeable with D2O, and the aromatic protons
appear as a complex pattern from δH 6.89–8.06 ppm.
Moreover, refluxing of compound 5a with chloroacetyl
chloride in dimethylformamide (DMF) for 20 h yielded the
quinoline derivative 6 (Scheme 2). The structure of the
resulted compound was confirmed by elemental and spec-
tral analysis. It’s FTIR spectra showed absorption band at
2227 cm−1 C≡N, a band at 1653 cm−1 and a broadband
Chemistry
Synthesis of 5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)
benzenesulfonamide derivatives
1
appeared at 1699 cm−1 for 3C=O groups. H NMR spec-
Enaminone 3 was obtained from the condensation of 5,5-
dimethyl-1,3-cyclohexandione 1 with sulfanilamide 2 in
absolute ethanol under reflux for 3 h, (Ghorab et al. 2009), it
was also obtained in 90% yield by using ultrasonic irra-
diation at 80 °C for 20 min. Treatment of enaminone 3 with
different arylidene malononitrile derivatives 4a–c in ethanol
containing a catalytic amount of triethylamine, as a base
catalyst, yielded the corresponding hexahydro quinoline
derivative 5a–c (Scheme 1). Compounds 5a–c were also
obtained by ultrasonic irradiation at 80 °C under the same
condition in better yield. Table 1 shows a slight increase in
the reaction yield in a relatively short reaction time in the
presence of ultrasonic irradiation. These results confirm that
ultrasonic irradiation played a crucial role in the enhance-
ment of the rapid synthesis of hydro quinoline derivatives
5a–c. The structures of these compounds were established
trum in (DMSO-d6) for compound 6 showed the dis-
appearance of NH2 signals at δH 5.89 ppm and a new two
singlet bands at δH 2.71 and 2.87 ppm for 2COCH2Cl.
When compound 5a was refluxed in acetic anhydride for
1 h the fused pyrimido[4,5-b]quinoline system 7 was
obtained in a good yield. The spectral and elemental data of
compound 7 confirmed the assigned structures. The FTIR
spectra of this particular sample show the disappearance of
the cyano group band, while two bands at 1697 and 1669
cm−1 for 2C=O groups were recorded. On the other hand,
1
it’s H NMR spectrum in (DMSO-d6) showed singlet band
at δH 1.89 ppm for 5H for COCH3 and C9-H2, singlet band
at δH 2.07 ppm for 5H for CH3 at C2 and C7-H2. Tow singlet
bands at δH 10.37 and 11.95 ppm, which is corresponding to
NH and OH, respectively were disappeared on adding D2O
(Scheme 2).

Med Chem Res
Scheme 1 Synthetic route to 5-
oxo-5,6,7,8-tetrahydroquinolin-1
(4H)-yl)benzenesulfonamide
derivatives variously substituted
in the 4-position 5a–c
Scheme 2 Synthetic scheme and structure of the quinolines 6,8,9, pyrimido[4,5-b]quinoline derivative 7, and benzo[b][1,8] naphthyridine
derivative 10
1
In addition, the fusion of compound 5a with ethyl cya-
noacetate yielded the corresponding acetamide derivative 8
(Scheme 2). The structure of compound 8 was confirmed by
elemental and spectral analysis. The FTIR showed bands at
3312, 3229, and 3123 cm−1 for NH and NH2 groups. The
new cyano groups at 2260 cm−1 were observed and two
bands at 1743 and 1680 cm−1 for two C=O groups were
recorded. 1H NMR spectrum in (DMSO-d6) showed the
CH2CN protons as singlet together with the C4-H at δH 3.94
ppm, and NH proton appeared as singlet signal at δH 10.17
ppm which is disappeared on adding D2O. In addition to
that, 4-(2-amino-5-(2-aminoethylamino)-3-cyano-4-(4-fluor-
ophenyl)-7,7-dimethyl-7,8-dihydroquinolin-1(4H)-yl) ben-
zenesulfonamide 9 was obtained by the treatment of
compound 5a with ethylenediamine in the presence of car-
bon disulfide (Scheme 2). The structure of compound 9 was
proved on the basis of its spectral and elemental data. FTIR
spectra showed a broadband from 3337–3193 cm−1 for NH
and NH2 groups, while C≡N appeared at 2201 cm−1. H
NMR spectrum in (DMSO-d6) showed singlet signal for C8-
H2 at δH 1.88 ppm, two new singlet signals at δH 2.38 and
2.51 ppm for NH and NH2 beside the original C2-NH2 at δH
5.77 ppm, and SO2NH2 at δH 8.30 ppm. On the other hand,
the two methylene protons appeared as a pair of triplet bands
at δH 3.63 and 3.81 ppm, while the C6-H appeared with
Ar–H in the range from δH 6.65 to 8.13 ppm.
Additionally, the octahydrobenzo[b][1,8] naphthyridine
derivative 10 was obtained by the reaction of compound 5a
with ethyl acetoacetate (Scheme 2). The structure of the
compound obtained was confirmed with their spectral and
elemental analysis. The FTIR spectra of compound 10
showed NH and NH2 absorption band at 3304, 3256, and
3225 cm−1, and three absorption bands at 1713, 1660, and
1632 cm−1 for three different CO groups. H NMR spec-
trum in (DMSO-d6) of this compound revealed two singlet
1
signals at δH 1.16 and 1.22 ppm due to 2CH3 group at C8,

Med Chem Res
Scheme 3 Synthetic route to 2,5-dioxo-5,6,7,8-tetrahydroquinolin-1(2H)-yl)benzenesulfonamide derivatives variously substituted in the
4-position 12a–f
two singlet signals at δH 2.24 and 2.55 ppm for 2CH2 of C9
and C7, respectively. The new singlet signal at δH 2.35 ppm
due to COCH3, more over two singlet bands at δH 3.57 and
4.09 ppm for C3-H and C5-H, respectively. A singlet signal
at δH 4.24 ppm due to NH proton at C4, and a signal at δH
15.72 ppm for OH of the iminol structure 10b (Fig. 3),
which were disappeared on adding D2O. In addition, a
complex pattern appeared at δH 6.04–8.50 ppm due to
aromatic protons together with SO2NH2 and endocyclic
NH. The observed iminol structure may be attributed to the
gain of energy enhanced by intramolecular hydrogen
bonding and the rate at which this tautomer interconvert is
slow compared with the inherent time scale of NMR
spectroscopy.
showed bands at 3372 and 3236 cm−1 for NH2 group and a
band at 2226 cm−1 for CN group, and two bands at 1715
1
and 1690 cm−1 for 2C=O groups. In addition H NMR
spectrum of compound 12a in (DMSO-d6) showed two
singlet signals at δH 0.87 and 1.02 ppm for 2CH3 groups,
pair of doublets bands at δH 2.03 and 2.23 ppm for C6
protons and pair of doublet bands at δH 2.46 and 2.51 ppm
of C8 protons, a singlet band at δH 8.30 ppm for SO2NH2
group (exchangeable with D2O), and the aromatic protons
appear as complex pattern from δH 6.99–7.55 ppm.
Fusion of compound 12a with dimethylformamide/
dimethylacetal (DMF/DMA) in a sand bath for 6 h gave the
corresponding enaminone 13 in 94% yield (Scheme 4). The
structure of compound 13 is assigned based on the ele-
1
mental analysis and spectral data. H NMR spectrum in
Synthesis of 2,5-dioxo-5,6,7,8-tetrahydroquinolin-1(2H)-yl)
benzenesulfonamide derivatives
(CDCl3) showed the absence of C6 protons, a new two
singlet signals at δH 3.04 and 3.15 ppm for –N(CH3)2, and a
new singlet signal at δH 7.71 ppm for olefinic CH. Treat-
ment of enaminone 13 with guanidine, (liberated in situ
from guanidine nitrate in the presence of sodium carbonate)
under fusion in a sand bath gave 4-(2-amino-9-cyano-10-(4-
fluorophenyl)-5,5-dimethyl-8-oxo-5,6-dihydropyrido[2,3-h]
quin-azolin-7(8H)-yl)benzenesulfonamide 14 in 97% yield.
The structure of compound 14 is assigned based on its
spectral and elemental analysis data. FTIR spectra for
compound 14 showed two broadband peaks at 3351 and
3201 cm−1 for 2NH2 groups, and at 1666 cm−1 for CO
group. 1H NMR spectrum in (DMSO-d6) showed the
absence of –N(CH3)2 signals, and a new, D2O exchangeable
–NH2 protons at δH 5.80 ppm. The C4-H proton appears in a
In one pot reaction, a mixture of diamidone 1, sulfanilamide
2, ethyl cyanoacetate, and benzaldehyde derivatives 11a–f,
were heated under reflux in the presence of ethanol to give
the corresponding 2,5-dioxo-5,6,7,8-tetrahydroquinolin-1
(2H)-yl)benzenesulfonamide derivatives 12a–f (Scheme 3).
The same reaction was repeated by using ultrasonic irra-
diation instead of the conventional method, the same pro-
ducts 12a–f as examined by thin layer chromatography
(TLC) were obtained in shorter time and better yield
(Table 2). The structures of the resulted compounds were
1
proved by FTIR, H NMR, 13C NMR and elemental ana-
lysis. Compound 12a as an example, it’s FTIR spectra

Med Chem Res
Scheme 4 Synthetic scheme and structure of the pyrido[2,3-h]quinazoline derivative 14, pyrazolo[3,4-f]quioline derivatives 15a,b, and pyrazolo
[1,5-a]pyrido[2,3-h]quinazoline derivatives 16a,b
complex pattern with aromatic protons and –SO2NH2 pro-
tons in a range from δH 6.53–8.30 ppm.
pyrazole derivatives under fusion in the sand bath in the
presence of catalytic amount of Triethylamine (TEA), it
afforded the corresponding derivatives 16a,b (Scheme 4).
The structure of compounds 16a,b was confirmed on the
Also, enaminone 13 undergo cyclo-condensation on
treatment with hydrazine derivatives under reflux in a sand
bath to afford compounds 15a,b (Scheme 4). The structure
of compounds 15a,b were assigned depending on their
spectral data and elemental analysis. FTIR spectra of
compound 15a showed a band at 1620 cm−1 for C=O. The
1H NMR spectrum in (CDCl3) for compound 15b showed
the disappearance of the –N(CH3)2 protons at δH 3.04 and
3.15 ppm, the ph-H and the CH of pyrazole ring appeared
with the complex pattern from δH 6.64–8.09 ppm.
1
basis of their spectral data and elemental analysis. The H
NMR spectrum in (CDCl3) of compound 16a showed a new
singlet signal at δH 2.67 ppm for C2-CH3, the phenyl pro-
tons appeared in the complex pattern with aromatic protons
and SO2NH2 protons ranged from δH 7.17–8.00 ppm. The
C5 proton for the fused pyrazolo pyrido derivative appeared
at δH 8.97 ppm.
The behavior of 4-(3-cyano-6-((dimethylamino)methy-
lene)-4-(4-fluorophenyl)-7,7-dimethyl-2,5-dioxo-5,6,7,8-
In vitro cytotoxic screening
tetrahydroquinolin-1(2H)-yl)
toward some amino pyrazole derivatives was also investi-
gated. Thus, when enaminone 13 was treated with amino
benzenesulfonamide
13
In the present work, 12 of the newly synthesized com-
pounds (5a,c), (7), (8), (10), (12a–d), (14), (15b), (16b)
were selected to evaluate their in vitro growth inhibitory

Med Chem Res
sulfonamide moiety using both classical and sonicated
methods. Selected examples of these newly synthesized
compounds were investigated against their in vitro antic-
ancer activity against human breast cancer cell line (MCF7).
Some of these new compounds exhibited significant antic-
ancer activity, when compared to DOX as a reference drug.
Since it was reported that compounds bearing a free sul-
fonamide group may show potent CA inhibition activity,
which is considered to be an interesting target for the design
of anticancer agents, the results obtained from the antic-
ancer screening may provide a suggestion that the synthe-
sized compounds may act as CA inhibitors that could
contribute to their anticancer activity.
Experimental section
General
Fig. 2 Representative examples of the newly synthesized compounds
All melting points (m.p.) were measured on a Mel-Temp
apparatus and were uncorrected. TLC was performed on
aluminum silica gel 60 F254 (E-Merk). The spots were
detected by iodine and UV light absorption. Infrared spectra
were recorded for the compounds in an FTIR, Perkin Elmr
SP 100 Spectrometer. 1H NMR and 13C spectra were
recorded on Burker WM 400 and 600 MHz spectrometer
using TMS (0.00 ppm) or the signal of the deuterated sol-
vent was used as internal standard. Reactions that carried
out by ultrasonic irradiation was done using Daihan
(Wiseclean, D-40 MHz) ultrasonic bath. Microanalysis was
performed by Perkin Elmer elemental analyzer. Biological
activity tests were performed at the National Cancer Insti-
tute, Cairo, Egypt.
Table 1 Synthesis of hexahydro quinoline derivative 5a–c under both
ultrasonic irradiation and using the conventional method
Compounds
Ultrasonic irradiation
Conventional method
Time (min)
Yield (%)
Time (h)
Yield (%)
5a
5b
5c
30
45
60
62
92
93
6
9
60
89
89
14
activities against human cultured breast carcinoma cell lines
(MCF7) in comparison to DOX, which is one of the most
efficient antitumor agents. According to the resultant data
presented in Table 3, which shows the in vitro cytotoxic
activity of the selected synthesized compounds, some
compounds exhibit significant activity compared to the
reference drug. From the results in Table 3, it was found
that the quinoline derivatives 12a,d and 16b (IC50 = 0.036,
0.025, 0.036, 0.015 μM, respectively) were the most potent
compounds in this screening, and exhibited a higher cyto-
toxic activity when compared with the reference drug DOX
Typical procedure for the reactions
Synthesis of 4-(5,5-dimethyl-3-oxocyclohex-1-enylamino)
benzenesulfonamide (3)
Method A: silent reaction Prepared according to reported
procedure (Ghorab et al. 2010).
(IC50 = 0.04 μM). Compounds 5c, 7, 10, and 12c (IC50
=
0.048, 0.040, 0.041, 0.044 μM, respectively) were nearly as
active as DOX, compounds 5a, 8, 12b, 14, and 15b showed
lower IC50 values than that of the reference drug, ranging
from 0.055–0.088 μM.
Method B: sonicated reaction A mixture of diamidone 1
(0.14 g, 1 mmol) and sulfanilamide 2 (0.172 g, 1 mmol) in
ethanol (7 ml) was sonicated at a frequency of 40 KHz for
20 min at 80 °C. Then the reaction mixture was cooled in
ice bath and the collected mass was filtered off, dried, and
crystallized from ethanol to give enaminone 3 as white
crystals (0.265 g, 90% yield); m.p. 235–237 °C. FTIR,
cm−1: 3400, 3310, 3290 (NH, NH2); 1630 (C=O);
1357–1150 (SO2).
Conclusion
In this work, we have synthesized novel quinoline deriva-
tives containing enaminone system and bearing
a

Med Chem Res
Fig. 3 Imine-iminol structures
of compound 10
Table 2 Synthesis of benzenesulfonamide derivatives 12a–f under
Table 3 The effect of some newly synthesized compounds against
both ultrasonic irradiation and using the conventional method
human breast carcinoma cell line (MCF7)
Compounds
Ultrasonic irradiation
Conventional method
Compounds
IC50 (μM)
Time (min)
Yield (%)
Time (h)
Yield (%)
5a
0.088
0.048
0.040
0.055
0.041
0.025
0.064
0.044
0.036
0.076
0.087
0.015
0.04
5c
12a
12b
12c
12d
12e
12f
10
10
50
30
20
20
85
96
95
82
70
80
3
4
72
50
80
65
40
69
7
8
30
20
16
16
10
12a
12b
12c
12d
14
Synthesis of 4-(2-amino-3-cyano-4-(aryl)-7,7-dimethyl-5-
oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)
benzenesulfonamide (5a–c)
15b
16b
DOX
Method A: silent reaction A mixture of compound 3 (2.94 g,
10 mmol) and different arylidene malononitrile 4a–c
(10 mmol) in EtOH (20 ml) containing three drops of TEA
was refluxed for 6–14 h (until disappearance of starting
material as examined by TLC). The reaction mixture was
filtered while hot and the solid obtained was filtered off and
dried.
3408, 3347, 3334 (2NH2); 2177 (C≡N); 1630 (C=O);
1357–1190 (SO2). 1H NMR (600 MHz, DMSO-d6) δH:
0.75, 0.90 (6H, 2s, 2CH3); 1.07 (2H, s, C8-H2); 2.09 (2H, s,
C6-H2); 4.45 (1H, s, C4-H); 5.80 (2H, s, NH2); 6.89–8.06
(8H, complex pattern, Ar–H); 8.54 (2H, s, SO2NH2). 13C
NMR (600 MHz, DMSO-d6) δC: 15.00 (2CH3); 18.00 (C7);
57.00 (C4); 79.00 (C8); 81.22 (C6); 81.24 (C3); 112.47
(C4′); 113.21, 128.06, 130.05, 160.2 (of p-flouro phenyl
ring); 114.20, 127.45, 133.55, 133.62 (of p-SO2NH2 phenyl
ring); 117.04 (CN); 160.20 (C8′); 164.36 (C2); 194.00 (C5).
Anal. calcd. for C24H23FN4O3S (466.53): C, 62.09; H, 4.97;
N, 12.01%. Found: C, 61.99; H, 4.85; N, 11.95%.
Method B: sonicated reaction A mixture of compound 3
(0.294 g, 1 mmol) and different arylidene malononitrile 4a–
c (1 mmol) in EtOH (7 ml) containing one drop of TEA was
sonicated at a frequency of 40 KHz for 30–60 min at 80 °C.
Then the reaction mixture was filtered and the collected
mass was filtered off and dried.
4-(2-Amino-3-cyano-4-(4-fluorophenyl)-7,7-dimethyl-5-
oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesulfona-
mide (5a): It was crystallized from ethanol as red crystals
(0.29 g, 62% yield); m.p. 119–120 °C. FTIR, cm−1: 3469,
4-(2-Amino-3-cyano-4-(4-nitrophenyl)-7,7-dimethyl-5-
oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesulfona-
mide (5b): It was crystallized from isopropanol to give dark

Med Chem Res
red crystals (0.45 g, 92% yield); m.p. 85–87 °C. FTIR,
cm−1: 3460, 3371, 3337, 3243 (2NH2); 2190 (C≡N); 1679
(C=O); 1344–1190 (SO2). 1H NMR (600 MHz, DMSO-d6)
δH: 0.70, 0.90 (6H, 2s, 2CH3); 1.35 (2H, s, C8-H2); 2.07
(2H, s, C6-H2); 4.37 (1H, s, C4-H); 5.79 (2H, s, NH2);
6.56–8.29 (8H, complex pattern, Ar–H); 8.34 (2H, s,
SO2NH2). 13C NMR (600 MHz, DMSO-d6) δC: 30.67
(2CH3); 45.69 (C7); 52.92 (C4); 58.00 (C8); 61.66 (C6);
79.00 (C3); 112.39 (C4′); 115.58, 129.98, 130.16, 134.13
(of p-SO2NH2 phenyl ring); 118.18 (CN); 123.63, 127.39,
142.93, 148.33 (of p-NO2 phenyl ring) 151.89 (C8′); 165.05
(C2); 194.00 (C5). Anal. calcd. for C24H23N5O5S (493.14):
C, 58.41; H, 4.70; N, 14.19%. Found: C, 58.49; H, 4.50; N,
14.13%.
and dried. It was crystallized from methanol to give pale
yellow crystals (0.48 g, 87% yield); m.p. 245–246 °C.
FTIR, cm−1: 3332, 3274 (NH, OH); 1697, 1669 (2C=O);
1371, 1156 (SO2). 1H NMR (600 MHz, DMSO-d6) δH:
0.75, 0.90 (6H, 2s, 2CH3); 1.89 (5H, s, C9-H2 and COCH3),
2.07 (5H, s, C7-H2 and C2-CH3); 3.15 (1H, s, C5-H);
7.16–8.54 (8H, m, Ar–H); 10.37 (1H, s, NH); 11.95 (1H, s,
OH). Anal. calcd. for C28H27FN4O5S (550.17): C, 61.08; H,
4.94; N, 10.18%. Found: C, 61.22; H, 5.01; N, 9.97%.
Synthesis of 2-cyano-N-(3-cyano-4-(4-fluorophenyl)-7,7-
dimethyl-5-oxo-1-(4-sulfamoylphenyl)-1,4,5,6,7,8-
hexahydroquinolin-2-yl)acetamide (8)
4-(2-Amino-3-cyano-4-(4-methoxyphenyl)-7,7-dimethyl-
5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesulfona-
mide (5c): It was crystallized from ethanol to give pale
yellow crystals (0.45 g, 93% yield); m.p. 148–149 °C.
FTIR, cm−1: 3475, 3380, 3311, 3235 (2NH2); 2218 (C≡N);
1623 (C=O); 1314–1149 (SO2). 1H NMR (600 MHz,
DMSO-d6) δH: 0.93, 1.01 (6H, 2s, 2CH3); 2.06 (2H, s,
C8-H2); 2.21 (2H, s, C6-H2); 3.69 (H, s, C4-H); 3.87 (3H, s,
O–CH3); 5.79 (2H, s, NH2); 6.56–7.97 (8H, complex
pattern, Ar–H); 8.37 (2H, s, SO2NH2). Anal. calcd. for
C25H26N4O4S (478.17): C, 62.74; H, 5.48; N, 11.71%.
Found: C, 62.94; H, 5.39; N, 11.64%.
A mixture of compound 5a (0.466 g, 1 mmol) and ethyl
cyanoacetate (10 ml) was refluxed together for 5 h. The
formed solid mass was filtered off and dried. It was crys-
tallized from methanol to give brown crystals (0.49 g, 92%
yield); m.p. 227–228.5 °C. FTIR, cm−1: 3312, 3229, 3123
(NH2, NH); 2260 (C≡N); 1743, 1680 (2C=O); 1360–1150
1
(SO2). H NMR (600 MHz, DMSO-d6) δH: 0.75, 0.90 (6H,
2s, 2CH3); 1.20 (2H, s, C8-H2); 2.06 (2H, s, C6-H2); 3.98
(3H, s, CH2CN and C4-H); 7.27–7.78 (8H, complex pattern,
Ar–H); 8.29 (2H, s, SO2NH2); 10.50 (1H, s, NH). 13C NMR
(600 MHz, DMSO-d6:CDCL3) δC: 23.00 (CH2CN); 26.93
(2CH3); 59.49 (C7); 60.74 (C4); 63.3 (C8); 66.91 (C6);
68.08 (C3); 112.00 (C4′); 114.80, 138.84, 130.00, 161.04
(p-F phenyl ring); 119.21, 130.20, 130.60, 141.24 (P-
SO2NH2 phenyl ring); 126.97 (CH-CN); 152.00 (C8′);
156.00 (C2); 172.43 (NHCO); 195 (C5). Anal. calcd. for
C27H24FN5O4S (533.15): C, 60.78; H, 4.53; N, 13.13%.
Found: C, 60.90; H, 4.32; N, 13.02%.
Synthesis of 2-chloro-N-(2-chloroacetyl)-N-(3-cyano-4-(4-
fluorophenyl)-7,7-dimethyl-5-oxo-1-(4-sulfamoylphenyl)-
1,4,5,6,7,8-hexahydroquinolin-2-yl)acetamide (6)
A mixture of compound 5a (0.466 g, 1 mmol) and chlor-
oacetyl chloride (0.08 ml, 1 mmol) in dimethyl formamide
(20 ml) was refluxed for 1 h. The reaction mixture was
poured onto cold water and the solid obtained was filtered
off and dried. It was crystallized from ethanol to give brown
Synthesis of 4-(2-amino-5-(2-aminoethylamino)-3-cyano-4-
(4-fluorophenyl)-7,7-dimethyl-7,8-dihydroquinolin-1(4H)-
yl)benzenesulfonamide (9)
crystals (0.28 g, 40% yield); m.p. 126–128 °C. FTIR, cm−1
:
3356, 3336 (NH2); 2227 (C≡N); br. 1699, 1653 (3C=O);
1303–1150 (SO2). 1H NMR (600 MHz, DMSO-d6) δH: 1.07
(6H, s, 2CH3); 2.53 (2H, s, C8-H2); 3.22 (2H, s, C6-H2);
2.71, 2.87 (4H, 2s, 2COCH2Cl); 3.99 (1H, s, C4-H);
6.56–7.93 (8H, complex pattern, Ar–H), 8.30 (2H, s,
SO2NH2). Anal. calcd. for C28H25Cl2FN4O5S (618.09): C,
54.29; H, 4.07; N, 9.04%. Found: C, 54.34; H, 4.00; N,
8.71%.
A mixture of compound 5a (0.466 g, 1 mmol) and ethyle-
nediamine (7 ml) was refluxed in carbon disulfide (7 ml) for
3 h. The reaction mixture was cooled and then poured onto
cold water. The solid obtained was filtered off and dried. It
was washed with ethyl acetate, crystallized from ethanol to
give brown crystals (0.234 g, 46% yield); m.p. 159–161 °C.
FTIR, cm−1
: 3337–3193 (NH, NH2); 2201 (C≡N);
Synthesis of N-(4-(5-(4-fluorophenyl)-4-hydroxy-2,8,8-
trimethyl-6-oxo-6,7,8,9-tetrahydropyrimido[4,5-b]quinolin-
10(5H)-yl) phenylsulfonyl) acetamide (7)
1324–1190 (SO2). 1H NMR (600 MHz, DMSO-d6) δH: 1.04
(6H, s, 2CH3); 1.88 (2H, s, C8-H2); 2.38, 2.51 (3H, 2s, NH
and NH2); 3.63, 3.81 (4H, 2t, 2CH2); 4.30 (1H, s, C4-H),
5.77 (2H, s, C2-NH2); 6.56–8.13 (9H, complex pattern,
Ar–H and C6-H); 8.3 (2H, s, SO2NH2). Anal. calcd. for
C26H29FN6O2S (508.21): C, 61.40; H, 5.75; N, 16.52%.
Found: C, 61.54; H, 5.40; N, 16.28%.
A solution of compound 5a (0.466 g, 1 mmol) in acetic
anhydride (20 ml) was refluxed for 1 h, the reaction mixture
was then concentrated, the solid obtained was filtered off

Med Chem Res
Synthesis of 4-(3-acetyl-5-(4-fluorophenyl)-4-imino-8,8-
dimethyl-2,6-dioxo-1,2,3,4,6,7,8,9-octahydrobenzo[b][1,8]
naphthyridin-10(5H)-yl)benzenesulfonamide (10)
(12b): It was crystallized from ethanol to give pale yellow
crystals (0.472 g, 96% yield); m.p. 165.5–167 °C. FTIR,
cm−1: 3459, 3342 (NH2); 2224 (C≡N); 1716, 1615
1
(2C=O); 1505 (NO2 arom.); 1344–1190 (SO2). H NMR
A mixture of compound 5a (0.466 g, 1 mmol) and ethyl
acetoacetate (10 ml) was refluxed together for 5 h. The
formed solid mass was filtered off and dried. It was washed
by ethylacetate, crystallized from toluene to give black
(600 MHz, CDCL3) δH: 1.20, 1.34 (6H, s, 2CH3); 1.42 (2H,
s, C6-H2); 1.52 (2H, s, C8-H2); 6.80–8.36 (10H, complex
pattern, Ar–H and SO2NH2). 13C (600 MHz, CDCl3) δC:
14.11 (2CH3); 20.00 (C7); 63.37 (C6 and C8); 107.38 (C4′);
114.00 (C3); 114.54 (CN); 123.80, 129.00, 131.52, 149.00
(of p-SO2NH2 phenyl ring); 124.00, 131.90, 136.90, 149.72
(of p-NO2 phenyl ring); 151.50 (C8′); 151.75 (C2); 161.40
(C4); 194.00 (C5). Anal. calcd. for C24H20N4O6S (492.11):
C, 58.53; H, 4.09; N, 11.38%. Found: C, 58.59; H, 4.02; N,
11.23%.
crystals (0.38 g, 70% yield); m.p. 130–132 °C. FTIR, cm−1
:
3304, 3256, 3225 (2NH, NH2); 1713, 1660, 1632 (3C=O);
1349–1198 (SO2). 1H NMR (600 MHz, DMSO-d6) δH:
1.16, 1.22 (6H, 2s, 2CH3); 2.24 (2H, s, C9-H2); 2.55 (2H, s,
C7-H2); 2.35 (3H, s, COCH3); 3.57 (1H, s, C3-H); 4.09 (1H,
s, C5-H); 4.24 (1H, s, C4-NH); 6.04–8.50 (9H, complex
pattern, Ar–H and endocyclic NH and SO2NH2); 15.72 (1H,
s, OH of the iminol structure). Anal. calcd. for
C28H27FN4O5S (550.17): C, 61.08; H, 4.94; N, 10.18%.
Found: C, 61.27; H, 5.03; N, 10.21%.
4-(3-Cyano-4-(4-methoxyphenyl)-7,7-dimethyl-2,5-
dioxo-5,6,7,8-tetrahydroquinolin-1(2H)-yl)benzenesulfona-
mide (12c): It was crystallized from ethanol to give pale
yellow crystals (0.453 g, 95% yield); m.p. 136–138 °C.
FTIR, cm−1: 3461, 3315 (NH2); 2264 (C≡N); 1687, 1624
1
Synthesis of 4-(3-cyano-4-(aryl)-7,7-dimethyl-2,5-dioxo-
5,6,7,8-tetrahydroquinolin 1(2H)-yl) benzenesulfonamide
(12a–f)
(2C=O); 1299–1144 (SO2). H NMR (600 MHz, DMSO-
d6) δH: 0.88, 1.01 (6H, 2s, 2CH3); 2.02, 2.22 (2H, 2d, C6-
H2); 2.42, 2.53 (2H, 2d, C8-H2) 3.66 (3H, s, OCH3);
5.78–7.47 (10H, complex pattern, Ar–H and SO2NH2). 13
C
Method A: silent reaction A mixture of diamidone 1 (0.14
g, 1 mmol) with sulfanilamide 2 (0.172 g, 1 mmol), different
aromatic aldehydes 11a–f (1 mmol) and ethyl cyanoacetate
(0.12 ml, 1 mmol) in ethanol (10 ml) was refluxed for 3–30
h, the obtained solid filtered off and dried.
NMR (600 MHz, DMSO-d6) δC: 26.46 (2CH3); 28.63 (C7);
31.85 (C8); 32.31 (C6); 54.86 (OCH3); 112.41 (C4′); 113.06,
127.38, 129.98, 161.91 (of p-OCH3 phenyl ring); 115.70
(C3 and CN); 127.00, 128.56, 138.46, 151.88 (of p-SO2NH2
phenyl ring); 157.29 (C8′); 159.04 (C2); 168.04 (C4); 195.91
(C5). Anal. calcd. for C25H23N3O5S (477.14): C, 62.88; H,
4.85; N, 8.80%. Found: C, 63.01; H, 4.72; N, 8.69%.
4-(4-(4-Chlorophenyl)-3-cyano-7,7-dimethyl-2,5-dioxo-
5,6,7,8-tetrahydroquinolin-1(2H)-yl)benzenesulfonamide
(12d): It was crystallized from ethanol to give white crystals
(0.381 g, 82% yield); m.p. 145–147 °C. FTIR, cm−1: 3476,
3371 (NH2); 2265 (C≡N); 1745, 1687 (2C=O); 1369–1143
Method B: sonicated reaction A mixture of diamidone 1
(0.14 g, 1 mmol) with sulfanilamide 2 (0.172 g, 1 mmol),
different aromatic aldehydes 11a–f (1 mmol) and with ethyl
cyanoacetate (0.12 ml, 1 mmol) in ethanol (10 ml) was
sonicated at a frequency of 40 KHz for 10–50 min at 80 °C.
Then the collected mass was filtered off and dried.
1
4-(3-Cyano-4-(4-fluorophenyl)-7,7-dimethyl-2,5-dioxo-
5,6,7,8-tetrahydroquinolin-1(2H)-yl)benzenesulfonamide
(12a): It was crystallized from ethanol to give colorless
crystals (0.395 g, 85% yield); m.p. 149–150 °C. FTIR,
cm−1: 3372, 3236 (NH2); 2226 (C≡N); 1715, 1690
(SO2). H NMR (600 MHz, DMSO-d6) δH: 0.87, 1.01 (6H,
2s, 2CH3); 2.02, 2.23 (2H, 2d, C6-H2); 2.42, 2.51 (2H, 2d,
C8-H2); 5.79–7.56 (10H, complex pattern, Ar–H and
SO2NH2). 13C NMR (600 MHz, DMSO-d6) δC: 26.53
(2CH3); 28.65 (C7); 31.39 (C8); 33.03 (C6); 112.49 (C4′);
115.10 (C3 and CN); 127.46, 129.63, 145.43, 162.39 (of p-
SO2NH2 phenyl ring); 127.72, 130.05, 130.34 (of p-
chlorophenyl ring); 151.96 (C8′); 159.16 (C2); 167.91
(C4); 195.99 (C5). Anal. calcd. for C24H20ClN3O4S
(481.09): C, 59.81; H, 4.18; N, 8.72%. Found: C, 59.92;
H, 3.99; N, 8.65%.
1
(2C=O); 1305–1145 (SO2). H NMR (600 MHz, DMSO-
d6) δH: 0.87, 1.02 (6H, 2s, 2CH3); 2.03, 2.23 (2H, 2d, C6-
H2); 2.46, 2.51 (2H, 2d, C8-H2); 6.99–7.55 (8H, complex
pattern, Ar–H); 8.30 (2H, s, SO2NH2). 13C (600MHz,
DMSO-d6) δC: 26.45, 28.57 (2CH3); 31.85 (C7); 32.69 (C8);
49.9 (C6); 112 (C4′); 114.26, 129.35, 162.12 (of p-flouro
phenyl ring); 114.4 (C3); 115.3 (CN); 126.00, 129.41,
142.51, 142.53 (of p-SO2NH2 phenyl ring); 159.59 (C8′);
161.19 (C2); 167.87 (C4); 195.83 (C5). Anal. calcd. for
C24H20FN3O4S (465.12): C, 61.92; H, 4.33; N, 9.03%.
Found: C, 62.03; H, 4.18; N, 8.95%.
4-(4-(4-Bromophenyl)-3-cyano-7,7-dimethyl-2,5-dioxo-
5,6,7,8-tetrahydroquinolin-1(2H)-yl)benzenesulfonamide
(12e): It was crystallized from ethanol to give yellow
crystals (0.367 g, 70% yield); m.p. 213–215 °C. FTIR,
cm−1: 3333, 3233 (NH2); 2263 (C≡N); 1743, 1682
1
4-(3-Cyano-7,7-dimethyl-4-(4-nitrophenyl)-2,5-dioxo-
5,6,7,8-tetrahydroquinolin-1(2H)-yl)benzenesulfonamide
(2C=O); 1369–1149 (SO2). H NMR (600 MHz, DMSO-
d6) δH: 1.04 (6H, s, 2CH3); 1.10, 1.2 (2H, 2d, C6-H2); 2.00,

Med Chem Res
2.1 (2H, 2d, C8-H2); 6.70–7.78 (10H, complex pattern,
Ar–H and SO2NH2). Anal. calcd. for C24H20BrN3O4S
(525.04): C, 54.76; H, 3.83; N, 7.98%. Found: C, 54.95; H,
3.80; N, 8.01%.
3351–3201 (2NH2); 2226 (C≡N); 1666 (C=O); 1336–1219
(SO2). H NMR (600 MHz, DMSO-d6) δH: 0.98, 1.04 (6H,
1
2s, 2CH3); 2.92 (2H, s. C6-H2); 5.80 (2H, s, NH2);
6.53–8.30 (11H, complex pattern, Ar–H and C4-H and
SO2NH2). Anal. calcd. for C26H21FN6O3S (516.14): C,
60.45; H, 4.10; N, 16.27%. Found: C, 60.49; H, 4.01; N,
16.17%.
4-(3-Cyano-4-(4-(dimethylamino)phenyl)-7,7-dimethyl-
2,5-dioxo-5,6,7,8-tetrahydroquinolin-1(2H)-yl)benzenesul-
fonamide (12f): It was washed by petroleum ether to give
yellow crystals (0.39 g, 80% yield); m.p. 122–123 °C.
FTIR, cm−1: 3400, 3373 (NH2); 2208 (C≡N); 1699, 1593
Synthesis of 4-(8-cyano-9-(4-fluorophenyl)-4,4-trimethyl-7-
oxo-4,5-dihydro-1H-pyrazolo[3,4-f]quinolin-6(7H)-yl)
benzenesulfonamide derivatives (15a,b)
1
(2C=O); 1274, 1227 (SO2). H NMR (600 MHz, DMSO-
d6) δH: 0.90, 1.08 (6H, 2s, 2CH3); 1.19, 1.33 (2H, 2d, C6-
H2); 2.15, 2.20 (2H, 2d, C8-H2); 3.45 (6H, s, N(CH3)2);
6.59–8.1 (10H, complex pattern, Ar–H and SO2NH2).13C
NMR (600 MHz, DMSO-d6) δC: 27.57, 29.09 (2CH3);
30.94 (C7); 32.72 (C8); 40.67 (N(CH3)2); 50.76 (C6); 81.45,
117.22, 128.76, 158.20 (of p-N(CH3)2 phenyl ring); 112.30
(C4′); 113.01 (C3 and CN); 114.01, 128.65, 134.27, 148.79
(of p-SO2NH2 phenyl ring); 161.01 (C8′); 162.87 (C2);
169.34 (C4); 196.58 (C5). Anal.calcd. for C26H26N4O4S
(490.17): C, 63.66; H, 5.34; N, 11.42%. Found: C, 63.80;
H, 5.16; N, 11.24%.
General method A mixture of enaminone 13 (1 g, 2 mmol)
and hydrazine derivatives (2 mmol) were fused together for
2–4 h, the residue obtained was crystallized.
4-(8-Cyano-9-(4-fluorophenyl)-1,4,4-trimethyl-7-oxo-
4,5-dihydro-1H-pyrazolo[3,4-f]quinolin-6(7H)-yl)benzene-
sulfonamide (15a): It was crystallized from ethanol to give
brown crystals (0.417 g, 83% yield); m.p. 101–103 °C.
FTIR, cm−1: 3323, 3270 (NH2); 2353 (C≡N); 1620 (C=O);
1
1220–1155 (SO2). H NMR (600 MHz, CDCl3) δH: 1.10,
1.20 (6H, 2s, 2CH3); 2.17 (2H, s, C5-H2); 3.80 (3H, s,
NCH3); 6.7–8.01 (11H, complex pattern, Ar–H and
SO2NH2). Anal. calcd. for C26H22FN5O3S (503.14): C,
62.02; H, 4.40; N, 13.91%. Found: C, 62.22; H, 4.35; N,
13.74%.
Synthesis of 4-(3-cyano-6-((dimethylamino) methylene)-4-
(4-fluorophenyl)-7,7-dimethyl-2,5-dioxo-5,6,7,8-
tetrahydroquinolin-1(2H)-yl) benzenesulfonamide (13)
A mixture of 12a (4.65 g, 10 mmol) and DMF/DMA (2 ml,
16.7 mmol) was fused together for 6 h at 100 °C. The
obtained solid by cooling was crystallized from ethanol to
give yellow crystals (0.48 g, 94% yield); m.p. 238–239 °C.
FTIR, cm−1: 3387, 3347 (NH2); 2206 (C≡N); 1666, 1625
4-(8-Cyano-9-(4-fluorophenyl)-4,4-dimethyl-7-oxo-1-
phenyl-4,5-dihydro-1H-pyrazolo[3,4-f]quinolin-6(7H)-yl)
benzenesulfonamide (15b): It was crystallized from dioxane
to give brown crystals (0.45 g, 80% yield); m.p. 141–142 °
C. FTIR, cm−1: 3450, 3348 (NH2); 2202 (C≡N); 1620
1
1
(2C=O); 1337–1153 (SO2). H NMR (600 MHz, CDCL3)
(C=O); 1340–1180 (SO2). H NMR (600 MHz, CDCL3)
δH: 1.09, 1.63 (6H, 2s, 2CH3); 2.48 (2H, s, C8-H2); 3.04,
3.15 (6H, 2s, N(CH3)2); 7.71 (1H, s, olifinic H); 6.80–8.60
(10H, complex pattern, Ar–H and SO2NH2). 13C (600 MHz,
CDCL3) δC: 28.55 (C7); 30.94 (2CH3); 35.63 (C8); 41.59 (N
(CH3)2); 108.00 (C3 and C4′); 109.65 (CN); 113.93, 119.70,
196.40 (of p-flouro phenyl ring); 117.75, 127.90, 139.89,
141.28 (of p-SO2NH2 phenyl ring); 128.67 (C6); 149.61
(CHN(CH3)2); 158.86 (C2); 159.10 (C8′); 200.56 (C4);
207.03 (C5). Anal. calcd. for C27H25FN4O4S (520.16): C,
62.29; H, 4.84; N, 10.76%. Found: C, 62.41; H, 4.81; N,
10.55%.
δH: 1.24 (6H, s, 2CH3); 2.17 (2H, s, C5-H2); 6.64–8.09
(16H, complex pattern, Ar–H and SO2NH2). Anal. calcd.
for C31H24FN5O3S (565.16): C, 65.83; H, 4.28; N, 12.38%.
Found: C, 66.03; H, 4.08; N, 12.22%.
Synthesis of 4-(10-Cyano-11-(4-fluorophenyl)-6,6-dimethyl-
9-oxo-6,7-dihydropyrazolo[1,5-a]pyrido[2,3-h]quinazolin-
8(9H)-yl) benzenesulfonamide derivatives (16a,b)
General method A mixture of enaminone 13 (0.52 g,
1 mmol) and amino pyrazole derivatives (1 mmol), and few
drops from TEA was fused together at 130 °C for 5 h. The
obtained mass was crystallized.
Synthesis of 4-(2-amino-9-cyano-10-(4-fluorophenyl)-5,5-
dimethyl-8-oxo-5,6-dihydropyrido[2,3-h]quinazolin-7(8H)-
yl)benzenesulfonamide (14)
4-(10-Cyano-11-(4-fluorophenyl)-2,6,6-trimethyl-9-oxo-
3-phenyl-6,7-dihydropyrazolo[1,5-a]pyrido[2,3-h]quinazo-
lin-8(9H)-yl) benzenesulfonamide (16a): It was crystallized
from toluene to give brown crystals (0.49 g, 79% yield); m.
p. 226–227 °C. FTIR, cm−1: 3480, 3397 (NH2); 2197
A mixture of enaminone 13 (0.52 g, 1 mmol) and guanidine
nitrate (0.122 g, 1 mmol) and sodium carbonate (0.12 g,
1 mmol) were fused at 180 °C for 2 h. The obtained solid on
cooling was crystallized from chloroform to give brown
1
(C≡N); 1663 (C=O); 1221, 1159 (SO2). H NMR (600
MHz, CDCL3) δH: 1.24 (6H, s, 2CH3); 2.59 (2H, s, C7-H2);
2.67 (3H, s, C2-CH3); 7.17–8.00 (15H, complex pattern,
crystals (0.5 g, 97% yield); m.p. 112–114 °C. FTIR, cm−1
:

Med Chem Res
Ar–H and SO2NH2); 8.97 (1H, s, C5-H). 13C NMR (600
MHz, CDCL3) δC: 14.00 (CH3 at C2); 29.27 (2CH3 at C6);
40.84 (C6); 50.70 (C7); 112.18 (C11′); 113.2 80 (C10);
114.78; 128.63, 128.72, 162.56 (of p-flouro phenyl ring);
115.39, 129.03, 131.24, 147.04 (of p-SO2NH2 phenyl ring);
115.75 (CN); 116.37 (C3); 127.04, 128.87, 129.10, 131.10
(of phenyl at C3); 129.80 (C3′); 129.9 (C5′); 146.41 (C2);
151.00 (C7′); 151.72 (C5); 156.62 (C9); 159.00 (C11″);
194.4 (C11). Anal. calcd. for C35H27FN6O3S (630.18): C,
66.65; H, 4.32; N, 13.33%. Found: C, 66.76; H, 4.21; N,
13.17%.
The relation between surviving fraction and drug con-
centration is plotted to get the survival curve of each tumor
cell line after the specified compound.
Acknowledgements The authors acknowledge with thanks the
NMR unit at King Abdulaziz University for their technical support.
Compliance with ethical standards
Conflict of interest The authors declare that they have no competing
interests.
4-(2-(4-Chlorophenyl)-10-cyano-11-(4-fluorophenyl)-
6,6-dimethyl-9-oxo-6,7-dihydropyrazolo[1,5-a]pyrido[2,3-
h]quinazolin-8(9H)-yl)benzenesulfonamide (16b): The
obtained mass was crystallized from ethanol to give brown
References
Abbas EMH, Farghaly TA (2010) Synthesis, reactions, and biological
activity of 1,4-benzothiazine derivatives. Monatsh Chem
141:661–667
Ahmed N, Brahmbhatt KG, Sabde S, Mitra D, Singh IP, Bhutani KK
(2010) Synthesis and anti-HIV activity of alkylated quinoline 2,4-
diols. Bioorg Med Chem 18:2872–2879
Alqasoumi SI, Al-Taweel AM, Alafeefy AM, Ghorab MM, Noaman E
(2010b) Discovering some novel tetrahydroquinoline derivatives
bearing the biologically active sulfonamide moiety as a new class
of antitumor agents. Eur J Med Chem 45:1849–1853
Alqasoumi SI, Al-Taweel AM, Alafeefy AM, Hamed MM, Noaman E,
Ghorab MM (2009) Synthesis and biological evaluation of 2-
Amino-7,7-dimethyl4-substituted-5-oxo-1-(3,4,5-trimethoxy)-
1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile derivatives as
potential cytotoxic agents. Bioorg Med Chem Lett 19:6939–6942
Alqasoumi SI, Al-Taweel AM, Alafeefy AM, Noaman E, Ghorab MM
(2010a) Novel quinolines and pyrimido[4,5-b]quinolines bearing
biologically active sulfonamide moiety as a new class of anti-
tumor agents. Eur J Med Chem 45:738–744
crystals (0.47 g, 72% yield); m.p. 117–118 °C. FTIR, cm−1
:
3336, 3254 (NH2); 2263 (C≡N); 1652 (C=O); 1221, 1159
(SO2). 1H NMR (600 MHz, CDCL3) δH: 1.16, 1.17 (6H, 2s,
2CH3); 2.60 (2H, s, C7-H2); 6.64 (C3-H); 6.84–8.10 (14H,
complex pattern, Ar–H and SO2NH2); 8.98 (C5-H). 13C
NMR (600 MHz, CDCL3) δC: 27.62 (2CH3); 37.31 (C6);
50.52 (C7); 95.97 (C3); 113.49 (C11′); 114.01 (C10); 114.79
(CN); 115.64, 127.73, 128.02, 147.32 (of p-flouro phenyl
ring); 116.37, 128.38, 128.93, 129.17 (of p-SO2NH2 phenyl
ring); 128.17, 128.22, 128.50, 128.63 (of p-chloro phenyl
ring); 128.63 (C5′); 129.52 (C7′); 129.90 (C3′); 130.19 (C2);
130.92 (C5); 158.72 (C9); 169.00 (C11″); 170.00 (C11).
Anal. calcd. for C34H24ClFN6O3S (650.13): C, 62.72; H,
3.72; N, 12.91%. Found: C, 62.93; H, 3.56; N, 12.83%.
Al-Said MS, Ghorab MM, Al-Dosari MS, Hamed MM (2011)
Synthesis and In-vitro anticancer evaluation of some novel hex-
ahydroquinoline derivatives having a benzenesulfonamide moi-
ety. Eur J Med Chem 46:201–207
Carta A, Briguglio I, Piras S, Corona P, Boatto G, Nieddu M,
Giunchedi P, Marongiu ME, Giliberti G, Iuliano F, Blois S, Ibba
C, Busonera B, Colla PL (2011) Quinoline tricyclic derivatives.
Design, synthesis and evaluation of the antiviral activity of three
new classes of RNA-dependent RNA polymerase inhibitors.
Bioorg Med Chem 19:7070–7084
Chen Z, W Y, Liu Y, Yu L, Zhou L, Yang S, Lai L (2011) Quinoline-
4-methyl esters as human nonpancreatic secretory phospholipase
A2 inhibitors. Bioorg Med Chem 19:3361–3366
Creaven BS, Duff B, Egan DA, Kavanagh K, Rosair G, Thangella VR,
Walsh M (2010) Anticancer and antifungal activity of Copper(II)
complexes of quinolin-2(1H)-one-derived schiff bases. Inorg
Chim Acta 363:4048–4058
Daniel L (2007) The organic chemistry of drug synthesis. Wiley,
Hoboken, pp 167–171
Edafiogho IO, Phillips OA, Udo EE, Samuel S, Rethish B (2009)
Synthesis, antibacterial and anticonvulsant evaluations of some
cyclic enaminones. Eur J Med Chem 44:967–975
Eddington ND, Cox DS, Roberts RR, Butcher RJ, Edafiogho IO,
Stables JP, Cooke N, Goodwin AM, Smith CA, Scott KR (2002)
Synthesis and anticonvulsant activity of enaminones. 4. Investi-
gations on isoxazole derivatives. Eur J Med Chem 37:635–648
Eddington ND, Cox DS, Roberts RR, Stables JP, Powell CB, Scott KR
(2000) Enaminones-versatile therapeutic pharmacophores. Fur-
ther advances. Curr Med Chem 7:417–436
In vitro cytotoxic screening
Twelve analogs (5a,c), (7), (8), (10), (12a–d), (14), (15b),
(16b) were selected as representative examples to evaluate
their in vitro inhibitory effects against cellular proliferation
in human cultured breast carcinoma cell line using DOX as
a reference drug. Breast cancer cell lines (MCF7) were
obtained from Cell Bank in National Cancer Institute, Cairo,
Egypt. The potential cytotoxicity of the selected newly
synthesized derivatives was done by SRB using the method
of (Skehan et al. 1990) as follows: Cells were plated in a 96-
multiwell plate (104 cells/well) for 24 h before treatment
with compounds to allow attachment of the cell to the wall
of the plate. Different concentrations of the compound
under test (5, 12.5, 25, and 50 μg/ml) were added to the cell
monolayer triplicate wells which were prepared for each
individual dose. Monolayer cells were incubated with the
compounds for 48 h at 37 °C and in an atmosphere of 5%
CO2. After 48 h, cells were fixed, washed, and stained with
Sulpho-Rhodamine-B stain. Excess stain was washed with
acetic acid and attached stain was recovered with Tris-
EDTA buffer. Color intensity was measured in an ELISA
reader. Measurements were done six times and averaged.

Med Chem Res
El-Hashim A, Yousefi S, Edafiogho I, Raghupathy R, Yousif M,
Simon HU (2010) Anti-inflammatory and immunosuppressive
effects of the Enaminone E121. Eur J Pharmacol 632:73–78
El-Hashim AZ, Edafiogho IO, Jaffal SM (2001) Anti-tussive and
Bronchodilator mechanisms of action for the Enaminone E121.
Life Sci 89:378–387
Korrichi L, Dalila B, Dalila S (2009) Quinolines antioxydant activity
structure activity relationship. Eur J Bio Sci 1:32–36
Kouznetsov VV, Gómez CMM, Derita MG, Svetaz L, Olmo Ed,
Zacchino SA (2012) Synthesis and antifungal activity of diverse
C-2 pyridinyl and pyridinylvinyl substituted quinolines. Bioorg
Med Chem 20:6506–6512
El-Sabbagh OI, Rady HM (2009) Synthesis of new acridines and
hydrazones derived from cyclic β-diketone for cytotoxic and
antiviral evaluation. Eur J Med Chem 44:3680–3686
El-Sabbagh OI, Shabaan MA, Kadry HH, Saad Al-Din E (2010) New
octahydroquinazoline derivatives: synthesis and hypotensive
activity. Eur J Med Chem 45:5390–5396
Kumar KS, Kumar SK, Sreenivas BY, Gorja DR, Kapavarapu R,
Rambabu D, Krishna GR, Reddy CM, Rao MVB, Parsa KVL, Pal
M (2012) C–C bond formation at C-2 of a quinoline ring:
synthesis of 2-(1H-indol-3-yl) quinoline-3-carbonitrile deriva-
tives as a new class of PDE4 inhibitors. Bioorg Med Chem
20:2199–2207
Gao M, Wang M, Miller KD, Hutchins GD, Zheng QH (2010)
Synthesis and in-vitro biological evaluation of carbon-11-labeled
quinoline derivatives as new candidate PET radioligands for
cannabinoid CB2 receptor imaging. Bioorg Med Chem
18:2099–2106
García GC, Bejarano BP, Ruiz IL, Nieto MA´G (2012) Comparison of
representational spaces based on structural information in the
development of QSAR models for benzylamino enaminone
derivatives. SAR QSAR Environ Res 23:751–774
Lu CM, Chen YL, Chen HL, Chen CA, Lu PJ, Yang CN, Tzeng CC
(2010) Synthesis and antiproliferative evaluation of certain Indolo
[3,2-c]quinoline derivatives. Bioorg Med Chem 18:1948–1957
Makawana JA, Patel MP, Patel RG (2012) Synthesis and in-vitro
antimicrobial activity of N-arylquinoline derivatives bearing 2-
morpholinoquinoline moiety. Chin Chem Lett 23:427–430
Michael J, de Koning C, Gravestock D, Hosken G, Howard A,
Jungmann C, Krause R, Parsons A, Pelly S, Stanbury T (1999)
Enaminones: versatile intermediates for natural product synthesis.
Pure Appl Chem 71:979–988
Perin N, Uzelac L, Piantanida I, Zamola GK, Kralj M, Hranjec M
(2011) Novel biologically active nitro and amino substituted
benzimidazo [1,2-a]quinolines. Bioorg Med Chem 19:6329–6339
Pretorius SI, Breytenbach WJ, Kock Cd, Smith PJ, N’Da DD (2013)
Synthesis, characterization and antimalarial activity of
quinoline–pyrimidine hybrids. Bioorg Med Chem 21:269–277
Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D,
Warren JT, Bokesch H, Kenney S, Boyd MR (1990) New col-
orimetric cytotoxicity assay for anticancer-drug screening. J Natl
Cancer 82:1107–1112
Garudachari B, Satyanarayana MN, Thippeswamy B, Shivakumar CK,
Shivananda KN, Hegde G, Isloor AM (2012) Synthesis, char-
acterization and antimicrobial studies of some new quinoline
incorporated benzimidazole derivatives. Eur
J Med Chem
54:900–906
Ghodsi R, Zarghi A, Daraei B, Hedayati M (2010) Design, synthesis
and biological evaluation of new 2,3-diarylquinoline derivatives
as selective cyclooxygenase-2 inhibitors. Bioorg Med Chem
18:1029–1033
Ghorab MM, Ragab FA, Heiba HI, Arafa RK, El-Hossary EM (2010)
In-vitro anticancer screening and radiosensitizing evaluation of
some new quinolines and pyrimido[4,5-b]quinolines bearing a
sulfonamide moiety. Eur J Med Chem 45:3677–3684
Supuran CT, Scozzafava A, Casini A (2003) Carbonic anhydrase
inhibitors. Med Res Rev 23:146–189
Ghorab MM, Ragab FA, Noaman E, Heiba HI, El-Hossary EM (2009)
Synthesis of some novel quinolines and pyrimido [4,5-b] qui-
nolines bearing a sulphonamide moiety as potential anticancer
and radioactive agents. Drug Res 57:795–803
Guo RH, Zhang Q, Maa YB, Huang XY, Luo J, Wang LJ, Geng CA,
Zhang XM, Zhou J, Jiang ZY, Chen JJ (2011) Synthesis and bio-
logical assay of 4-aryl-6-chloro-quinoline derivatives as novel non-
nucleoside anti-HBV agents. Bioorg Med Chem 19:1400–1408
Jackson PL, Hanson CD, Farrell AK, Butcher RJ, Stables JP,
Eddington ND, Scott KR (2012) Enaminones 12. An explanation
of anticonvulsant activity and toxicity per linus pauling’s clathrate
hypothesis. Eur J Med Chem 51:42–51
Thiry A, Ledecq M, Cecchi A, Dogne JM, Wouters J, Supuran CT,
Masereel B (2006) Indanesulfonamides as carbonic anhydrase
inhibitors. Toward structure-based design of selective inhibitors of
the tumor-associated isozyme CA IX. J Med Chem 49:2743–2749
Vandurm P, Cauvin C, Guiguen A, Georges B, Van KL, Martinelli V,
Cardona C, Mbemba G, Mouscadet JF, Hevesi L, Lint CV,
Wouters J (2009) Structural and theoretical studies of [6-bromo-
1-(4-fluorophenylmethyl)-4(1H)-quinolinon-3-yl)]-4-hydroxy-2-
oxo-3-butenoïc acid as HIV-1 integrase inhibitor. Bioorg Med
Chem Lett 19:4806–4809
Wang L, witalska M, Mei ZW, Lu WJ, Takahara Y, Feng XW, El-
Sayed I, Wietrzyk J, Inokuchi T (2012) Synthesis and in-vitro
Antiproliferative activity of new 11-aminoalkylamino-substituted
5H- and 6H-Indolo[2,3-b]quinolines; structure activity relation-
ships of neocryptolepines and 6-methyl congeners. Bioorg Med
Chem 20:4820–4829
Jayagobi M, Raghunathan R, Sainath S, Raghunathan M (2011)
Synthesis and antibacterial property of pyrrolopyrano
quinolinones and pyrroloquinolines. Eur
J
Med Chem
46:2075–2082