Design and synthesis of novel cytotoxic agents based on combined framework of quinoline and nimesulide

Article abstract of DOI:10.1002/jhet.801

Functionalization of quinoline aldehydes, derived from nimesulide framework was carried out using Morita-Baylis-Hillman (MBH) chemistry. A number of novel quinoline-based diverse MBH adducts was prepared via the reaction of derivatives of 2-chloroquinolin

Full text of DOI:10.1002/jhet.801

80
Design and Synthesis of Novel Cytotoxic Agents Based on
Combined Framework of Quinoline and Nimesulide
Vol 49
Lingam Venkata Reddy,a Mohan Kethavath,a Mamatha Nakka,a Syed Sultan Beevi,a
Lakshmi Narasu Mangamoori,a Khagga Mukkanti,a and Sarbani Palb*
aJNT University, Kukatpally, Hyderabad-500072, India
bDepartment of Chemistry, MNR Degree and PG College, Kukatpally, Hyderabad-500072, India
*E-mail: sarbani277@yahoo.com
Received August 26, 2010
DOI 10.1002/jhet.801
Published online 29 August 2011 in Wiley Online Library (wileyonlinelibrary.com).
Functionalization of quinoline aldehydes, derived from nimesulide framework was carried out using
Morita–Baylis–Hillman (MBH) chemistry. A number of novel quinoline-based diverse MBH adducts
was prepared via the reaction of derivatives of 2-chloroquinoline-3-carbaldehyde and various activated
alkenes in good yields. Many of these compounds were found to be potent when tested against human
prostate cancer (Pc-3) cell line in vitro. Among all the compounds tested N-(2-chloro-3-(2-cyano-1-
hydroxyallyl)-7-phenoxyquinolin-6-yl)formamide (IC50 ¼ 1.2 lg mLꢀ1) was identified as the most
potent compound in this series.
J. Heterocyclic Chem., 49, 80 (2012).
INTRODUCTION
pharmaceutical research worldwide. Along with other
nitrogen containing heterocyclic moieties quinoline frame-
work has also been explored for this purpose. Recently,
cytotoxicity studies of a variety of quinoline derivatives
have been reported [12]. Because of our continuing inter-
est in the synthesis and identification of novel cytotoxic
agents, we became interested in the synthesis and pharma-
cological evaluation of quinoline-based small molecules.
Recently, (2-chloro-6-methoxyquinolin-3-yl)methanol
A (Fig. 1) has been reported to exhibit significant cyto-
toxic activities when tested in vitro (IC50 ¼ 42.5 and 47.4
lg mLꢀ1 on HeLa and Vero cells, respectively) [13]. On
the other hand, compounds containing sulfonamide moiety,
for example, 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-
1H-pyrazol-1-yl]benzenesulfonamide (SC236) showed
enhanced cytotoxic effects of doxorubicin on HKESC-1
and HKESC-2 cells [14]. Nimesulide [15] B (Fig. 1), a
sulfonamide based well-known anti-inflammatory agent,
is presently in patient’s use in certain countries. In our
effort to develop novel cytotoxic agents, we designed
the structure C by (i) introducing appropriately function-
alized side chain to the hydroxymethyl carbon of A and
(ii) incorporating the structural features of nimesulide B.
We hypothesized that this combination may lead to the
identification of potent cytotoxic agents that might pos-
sess anti-inflammatory properties as well.
The Morita–Baylis–Hillman reaction (MBH) is an
attractive method for CAC bond forming reaction
affording highly functionalized products containing a
new stereocenter known as Baylis–Hillman adducts [1–
4]. The reaction, typically catalyzed by tertiary amines
or tertiary phosphines, involves a coupling of aldehydes
with activated alkenes to give adducts containing a-
methylene-b-hydroxy moiety. Substituted quinolines,
one of the oldest known heterocyclic pharmaceutical
agents, exhibit a wide range of medicinal properties,
including antimalarial activities [5]. Not surprisingly, an
array of synthetic methods has been developed to access
quinoline derivatives, including the classic Skraup,
Doebner–vonMiller, Conrad–Limpach, and Knorr syn-
theses [5,6]. The use of Baylis–Hillman reaction for the
preparation of functionalized quinolines has also been
reported [7]. Although the use of simple quinoline alde-
hydes to generate the corresponding MBH adducts has
been reported earlier [8–11], the application of this
methodology to more complex quinoline system is not
common in the literature. As cancer has been a major
killer in most developed, developing, and underdevel-
oped countries, the search for new and effective anti-
cancer agents has become an important area of current
C
V
2011 HeteroCorporation

January 2012
Design and Synthesis of Novel Cytotoxic Agents Based on Combined Framework
of Quinoline and Nimesulide
81
Figure 1. Design of novel cytotoxic agents based on quinoline and nimesulide.
RESULTS AND DISCUSSION
ent in the aldehyde 1b and c, respectively, was tolerated
during the reaction. The duration of the reaction, how-
ever, was longer, that is, 24–36 h, in these cases, com-
pared to 1a perhaps due to the electron-donating effect
of phenoxy group at C-7. Moreover, DABCO-mediated
deprotonation of ANHSO2Me or ANHCHO moiety
increases the electron density on the quinoline ring,
thereby, decreasing the reactivity of aldehyde group.
Nevertheless, all the compounds synthesized were well
characterized by spectral and analytical data. The pres-
ence of OH and AC¼¼CA was indicated by the appear-
ance of IR absorption in the region 3400–3200 and
To test our hypothesis, we prepared few simple ana-
logues of C via applying the MBH reaction according to
a known method [16]. Thus, 2-chloro-3-formyl quinoline
1a (X and Y ¼ H), prepared from acetanilide using
DMF/POCl3 [17–19], was treated with activated alkenes
2a–d electron withdrawing group (EWG) in the pres-
ence of 1,4-diazabicyclo[2.2.2]octane (DABCO) at room
temperature under a solvent-free condition to give the
desired products 3a–d (Scheme 1 and Table 1; entries
1–4). Some of these compounds were tested in vitro
against the human prostate cancer cell line (Pc-3) based
on an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (MTT) assay [20]. The percentage of cell death
was measured for each compound at various concentra-
tions and finally, the IC50 (half maximal inhibitory con-
centration) values were determined to measure the cyto-
1
1630–1600 cmꢀ1, respectively. The H NMR spectra of
two representative compounds 3h and 3l (both of which
showed a strong IR absorption at 2226 cmꢀ1 corre-
sponding to ACN moiety) are shown in Figure 2 and 3,
respectively. The presence of olefinic, ACHOHA and
the MeSO2A protons for compound 3h was indicated by
the appearance of signals at d 6.32 and 6.28, 5.60, and
3.20, respectively. Similarly, the presence of CHO (d
8.9), olefinic (d 6.32 and 6.28) and CHOH (d 5.60)
groups can be observed in case of 3l.
toxic activities (Table 2). Because IC is inversely pro-
portional to the cytoxicity of a compound (i.e., lower is
50
the IC value, higher is the activity), compound 3b was
identified as a promising cytotoxic agent.
50
Encouraged by this observation, we planned to syn-
thesize compounds represented by C. Accordingly,
nimesulide was converted to N-(2-chloro-3-formyl-
7-phenoxyquinolin-6-yl)methanesulfonamide (1b; X¼
NHSO2Me and Y ¼ OPh) and N-(2-chloro-3-formyl-7-
phenoxyquinolin-6-yl)formamide (1c; X ¼ NHCHO and
Y ¼ OPh) following the procedure developed by us pre-
viously (Scheme 2) [21,22]. Both 1b and c were con-
verted to the corresponding MBH adducts as shown in
Scheme 1 and results are summarized in Table 1 (entries
5–9). All the alkenes 2a–d reacted well with the
aldehydes 1b and c at room temperature, affording
the desired products 3e–3l. The methanesulfonamide
(ANHSO2Me) and formamide (ANHCHO) group pres-
According to the objective of our present study (i.e.,
identification of novel cytotoxic agents), some of the
compounds synthesized were evaluated for their activ-
ities in vitro. Compounds 3e, 3f, 3k, and 3l were tested
in vitro against the human prostate cancer cell line (Pc-
3) based on an MTT assay. The percentage of cell death
measured for each compound at various concentrations
along with IC50 values are shown in Table 2. All these
compounds showed promising cytotoxic effects and the
compound 3l being the most notable among them as it
showed the effect at lower concentration. Although a
dramatic increase in its activity was observed at the con-
centration of 2.0 lg mLꢀ1, further enhancement with
the increase of dose was not observed perhaps due to
Scheme 1. Synthesis of quinoline derivatives 3.
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L. V. Reddy, M. Kethavath, M. Nakka, S. S. Beevi, L. N. Mangamoori, K. Mukkanti, and S. Pal Vol 49
Table 1
Preparation of MBH adducts 3 from 2-chloro-3-formyl quinoline
(or its derivatives) 1 and activated alkenes 2.a
Quinoline
1
Alkene
2
Time
(h)
MBH
adduct 3
%
Entries
1
Yieldb
6.0
5.0
55
1a
2a
3a
2
3
4
5
6
7
8
9
1a
1a
1a
60
2b
2c
3b
5.3
3.0
24
65
65
54
60
60
65
55
3c
2d
3d
2a
2b
2c
2d
2a
1b
3e
1b
1b
1b
25
3f
32
3g
24
3h
24
1c
3i
(Continued)
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Design and Synthesis of Novel Cytotoxic Agents Based on Combined Framework
of Quinoline and Nimesulide
83
Table 1
(Continued)
Quinoline
1
Alkene
2
Time
(h)
MBH
adduct 3
%
Entries
10
Yieldb
1c
1c
1c
2b
2c
2d
28
36
28
52
55
60
3j
11
12
3k
3l
a Reaction conditions: 1 (10 mmol), alkene 2 (20 mmol), DABCO (1.3 mmol), room temperature.
b Isolated yield.
reaching the saturation point at an early dose. Neverthe-
less, satisfactory dose response curves (DRC) for
selected compounds is shown in Figure 4. Studies on
the interaction of a number of acrylate esters with bio-
logical nucleophiles have shown that these esters inter-
act significantly with cellular glutathione (GSH) rather
than deoxyribonucleosides [23]. GSH, a tripeptide, con-
tains an unusual peptide linkage between the amine
group of cysteine and the carboxyl group of the gluta-
mate side chain. Being an antioxidant, it helps to protect
cells from reactive oxygen species such as free radicals
and peroxides. Notably, the GSH levels were found to
be higher in human cancer cell lines than in normal cell
[24,25] and, therefore, depletion of GSH in these cells
make them more vulnerable to the effects of anticancer
drugs or the gene that promotes apoptosis (cell death).
Because of the presence of a nucleophilic thiol (ASH)
group GSH can interact with acrylate ester via addition
across the a,b-unsaturated bond (a Michael-type reac-
tion) [26]. Thus, the proposed interaction of GSH with
the quinoline derivative 3 can be presented schemati-
cally as shown in Figure 5. The path a, based on the
known interaction of GSH with acrylate ester may lead
to the generation of metabolic product M1. However,
taking into consideration of (i) the nucleophilicity of
amino group of GSH in addition to thiol moiety, (ii)
reactivity of chloro group of 3 and (iii) the recent report
on the reaction of various amines with the quinoline-
Table 2
Cytotoxic activity of quinoline derivatives for Pc-3 cancer cell line determined by MTT assay protocol.a
Percentage of cell death at various concentrations (lg mLꢀ1
)
S. No
Compd
1.0
2.0
5.0
10
25
IC50 (lg mLꢀ1
)
1
2
3
4
5
6
7
8
9
3a
3b
3d
3e
3f
3h
3i
3k
3l
2.5
8
21
28
65
36
25
9.5
13
25
76
26
45
73.5
48
36
26
20
39
29
78
75
73
64
79
77
74
77
78
73
77
83
n.d.
3.98
n.d.
4.79
7.61
n.d.
n.d.
6.64
1.2
21
23
18
1.2
5
60
78.5
34
19
40
64
82
80
n.d. ¼ not done.
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L. V. Reddy, M. Kethavath, M. Nakka, S. S. Beevi, L. N. Mangamoori, K. Mukkanti, and S. Pal Vol 49
Scheme 2. Preparation of derivatives of 2-chloro-3-formyl quinoline 1b and 1c from nimesulide.
based MBH adduct [16] an alternative interaction (path
b) leading to the generation of product M2 can be pro-
posed. This path essentially involves a Michael-type
addition of GSH with 3 followed by intramolecular cy-
clization via the displacement of chloro group by the
secondary amine generated. In order to gain further evi-
dence compound 3g was treated with n-butyl amine in
EtOH in the presence of triethylamine at room tempera-
ture for 6.0 h and the corresponding adduct, that is,
methyl-1-butyl-1,2-dihydrobenzo[b][1,8]naphthayridine-
3-carboxylate derivative was isolated in 70% yield.
of these compounds is thought to be due to the interaction
of the carbon–carbon double bond present in compound 3
with the cellular glutathione. Among all the compounds
tested N-(2-chloro-3-(2-cyano-1-hydroxyallyl)-7-phenoxy-
quinolin-6-yl)formamide 3l (IC50 ¼ 1.2 lg mLꢀ1) was
identified as most potent compound in this series. Fur-
ther pharmacological studies are ongoing to evaluate
anticancer properties of these compounds.
EXPERIMENTAL
General methods. Melting points were all determined by
open glass capillary method on a Cintex melting point appara-
tus and uncorrected. IR spectra were recorded on a Perkin
Elmer spectrometer in KBr pellets. 1H NMR spectra were
recorded on a Varian 400 MHz spectrometer using DMSO-d6
as a solvent with tetramethylsilane as internal reference (TMS,
d ¼ 0.00). Chemical shift (d) values are presented as singlet
(s), doublet (d), triplet (t), or multiplet (m). Elemental analyses
were performed by Varian 3LV analyzer series CHN analyzer.
Mass spectra were recorded on a Jeol JMCD-300 instrument.
All solvents used were commercially available and distilled
before use. All reactions were monitored by TLC on precoated
CONCLUSIONS
In conclusion, we have described design, synthesis
and in vitro cytotoxicities of a number of novel quino-
line-based diverse Morita–Baylis–Hillman [27] adducts
incorporating the structural features of a well-known
anti-inflammatory agent nimesulide. Many of these com-
pounds were found to be potent when tested against
human prostate cancer (Pc-3) cell line in vitro. Activity
Figure 2. 1H NMR spectra of compound 3h in DMSO-d6.
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Design and Synthesis of Novel Cytotoxic Agents Based on Combined Framework
of Quinoline and Nimesulide
85
Figure 3. 1H NMR spectra of compound 3l in DMSO-d6.
silica gel plates (60 F 254; Merck). Column chromatography
was performed on 100–200 mesh silica gel (SRL, India) using
10–20-fold excess (by weight) of the crude product. The or-
ganic extracts were dried over anhydrous Na2SO4.
ArH), 6.90 (1H, s, ACH¼¼C), 5.9 (1H, bs, OH), 5.8 (1H, s,
CHOH), 2.40 (4H, m, 2CH2), 1.90 (2H, m, CH2); Elemental
analysis found: C, 66.52; H, 4.91.;N, 4.99; C16H14ClNO2
requires C, 66.79; H, 4.90; N, 4.87.
Ethyl 2-((2-Chloroquinolin-3-yl)(hydroxy)methyl)acrylate
(3b). Pale yellow solid; m.p. 75–76ꢂC (lit [10] 75–77ꢂC);
Rf ¼ 0.41 (CHCl3/EtOAc 4:1); MS m/z 292.0 (Mþ, 100%),
General procedure for the synthesis of MBH adduct
(3). A mixture of 2-chloro-3-formyl quinoline (or its deriva-
tives) 1 (10 mmol) and activated alkenes 2 (20 mmol) and
DABCO (1.3 mmol, 145.8 mg) was stirred at room tempera-
ture for the time indicated in Table 1 under solvent-free condi-
tions. After completion of the reaction (indicated by TLC), the
mixture was extracted with Et2O (3 ꢁ 15 mL). The organic
layers were collected, combined, washed with cold brine (2 ꢁ
15 mL), dried over anhydrous Na2SO4, filtered, and concen-
trated. The residue was purified by column chromatography on
silica gel (hexane-EtOAc) to give the desired product.
294.0 (Mþ2); IR (KBr) mmax (cmꢀ1
) 3401.78, 2923.05,
2871.73,1687.86, 1614.71; 1H NMR (400 MHz, DMSO-d6) d
8.40 (1H, s, ArH), 8.05 (1H, d, J ¼ 8.2 Hz, ArH), 7.95 (1H, d,
J ¼ 8.2 Hz, ArH), 7.80 (1H, m, ArH), 7.67 (1H, m, ArH),
6.35 (1H, s, CH¼¼C), 6.22 (1H, s, CH¼¼C), 5.95 (1H, s,
CHOH), 5.67 (1H, s, OH), 4.25 (2H, q, J ¼ 7.3 Hz, OCH2),
1.25 (3H, t, J ¼ 7.3 Hz, CH3).
Methyl 2-((2-Chloroquinolin-3-yl)(hydroxy)methyl)acrylate
(3c). Off white solid; m.p. 69–70ꢂC (lit [9] 69–71ꢂC); Rf ¼
0.40 (CHCl3/EtOAc 4:1); MS m/z 278.1 (Mþ, 100%), 280.1
2-((2-Chloroquinolin-3-yl)(hydroxy)methyl)cyclohex-2-enone
(3a). Semi solid; Rf ¼ 0.42 (CHCl3/EtOAc 4:1); MS m/z 288.0
(Mþ, 100%), 290.0 (Mþ2, 33%); IR (KBr) mmax (cmꢀ1) 3421,
2925, 2865, 1655; 1H NMR (400 MHz, DMSO-d6) d 8.45
(1H, s, ArH), 8.10 (1H, d, J ¼ 8 Hz, ArH), 7.90 (1H, d, J ¼ 8
Hz, ArH), 7.80 (1H, t, J ¼ 6 Hz, ArH), 7.65 (1H, t, J ¼ 6 Hz,
(Mþ2, 33%); IR (KBr) mmax (cmꢀ1
) 3250.69, 3050.63,
1
1641.13; H NMR (400 MHz, DMSO-d6) d 8.40 (1H, s, ArH),
8.10 (1H, d, J ¼ 8 Hz, ArH), 7.96 (1H, d, J ¼ 8 Hz, ArH),
7.82 (1H, t, J ¼ 6 Hz, ArH), 7.66 (1H, t, J ¼ 6 Hz, ArH),
6.34 (1H, s, CH¼¼C), 6.18 (1H, s, CH¼¼C), 5.90 (1H, s,
CHOH), 5.80 (1H, bs, OH), 3.65 (3H, s, OCH3).
2-((2-Chloroquinolin-3-yl)(hydroxy)methyl)acrylonitrile (3d).
Light brown solid; m.p. 118–120ꢂC; Rf ¼ 0.36 (CHCl3/EtOAc
4:1) MS m/z 245.2 (Mþ, 100%), 247.2 (Mþ2); IR (KBr) mmax
(cmꢀ1) 3233.45, 2923.59, 2226.96, 1589.59; 1H NMR (400
MHz, DMSO-d6) d 8.64 (1H, s, ArH), 8.20 (1H, d, J ¼ 8 Hz,
ArH), 8.0 (1H, d, J ¼ 8 Hz, ArH), 7.90 (1H, t, J ¼ 6 Hz,
ArH), 7.60 (1H, t, J ¼ 6 Hz, ArH), 6.80 (1H, s, D2O
exchangeable, OH), 6.42 (1H, s, ACH¼¼C), 6.38 (1H, s,
ACH¼¼C), 5.70 (1H, s, CHOH); Elemental analysis found: C,
63.67; H, 3.58.;N, 11.63; C13H9N2ClO requires C, 63.81; H,
3.71; N, 11.45.
N-(2-chloro-3-(hydroxy(6-oxocyclohex-1-enyl)methyl)-7-
phenoxyquinolin-6-yl)methanesulfonamide (3e). Pale yel-
low solid; m.p. 118–120ꢂC; Rf ¼ 0.35 (CHCl3/EtOAc 4:1) MS
m/z 472.9 (Mþ, 100%) 475 (Mþ2); IR (KBr) mmax (cmꢀ1) 3246.93
(OH), 2927.93 (CH), 1668.07 (CO), 1626.46 (C¼¼C),1589.19;
Figure 4. Dose response curve (DRC) of selected compounds.
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L. V. Reddy, M. Kethavath, M. Nakka, S. S. Beevi, L. N. Mangamoori, K. Mukkanti, and S. Pal Vol 49
Figure 5. Proposed interaction of MBH adduct with GSH.
1H NMR (400 MHz, DMSO-d6) d 9.20 (1H, D2O exchangeable,
NH), 8.28 (1H, s, ArH), 7.98 (1H, s, ArH), 7.50 (2H, t, J ¼ 8 Hz,
ArH), 7.30 (1H, d, J ¼ 8 Hz, ArH), 7.20 (2H, d, J ¼ 8 Hz, ArH),
7.0 (1H, s, ArH), 6.90 (1H, s, ACH¼¼C), 5.80 (1H, s, ACHOH),
5.75 (1H, bs, OH), 3.0 (3H, s, ASO2CH3), 2.40 (4H, m, 2CH2)
2.00 (2H, m, CH2); Elemental analysis found: C, 58.51; H, 4.36;
N, 5.83; C23H21N2ClSO5 requires C, 58.41; H, 4.48; N, 5.92.
Ethyl 2-((2-chloro-6-(methylsulfonamido)-7-phenoxyquino-
lin-3-yl)(hydroxy)methyl) acrylate (3f). Cream colored solid;
Rf ¼ 0.40 (CHCl3/EtOAc 4:1) m.p. 98–100ꢂC; MS m/z 477.1
(Mþ, 100%), 479.1 (Mþ2); IR (KBr) mmax (cmꢀ1) 3205.98
(OH), 2925.72 (CH), 1668.59 (CO),1626.41(C¼¼C), 1H NMR
(400 MHz, DMSO-d6) d 10.09 (1H, D2O exchangeable, NH),
8.28 (1H, s, ArH), 7.98 (1H, s, ArH), 7.50 (2H, t, J ¼ 8 Hz,
ArH), 7.30 (1H, t, J ¼ 8 Hz, ArH), 7.20 (2H, d, J ¼ 8 Hz,
ArH), 7.0 (1H, bs, ArH), 6.35 (1H, s, ACHOH), 5.82 (1H, s,
ACH¼¼CA), 5.78 (1H, s, ACH¼¼CA), 5.70 (1H, s, OH), 4.10
(2H, q, J ¼ 6 Hz, OCH2), 3.0 (3H, s, SO2CH3), 1.20 (3H, t,
J ¼ 6 Hz); Elemental analysis found: C, 55.27; H, 4.48.;N,
6.03; C22H21N2ClSO6 requires C, 55.40; H, 4.44; N, 5.87.
Methyl 2-((2-chloro-6-(methylsulfonamido)-7-phenoxyqui-
nolin-3-yl)(hydroxy)methyl)acrylate (3g). Cream colored solid;
Rf ¼ 0.38 (CHCl3/EtOAc 4:1); MS m/z 463.1 (Mþ, 100%),
465.1 (Mþ2); IR (KBr) tmax (cmꢀ1) 3246.90 (OH), 2927.95
(CH), 1668.0 (CO),1626.45 (C¼¼C),1589.20; 1H NMR (400
MHz, DMSO-d6) d 10.09 (1H, D2O exchangeable, NH), 8.28
(1H, s, ArH), 7.98 (1H, s, ArH), 7.50 (2H, t, J ¼ 8 Hz, ArH),
7.30 (1H, t, J ¼ 8 Hz, ArH), 7.20 (1H, d, J ¼ 8 Hz, ArH),
7.0 (2H, bs, ArH), 6.35 (1H, s, ACHOH), 5.82 (1H, s,
ACH¼¼CA), 5.78 (1H, s, ACH¼¼CA), 5.67 (1H, s, OH), 3.75
(3H, s, OCH3), 3.0 (3H, s, SO2CH3); Elemental analysis found:
C, 54.57; H, 4.08; N, 5.97; C21H19N2ClSO6 requires C, 54.49;
H, 4.14; N, 6.05.
N-(2-Chloro-3-(2-cyano-1-hydroxyallyl)-7-phenoxyquinolin-
6-yl)methanesulfonamide (3h). Pale yellow solid; m.p. 120–
122ꢂC; Rf ¼ 0.39 (CHCl3/EtOAc 4:1) MS m/z 429.9 (Mþ,
100%), 432 (Mþ2); (KBr) tmax (cmꢀ1
) 3253.98 (OH),
2927.93 (CH), 2852.30 (CH), 2226.35 (CN), 1626.46 (C¼¼C),
1
1589.19; H NMR (400 MHz, DMSO-d6) d 9.90 (1H, s, D2O
exchangeable NH) 8.60 (1H, s, ArH), 8.20 (1H, s, ArH), 7.60
(2H, t, J ¼ 8 Hz, ArH), 7.40 (1H, t, J ¼ 6 Hz, ArH), 7.20
(2H, d, J ¼ 8 Hz, ArH), 7.00 (1H, s, ArH), 6.80 (1H, s, D2O
exchangeable, OH), 6.32 (1H, s, CH¼¼C), 6.28 (1H, s,
CH¼¼C), 5.60 (1H, s, CHOH), 3.20 (3H, s, ASO2CH3); Molec-
ular formula: Elemental analysis found: C, 55.51; H, 3.78.; N,
9.93; C20H16ClN3O4S requires C, 55.88; H, 3.75; N, 9.77.
N-(2-Chloro-3-(hydroxy(6-oxocyclohex-1-enyl)methyl)-7-
phenoxyquinolin-6-yl)formamide (3i). Pale yellow solid;
m.p. 110–112ꢂC; Rf ¼ 0.45 (CHCl3/EtOAc 4:1); MS m/z
423.2 (Mþ, 100%), 425.2 (Mþ2, 33%); IR (KBr) tmax(cmꢀ1
)
3354.36 (OH), 2926.33 (CH), 1674.67 (CO); 1H NMR (400
MHz, DMSO-d6) d 10.40 (1H, s, D2O exchangeable, NH),
8.90 (1H, s, CHO), 8.50 (1H, s, ArH), 8.30 (1H, s, ArH), 7.55
(2H, m, ArH), 7.30 (3H, m, ArH), 7.0 (1H, s, ArH), 6.90 (1H,
s, CH¼¼C), 5.85 (1H, s, CHOH), 5.75 (1H, s, OH), 2.85 (2H,
m), 2.20 (2H, m), 2.0 (2H, m); Elemental analysis found: C,
65.15; H, 4.58.; N, 6.78; C23H19ClN2O4 requires C, 65.33; H,
4.53; N, 6.62.
Ethyl 2-((2-chloro-6-formamido-7-phenoxyquinolin-3-yl)-
(hydroxy)methyl)acrylate (3j). White solid; m.p. 120–122ꢂC;
Rf ¼ 0.45 (CHCl3/EtOAc 4:1); MS m/z 427.0 (Mþ, 100%),
428.9 (Mþ2); IR (KBr) tmax (cmꢀ1) 3372.56 (OH), 2925.23
(CH), 1694.0 (CO), 1620 (C¼¼C); 1H NMR (400 MHz,
DMSO-d6) d 10.45 (1H, s, D2O exchangeable, NH), 8.85 (1H,
s, CHO), 8.45 (1H, s, ArH), 8.25 (1H, s, ArH), 7.60 (3H, m,
ArH), 7.25 (2H, m, ArH), 7.0 (1H, s, ArH), 6.40 (1H, s, OH),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2012
Design and Synthesis of Novel Cytotoxic Agents Based on Combined Framework
of Quinoline and Nimesulide
87
6.05 (1H, s, CHOH), 5.85 (1H, s, CH¼¼C), 5.80 (1H, s,
CH¼¼C), 4.0 (2H, q, J ¼ 3.8 Hz, OCH2), 1.2 (3H, t, J ¼ 3.8
Hz, CH3); Elemental analysis found: C, 61.53; H, 4.48.; N,
6.73; C22H19ClN2O5 requires C, 61.90; H, 4.49; N, 6.56.
Methyl 2-((2-chloro-6-formamido-7-phenoxyquinolin-3-yl)-
(hydroxy)methyl)acrylate (3k). Pale yellow solid; m.p. 98–
100ꢂC; Rf ¼ 0.41 (CHCl3/EtOAc 4:1); MS m/z 413.3 (Mþ,
100%) 415.3 (Mþ2,33%); IR (KBr) tmax (cmꢀ1) 3372.56
(OH), 2925.23 (CH), 1694.0 (CO), 1620 (C¼¼C); 1H NMR
(400 MHz, DMSO-d6) d 10.45 (1H, s, D2O exchangeable,
NH), 8.85 (1H, s, CHO) 8.45 (1H, s, ArH), 8.25 (1H, s, ArH),
7.55 (2H, m, ArH), 7.36 (3H, m, ArH), 7.0 (1H, s, ArH), 6.40
(1H, s, OH), 6.10 (1H, s, CHOH), 5.85 (1H, s, CH¼¼C), 5.80
(1H, s, CH¼¼C), 3.85 (3H, s, OCH3); Molecular formula: Ele-
mental analysis found: C, 61.33; H, 4.10.; N, 6.63;
C21H17ClN2O5 requires C, 61.10; H, 4.15; N, 6.79.
whereas absorbance from nontreated control cells was defined as
100% live cells. The percent dead cells was plotted (Y-axis) against
concentration (X-axis) of compounds, where IC50 values could be
interpolated from the graph.
Acknowledgments. The author (S. Pal) thanks M. N. Raju, the
Chairman of M. N. R. Educational Trust for his constant
encouragement.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet