Synthesis and biological studies of some new acrylic acid ethyl esters of quinolinone

Article abstract of DOI:10.1007/s00706-011-0692-2

A series of new acrylic acid ethyl esters of quinolinones were synthesized from 4-(bromomethyl)-quinolinones and screened for in vitro antimicrobial and in vivo analgesic and anti-inflammatory activities. Most of the compounds with chloro substitution at

Full text of DOI:10.1007/s00706-011-0692-2

Monatsh Chem (2012) 143:1075–1086
DOI 10.1007/s00706-011-0692-2
ORIGINAL PAPER
Synthesis and biological studies of some new acrylic acid
ethyl esters of quinolinone
•
Rajesh G. Kalkhambkar G. Aridoss
•
•
Geeta M. Kulkarni R. M. Bapset J. C. Kadakol
•
•
•
N. Premkumar Yeon Tae Jeong
Received: 5 April 2011 / Accepted: 22 November 2011 / Published online: 10 January 2012
Ó Springer-Verlag 2012
Abstract A series of new acrylic acid ethyl esters of
quinolinones were synthesized from 4-(bromomethyl)-
quinolinones and screened for in vitro antimicrobial and in
vivo analgesic and anti-inflammatory activities. Most of the
compounds with chloro substitution at the C-6 or C-7
position in the quinolinone moiety and a methoxy group in
the aryloxy moiety showed potent antibacterial and anti-
fungal activities when compared with non-halogenated
quinolinones and the quinolinones bearing a CH3 at the C-8
position. In a pharmacological evaluation, the halogen sub-
stitution at the C-6 or C-7 position in quinolinones was found
to enhance both analgesic and anti-inflammatory activities of
the molecule when compared with a simple unsubstituted
(non-halogenated) quinolinone. The structures of all newly
synthesized compounds were characterized by elemental
analysis, IR, 1H NMR, 13C NMR, and FAB-MS.
Keywords Quinolinones Á Antibacterial activity Á
Antifungal activity Á Analgesic activity Á
Anti-inflammatory activity
Introduction
Quinolinones belong to the class of lactams which is an
indispensable heterocyclic unit to both chemists and
biochemists. The natural occurrence and antimicrobial, anti-
inflammatory, anti-cancer, anti-HIV, and other miscella-
neous properties of this system were recently reviewed [1].
Quinolinone derivatives are metabolized to the correspond-
ing 8-hydroxycoumarins in biological systems and are
therefore very good anti-inflammatory and analgesic agents
[2]. The triheterocyclic thiazoles synthesized from 4-(ami-
nomethyl)quinolinones and 3-(bromoacetyl)coumarins [3]
in our laboratory exhibit promising anti-inflammatory and
analgesic activity even after 24 h. We also reported that the
introduction of halogens in general and fluorine in particular
at position 4 in the aryloxy and arylamino moieties of cou-
marin and quinolinone [4–6] enhances the antimicrobial as
well as analgesic and anti-inflammatory activities. Interest in
quinolinones as antibiotics is due to their potent inhibition of
bacterial DNA gyrase, which is involved in the growth [7, 8].
Vanillins exhibit antimicrobial properties and have been
accepted as safer flavoring agents [9, 10]. In view of this, we
reported the analgesic and potent anti-inflammatory activi-
ties of the vanillin ethers derived from 4-substituted
coumarins (Fig. 1) [11], and novel ethers of a nitrogen ana-
logue of coumarin also known as 1-azacoumarin or
quinolinone linked with coumarins [12]. The observed anti-
inflammatory activity of quinolinones is due to the genera-
tion of a carboxyl group in the biological system [13]. The
R. G. Kalkhambkar Á G. M. Kulkarni
Department of Chemistry, Karnatak University’s Karnatak
Science College, Dharwad, Karnataka 580001, India
R. M. Bapset
Department of Chemistry, D.M.S Mandal’s Bahurao Kakatkar
Science College, Club Road, Belgaum, Karnataka 590001, India
J. C. Kadakol
Department of Biotechnology, Karnatak University’s Karnatak
Science College, Dharwad, Karnataka 580001, India
N. Premkumar
Department of Pharmacology, Krupanidhi College of Pharmacy,
Bangalore, Karnataka 560034, India
G. Aridoss Á Y. T. Jeong (&)
Department of Image Science and Engineering, Pukyong
National University, Busan 608-739, Republic of Korea
e-mail: ytjeong@pknu.ac.kr
123

1076
R. G. Kalkhambkar et al.
Fig. 1 Biologically active
coumarin molecules
H
O
O
O
O
O
O
O
H
R
R
R
O
O
O
O
O
O
NC
O
O
O
mechanism of action of the generation of carboxyl group
containing anti-inflammatory drugs like indomethacin is
based on the interference with prostaglandin synthesis via
cyclooxygenase inhibition. Thus the structure of a potential
drug should mimic that of arachidonic acid to be viable.
Encouraged by our earlier studies, it was thought of interest
to synthesize some new aryloxymethyl quinolinones with
vanillin and p-hydroxybenzaldehyde. They were further
converted into corresponding cyanoesters and acetoesters
which can act as precursors for generating the carboxylic
group and hence are expected to exhibit good anti-inflam-
matory properties. The present paper reports the synthesis
and preliminary biological evaluation of new acrylic acid
ethyl esters of quinolinone.
and dry ethanol at 100 °C. Similarly the acetoesters 6a–6d
and 7a–7d were prepared by the condensation of 4-(bromo-
methyl)quinolinones with 2-acetyl-3-(4-hydroxyphenyl)-
acrylic acid ethyl ester (9a) and 2-acetyl-3-(4-hydroxy-3-
methoxyphenyl)acrylic acid ethyl ester (9b) in the presence
of anhydrous potassium carbonate and dry ethanol at 100 °C
(Scheme 2). This method of preparation is easier than the
earlier method (Scheme 1) because the products are obtained
in better yield and purity. Synthesis of compounds 2a–2d and
3a–3d was carried out (Scheme 1) in order to study their
biological activities in comparison with compounds 4a–4d,
5a–5d, 6a–6d, and 7a–7d.
All products gave satisfactory analytical and spectro-
scopic data, which are in full accordance with their
assigned structures. The ORTEP diagram of the interme-
diate compound 4-[(4-formylphenoxy)methyl]quinolinone
(2a) is shown in Fig. 2 [15].
Results and discussion
Syntheses
Antimicrobial activity
Various 4-(bromomethyl)quinolinones 1a–1d were synthe-
sized by the bromination of acetoacetanilides and cyclization
of the intermediate x-bromoacetoacetanilides in sulfuric acid
[4, 14]. The various substituted 4-[(4-formylphenoxy)-
methyl]quinolinones 2a–2d were prepared by the reaction of
4-(bromomethyl)quinolinones and p-hydroxybenzaldehyde
in the presence of anhydrous potassium carbonate and dry
ethanol at 100 °C. The corresponding cyanoesters 4a–4d and
acetoesters 6a–6d were synthesized by the condensation of
ethyl cyanoacetate and ethyl acetoacetate in the presence of a
catalytic amount of piperidine in dry ethanol (Scheme 1).
Similarly, the synthesis of substituted 4-[(4-formyl-2-
methoxyphenoxy)methyl]quinolinones 3a–3d was achieved
by the reaction of 4-(bromomethyl)quinolinones and vanillin
in the presence of anhydrous potassium carbonate and dry
ethanol at 100 °C. The corresponding cyanoesters 5a–5d and
acetoesters 7a–7d were synthesized by the condensation of
ethyl cyanoacetate and ethyl acetoacetate in the presence of a
catalytic amount of piperidine in dry ethanol.
The antibacterial (against Escherichia coli and Bacillus cir-
rhosis) and antifungal (against Aspergillus niger and
Rhizoctonia bataticola) activities of the compounds were
testedatthreeconcentrations(25,50, and100 lg cm-3) using
norfloxacin and griseofulvin as standard antibacterial and
antifungal drugs, respectively [16–18]. Tables 1 and 2 list the
zones of growth inhibition (in millimeters and as percentage
values) obtained against the tested bacteria and fungi. Most of
the compounds exhibited pronounced activity against E. coli
at 50 and 100 lg cm-3, whereas at 25 lg cm-3 all com-
pounds are inactive except 2b, 2c, 3b, 3c, 7b, and 7c bearing
chlorine functionality in the quinolinone ring system. Con-
versely, against B. cirrhosis, nearly all compounds showed
inhibition potency, which ranged from 12 to 83%. In partic-
ular, though compounds 2b and 2c exhibited marked
antibacterial activity against both the bacterial strains, their
vanillinanalogues3b and3c exhibitedstrikingly highpotency
of up to 72 and 75% inhibition of E. coli and similarly 80 and
83% inhibition of B. cirrhosis at 100 lg cm-3. On the other
hand, modification of the aldehyde moiety in 2a–3d either by
condensation with ethyl acetoacetate or ethyl cyanoacetate
(i.e., compounds 4a–7d) did not show any sign of improved
activity against E. coli and B. cirrhosis. However, compounds
7b and 7c exhibited comparable potency of about 46 and 48%
Cyanoesters 4a–4d and 5a–5d were also prepared by the
condensation of 4-(bromomethyl)quinolinones with 2-
cyano-3-(4-hydroxyphenyl)acrylic acid ethyl ester (8a) and
2-cyano-3-(4-hydroxy-3-methoxyphenyl)acrylic acid ethyl
ester (8b) in the presence of anhydrous potassium carbonate
123

New acrylic acid ethyl esters of quinolinone
1077
Scheme 1
O
O
O
R
R
O
O
O
O
N
O
NC
CN
O
N
H
H
4a-4d
5a-5d
Piperidine
EtOH
Piperidine
EtOH
Ethyl
cyanoacetate
Ethyl
cyanoacetate
O
O
Br
O
p-Hydroxy-
benzaldehyde
H
H
O
Vanillin
R
R
R
O
O
K2CO3
EtOH
K2CO3
EtOH
N
O
N
H
O
N
H
H
3a-3d
2a-2d
1a-1d
Piperidine Ethyl
EtOH acetoacetate
Piperidine Ethyl
EtOH acetoacetate
O
O
O
R
R
O
O
O
O
N
H
N
O
H
O
O
O
a, R = H; b, R = 6-Cl;
c, R = 7-Cl; d, R = 8-CH3
7a-7d
6a-6d
Scheme 2
O
O
O
O
O
O
H
H
H
Ethyl
acetoacetate
Ethyl
cyanoacetate
NC
R'
R'
R'
Piperidine,
EtOH
Piperidine,
EtOH
OH
OH
OH
8a, R' = H
8b, R' = OCH3
9a
9b
, R' = H
, R' = OCH3
K2CO3
EtOH
4-Bromomethyl-
carbostyrils
K2CO3
EtOH
4-Bromomethyl-
carbostyrils
R'
O
R'
O
R
R
O
O
N
H
O
N
H
O
NC
O
O
O
6a 6d
7a 7d
- , R' = OCH3
a
c
b
4a 4d
- , R' = H
5a 5d
- , R' = OCH3
-
, R' = H
, R = H; , R = 6-Cl;
d
, R = 7-Cl; , R = 8-CH3
123

1078
R. G. Kalkhambkar et al.
Fig. 2 ORTEP drawing of 4-[(4-
formylphenoxy)methyl]quinoline-
2(1H)-one (2a)
Table 1 Antibacterial activity
of selected compounds (at 25,
50, and 100 lg/cm3)
Compound Zone of inhibition
E. coli (gram negative)
B. cirrhosis (gram positive)
100 lg/cm3 50 lg/cm3
100 lg/cm3
50 lg/cm3
25 lg/cm3
25 lg/cm3
mm
%
mm
%
mm
%
mm
%
mm
%
mm
%
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
7d
Std
Ctr
82
26
48
51
32
72
75
28
33
37
38
42
43
29
39
37
40
46
48
33
100
–
–
–
–
–
98
35
56
58
40
80
83
40
44
48
50
58
60
38
47
53
44
71
68
37
100
–
45
13
40
41
15
63
65
22
23
30
33
40
43
16
27
34
21
57
44
15
100
–
–
–
132
138
94
86
92
–
34
37
–
38
44
–
12
17
–
144
148
108
198
204
110
118
126
132
148
152
104
124
138
118
178
170
102
240
20
92
48
48
–
21
21
–
94
48
186
194
86
121
127
–
53
56
–
62
69
–
30
35
–
134
138
60
66
78
–
35
44
–
98
42
48
46
60
64
–
11
14
13
21
23
–
–
–
62
–
–
106
108
118
120
88
–
–
74
36
40
44
50
–
12
15
18
23
–
–
–
80
–
–
92
–
–
98
–
–
50
110
106
112
126
132
98
46
40
60
84
90
46
210
20
13
10
21
33
36
13
100
–
–
–
70
–
–
–
–
82
40
–
15
–
–
–
58
36
44
–
11
17
–
124
118
48
54
48
–
26
21
–
Std standard (norfloxacin, 100%
inhibition at each
concentration), Ctr control
(N,N-dimethylformamide,
DMF)
250
20
160
20
100
–
200
20
150
20
100
–
inhibition of E. coli at 100 lg cm-3 but fairly good activity
of 71 and 68% inhibition of B. cirrhosis at the same
concentration.
The results of antibacterial activities (Table 1) show that
compounds 3b and 3c showed a very good antibacterial
activity of up to 72 and 75% inhibition of E. coli and
123

New acrylic acid ethyl esters of quinolinone
1079
Table 2 Antifungal activity of
the selected compounds (at 25,
50, and 100 lg/cm3)
Compound Zone of inhibition
A. niger
R. bataticola
100 lg/cm3
50 lg/cm3
25 lg/cm3
100 lg/cm3
50 lg/cm3
25 lg/cm3
mm
%
mm
%
mm
%
mm
%
mm
%
mm
%
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
7d
Std
Ctr
62
19
52
55
35
79
84
23
36
40
35
52
54
18
41
40
35
64
68
40
100
–
–
–
–
–
102
160
164
110
206
214
118
132
136
100
126
138
110
142
148
100
212
218
136
260
20
34
58
60
37
78
80
40
46
48
33
44
49
37
50
53
33
80
82
48
100
–
–
–
–
–
136
142
98
84
78
54
132
140
–
35
32
18
62
66
–
38
34
–
12
10
–
94
37
40
26
64
67
27
36
36
–
58
62
–
25
28
–
100
72
194
206
72
66
82
–
32
44
–
148
154
74
84
88
–
42
45
–
100
110
98
58
66
50
78
80
–
21
25
16
32
33
–
–
–
92
50
50
–
20
20
–
–
–
92
–
–
–
136
140
60
38
38
–
12
12
–
90
35
40
25
40
45
–
48
60
–
18
26
–
100
68
112
108
98
66
64
55
92
98
60
200
20
25
24
17
40
43
22
100
–
–
–
100
110
–
56
62
–
24
28
–
–
–
–
–
162
170
110
240
20
58
62
–
27
30
–
150
154
90
65
67
35
100
–
80
90
40
170
20
40
46
13
100
–
Std standard (griseofulvin,
100% inhibition at each
concentration), Ctr control
(DMF)
160
20
100
–
220
20
similarly 80 and 83% inhibition of B. cirrhosis at
100 lg cm-3. The same compounds were even active at
25 lg cm-3 and showed 30, 35, 35, and 44% inhibition of
both the bacteria. Compounds 7b and 7c showed moderate
activity of 46 and 48% inhibition of E. coli at
100 lg cm-3, but fairly good activity of 71 and 68%
inhibition of B. cirrhosis at the same concentration. Most
of the tested compounds showed no activity at 25 lg cm-3
and moderate activity at 100 lg cm-3 for both the bacteria.
Similar to antibacterial activities, the inhibitory profiles
of all compounds against fungal strains also registered the
same trend at the three studied concentrations. Compounds
2b, 2c, 5b, and 5c showed a moderate inhibition of 52, 55,
52, and 54%, respectively, at 100 lg cm-3 for A. niger,
and 58, 60, 44, and 49%, respectively, at the same con-
centration for R. bataticola (Table 2). The same
compounds showed low activity from 12 to 26% inhibition
at 25 lg cm-3 for both fungi. Compounds 3b, 3c, 7b, and
7c showed a very good inhibition of 79, 84, 64, 68% and
78, 80, 80, 82%, respectively, at 100 lg cm-3 for both
fungi. Compounds 3b and 3c showed moderate activity of
32, 44, 42, and 45% even at 25 lg cm-3 for both fungi.
Similarly compounds 7b and 7c showed moderate activ-
ity of 40 and 46%, respectively, at 25 lg cm-3 for
R. bataticola. Most of the compounds showed moderate
activity for both the fungi at 100 lg cm-3 and some of the
compounds showed no activity at 25 lg cm-3
.
Acute toxicity studies
The acute toxicity studies of the test compounds were
performed on albino mice fasted for 24 h [19]. The test
compounds were administered orally and intraperitonally
(i.p.). The animals were watched for mortality and symp-
toms until the eighth day. It was found that all compounds
possess a good safety profile and no mortality of animals
was observed even after 24 h.
Analgesic activity
Abdominal constriction response induced by acetic acid is
a sensitive procedure to establish the efficacy of peripher-
ally acting analgesics. Intraperitonial administration of
acetic acid causes an increase in the level of PGE2 and
PGF 2a [20]. The results of analgesic activity (Tables 3
and 4) indicate that compounds 3a, 4a, 6b, and 7b showed
the highest analgesic activity, more than the standard.
Compounds 3b, 6c, and 7c showed more than 50%
123

1080
R. G. Kalkhambkar et al.
Table 3 Anti-inflammatory and analgesic activities of selected compounds
Compound
Edema volume at different time intervals (% of inhibition)
Analgesic
activity
(number of
0.5 h
1 h
2 h
4 h
8 h
12 h
24 h
writhings)
Std.
Ctr.
3a
0.63 (3)
0.65
0.78 (8)
0.85
0.85 (11)
0.95
0.65* (35)
1.00
0.60* (41)
1.01
0.78 (15)
0.82
0.95 (13)
0.95
19*
35
0.71 (0)
0.61 (6)
0.75 (0)
0.73 (0)
0.60 (8)
0.51 (22)
0.58 (11)
2.83
1.16 (0)
1.01 (0)
1.06 (0)
1.05 (0)
1.01 (0)
0.78 (8)
0.75 (12)
38.3
0.85 (11)
0.66* (31)
0.98 (0)
0.61* (36)
0.55* (42)
0.78 (18)
0.75 (21)
12.0
0.56* (44)
0.56* (44)
0.40* (60)
0.38* (62)
0.28* (72)
0.75*** (25)
0.58* (42)
21.4
0.46* (54)
0.50* (50)
0.31* (69)
0.28* (72)
0.23* (77)
0.23* (77)
0.26* (74)
27.0
0.51** (38)
0.73 (11)
0.60*** (27)
0.45* (45)
0.50* (39)
0.56*** (32)
0.45* (45)
10.6
0.96 (0)
1.10 (0)
0.88 (7)
0.98 (0)
0.86 (9)
0.86 (9)
0.91 (4)
2.51
25*
15*
22*
13*
9*
3b
6b
6c
7a
7b
24*
13*
86.41
7c
F value
Standard error of the mean (SEM) 0.05–0.15. Test compounds were administered at a dose of 100 mg kg-1
Std standard (indomethacin at a dose of 10 mg kg-1), Ctr control (carbethoxymethyl cellulose, CMC; 2%)
* P \ 0.05, ** P \ 0.01, *** P \ 0.001 when compared to control
Table 4 Anti-inflammatory and analgesic activities of selected compounds
Compound
Edema volume at different time intervals (% of inhibition)
Analgesic
activity
(number of
writhings)
0.5 h
1 h
2 h
4 h
8 h
12 h
24 h
Std.
Ctr.
4a
0.63 (3)
0.65
0.78 (8)
0.85
0.85 (11)
0.95
0.65* (35)
1.00
0.60* (41)
1.01
0.78 (15)
0.82
0.95 (13)
0.95
19*
35
0.65 (0)
0.61 (6)
0.53 (19)
0.43 (34)
0.40 (39)
3.28
0.65 (24)
0.68 (20)
0.65 (24)
0.58* (32)
0.50* (41)
5.45
0.82 (14)
0.73 (23)
0.70*** (26)
0.62** (35)
0.42* (56)
10.4
0.50* (50)
0.37* (63)
0.52* (48)
0.40* (60)
0.13* (87)
37.08
0.48* (52)
0.30* (70)
0.28* (72)
0.36* (64)
0.10* (90)
34.09
0.68 (17)
0.66 (20)
0.66 (20)
0.70 (15)
0.52** (37)
3.05
0.75 (21)
0.70*** (26)
0.70*** (26)
0.65* (8)
0.60** (6)
4.47
17*
10*
8*
4b
4c
5b
9*
5c
4*
F value
192.23
SEM 0.05–0.15. Test compounds were administered at a dose of 100 mg kg-1
Std standard (indomethacin at a dose of 10 mg kg-1), Ctr control (2% CMC)
* P \ 0.05, ** P \ 0.01, *** P \ 0.001 when compared to control
inhibition of writhing when compared to the control and
the standard group.
maximum of 90% inhibition of inflammation at 8 h and
maintained activity at 12 and 24 h. The metabolites of this
compound may also show some anti-inflammatory activity.
Compound 5c may be more potent than the standard. Simi-
larly compounds with chloro substitution at the C-6 or C-7
positionin the quinolinone moiety (4b, 4c, 6b, 6c, 7b, and 7c)
showed 69–77% inhibition of inflammation at 8 h. All
compounds showed their highest activity until 8 h and some
of the compounds (4b, 4c, 6b, 7a, and 7b) were active even at
12 and 24 h. Hence it can be concluded that these can act
as prodrugs. A graphical representation of the anti-inflam-
matory activity of some of the compounds is given in Figs. 3
and 4.
Anti-inflammatory activity
The anti-inflammatory activity of the test compounds was
assessed by the formalin-induced rat paw edema method [21]
and the results are given in Tables 3 and 4. Most of the
compounds showed an extremely significant anti-inflam-
matory activity when compared to the control and the
standard group, and their onset of action was much quicker
than the standard, because they showed significant anti-
inflammatory activity at 2 h. Compound 5c showed a
123

New acrylic acid ethyl esters of quinolinone
1081
pellets. 1H NMR and 13C NMR spectra were recorded on a
Bruker AC-300F 300 MHz spectrometer in CDCl3, DMSO-
d6, or a mixture of CDCl3 and CF3COOH using TMS as an
internal standard. D2O exchange was applied to confirm the
assignment of the signals of NH protons. The mass spectra
were recorded on an Autospec ESI–MS. The elemental
analysis was carried out by using a Heraus CHN rapid ana-
lyzer. C, H, and N values of all compounds were well within
0.4% from the theoretical values. The homogeneity of the
compounds was determined by TLC on silica gel 60 F254
(Merck) aluminum plates visualized by UV light (254 nm)
and iodine vapor. The reagents were all analytical reagent
grade or chemically pure. All solvents (including dry ethanol)
were dried, deoxygenated, and redistilled before use by
standard procedures [22].
80
70
60
50
40
30
20
10
0
0.5h
1h
2h
4h
8h
12h
24h
std
3a
3b
4a
4b
4c
5b
Compounds
Fig. 3 Anti-inflammatory activity of selected compounds (3a–5b)
and standard
100
90
General procedure for the synthesis of compounds
2a–2d
0.5h
1h
80
70
60
50
40
30
20
10
0
A mixture of substituted 4-(bromomethyl)quinolinone
1a–1d (4.00 mmol), 4-hydroxybenzaldehyde (4.00 mmol),
and anhydrous potassium carbonate (4.00 mmol) in 20 cm3
dry ethanol was refluxed on a water bath for 8 h. The
separated solid was filtered off, washed with 20% HCl and
with excess of cold water, dried, and crystallized from a
suitable solvent.
2h
4h
8h
12h
24h
std
5c
6b
6c
7a
7b
7c
Compounds
4-[(1,2-Dihydro-2-oxoquinolin-4-yl)methoxy]-
benzaldehyde (2a, C17H13NO3)
Yield: 87%; colorless crystals (acetic acid); m.p.: 250–252
Fig. 4 Anti-inflammatory activity of selected compounds (5c–7c)
and standard
°C; IR (KBr):vꢀ = 3,431 (N–H stretching), 1,688 (C=O
Conclusion
stretching, aldehyde), 1,669 (C=O stretching, amide) cm-1
;
1H NMR (300 MHz, CDCl3): d = 5.50 (s, 2H, C4-CH2),
6.60 (s, 1H, C3-H of quinolinone), 7.20–7.92 (m, 9H,
Ar–H), 9.92 (s, 1H, CHO), 11.80 (s, 1H, NH) ppm; 13C
NMR (75 MHz, CDCl3): d = 162.50, 160.44, 158.28,
156.34, 154.28, 136.89, 133.48, 132.80, 127.08, 124.60,
119.40, 116.30, 116.21, 114.47, 114.30, 109.10, 65.98 ppm;
FAB-MS: m/z = 280 (M ? H).
The present study has shown that the newly synthesized
quinolinonecompounds2b, 2c, 3b, 3c, 5b, 5c, 7b, and 7c with
chloro substitution on quinolinone and a methoxy group in the
aryloxy moiety showed potent antibacterial and antifungal
activities when compared with unsubstituted quinolinones.
The halogen substitution at the C-6 or C-7 position in quino-
linones 3a, 3b, 4a, 4b, 6b, and 7b was found to enhance both
analgesic and anti-inflammatory activities of the molecule in
comparison with non-halogenated molecules. Our findings
will be usefulfor chemists and biochemists conductingfurther
investigations in this field in search of potent antimicrobial,
analgesic, and anti-inflammatory agents.
4-[(6-Chloro-1,2-dihydro-2-oxoquinolin-4-yl)methoxy]-
benzaldehyde (2b, C17H12ClNO3)
Yield: 82%; colorless crystals (ethanol); m.p.: 198–200 °C;
IR (KBr):vꢀ = 3,438 (N–H stretching), 1,680 (C=O stretch-
1
ing, aldehyde), 1,658 (C=O stretching, amide) cm-1; H
NMR (300 MHz, CDCl3): d = 5.45 (s, 2H, C4-CH2), 6.68
(s, 1H, C3-H of quinolinone), 7.10–7.90 (m, 8H, Ar–H),
9.90 (s, 1H, CHO), 11.78 (s, 1H, NH) ppm; 13C NMR
(75 MHz, CDCl3): d = 163.56, 161.84, 158.28, 157.34,
153.28, 134.89, 133.48, 132.80, 128.08, 127.60, 119.40,
116.30, 115.21, 114.47, 114.30, 108.10, 64.98 ppm;
FAB-MS: m/z = 315 (M ? H).
Experimental
The melting points of the products were determined by open
capillariesonaBu¨chi apparatus. The IRspectra wererecorded
on a Nicolet Impact-410 FT-IR spectrophotometer using KBr
123

1082
R. G. Kalkhambkar et al.
1
4-[(7-Chloro-1,2-dihydro-2-oxoquinolin-4-yl)methoxy]-
benzaldehyde (2c, C17H12ClNO3)
aldehyde), 1,662 (C=O stretching, amide) cm-1; H NMR
(300 MHz, CDCl3): d = 3.96 (s, 3H, OCH3), 5.38 (s, 2H, C4-
CH2), 6.60 (s, 1H, C3-H of quinolinone), 6.80–7.50 (m, 6H,
Ar–H), 9.80 (s, 1H, CHO), 11.52 (s, 1H, NH) ppm; 13C NMR
(75 MHz, CDCl3): d = 163.50, 160.94, 158.18, 157.24,
154.48, 134.89, 133.48, 132.80, 128.08, 127.60, 119.40,
117.30, 116.21, 114.47, 113.30, 108.10, 65.78, 54.60 ppm;
FAB-MS: m/z = 346 (M ? H).
Yield: 78%; colorless crystals (ethanol ? dioxan); m.p.:
210–212 °C; IR (KBr):vꢀ = 3,440 (N–H stretching), 1,689
(C=O stretching, aldehyde), 1,665 (C=O stretching, amide)
1
cm-1; H NMR (300 MHz, CDCl3): d = 5.52 (s, 2H, C4-
CH2), 6.65 (s, 1H, C3-H of quinolinone), 7.08–7.88 (m,
8H, Ar–H), 9.94 (s, 1H, CHO), 11.80 (s, 1H, NH) ppm; 13
C
NMR (75 MHz, CDCl3): d = 162.58, 160.90, 158.68,
156.34, 155.28, 136.89, 134.48, 133.80, 128.08, 127.60,
119.40, 117.30, 116.21, 115.47, 114.30, 109.10,
66.98 ppm; FAB-MS: m/z = 315 (M ? H).
4-[(7-Chloro-1,2-dihydro-2-oxoquinolin-4-yl)methoxy]-3-
methoxybenzaldehyde (3c, C18H14ClNO4)
Yield: 73%; colorless crystals (ethanol ? dioxan); m.p.:
215–217 °C; IR (KBr):vꢀ = 3,440 (N–H stretching), 1,689
(C=O stretching, aldehyde), 1,665 (C=O stretching, amide)
4-[(1,2-Dihydro-8-methyl-2-oxoquinolin-4-yl)methoxy]-
benzaldehyde (2d, C18H15NO3)
1
cm-1; H NMR (300 MHz, CDCl3): d = 5.52 (s, 2H, C4-
Yield: 88%; colorless crystals (ethanol ? dioxan); m.p.:
212–214 °C; IR (KBr):vꢀ = 3,434 (N–H stretching), 1,692
(C=O stretching, aldehyde), 1,670 (C=O stretching, amide)
;
cm-1 1H NMR (300 MHz, CDCl3): d = 2.50 (s, 3H,
C8-CH3 of quinolinone), 5.55 (s, 2H, C4-CH2), 6.65 (s, 1H,
C3-H of quinolinone), 7.20–7.94 (m, 8H, Ar–H), 9.90 (s,
1H, CHO), 11.81 (s, 1H, NH) ppm; 13C NMR (75 MHz,
CDCl3): d = 164.58, 161.90, 159.68, 157.34, 156.28,
137.89, 135.48, 134.80, 129.08, 128.60, 118.40, 117.30,
116.21, 115.47, 114.30, 108.10, 65.90, 18.20 ppm;
FAB-MS: m/z = 295 (M ? H).
CH2), 6.65 (s, 1H, C3-H of quinolinone), 7.08–7.88 (m,
8H, Ar–H), 9.94 (s, 1H, CHO), 11.80 (s, 1H, NH) ppm; 13
C
NMR (75 MHz, CDCl3): d = 162.58, 160.90, 158.68,
156.34, 155.28, 136.89, 134.48, 133.80, 128.08, 127.60,
119.40, 117.30, 116.21, 115.47, 114.30, 109.10,
66.98 ppm; FAB-MS: m/z = 346 (M ? H).
4-[(1,2-Dihydro-8-methyl-2-oxoquinolin-4-yl)methoxy]-
3-methoxybenzaldehyde (3d, C19H17NO4)
Yield: 80%; colorless crystals (ethanol ? dioxan); m.p.:
220–222 °C; IR (KBr):vꢀ = 3,434 (N–H stretching), 1,662
(C=O stretching, aldehyde), 1,658 (C=O stretching, amide)
General procedure for the preparation of compounds
3a–3d
1
cm-1; H NMR (300 MHz, CDCl3): d = 2.45 (s, 3H, C8-
CH3 of quinolinone), 3.96 (s, 3H, OCH3), 5.48 (s, 2H, C4-
CH2), 6.60 (s, 1H, C3-H of quinolinone), 6.80–7.81 (m,
7H, Ar–H), 9.80 (s, 1H, CHO), 11.82 (s, 1H, NH) ppm; 13
A mixture of substituted 4-(bromomethyl)quinolinone
1a–1d (4.00 mmol), vanillin (4.00 mmol), and anhydrous
potassium carbonate (4.00 mmol) in 20 cm3 dry ethanol
was refluxed on a water bath for 8 h. The separated solid
was filtered off, washed with 20% HCl and with excess of
cold water, dried, and crystallized from a suitable solvent.
C
NMR (75 MHz, CDCl3): d = 163.18, 161.90, 158.58,
157.34, 156.28, 137.89, 136.48, 134.80, 129.08, 128.66,
119.40, 117.30, 116.21, 115.47, 114.30, 109.10, 65.90,
55.06, 20.10 ppm; FAB-MS: m/z = 326 (M ? H).
4-[(1,2-Dihydro-2-oxoquinolin-4-yl)methoxy]-3-
methoxybenzaldehyde (3a, C18H15NO4)
General procedure for the preparation of compounds
4a–4d
Yield: 77%; colorless crystals (ethanol); m.p.: 208–210 °C;
IR (KBr):vꢀ = 3,443 (N–H stretching), 1,680 (C=O stretch-
ing, aldehyde), 1,659 (C=O stretching, amide) cm-1; H
1
A mixture of substituted 4-[(4-formylphenoxy)methyl]
quinolin-2(1H)-one 2a–2d (4.0 mmol), ethyl cyanoactate
(4.0 mmol), and a catalytic amount of piperidine in 20 cm3
ethanol was stirred for 6 h at room temperature and left
overnight. The resulting yellow liquid was poured onto
crushed ice. The yellow solid obtained was filtered off,
washed with excess of cold water, dried, and crystallized
from a suitable solvent.
NMR (300 MHz, CDCl3): d = 3.74 (s, 3H, OCH3), 5.25 (s,
2H, C4-CH2), 6.59 (s, 1H, C3-H of quinolinone), 6.84–7.47
(m, 7H, Ar–H), 9.64 (s, 1H, CHO), 11.48 (s, 1H, NH) ppm;
13C NMR (75 MHz, CDCl3): d = 163.56, 161.40, 158.68,
156.34, 154.28, 136.89, 133.48, 132.86, 128.18, 125.65,
119.40, 116.30, 116.21, 114.47, 114.30, 108.10, 65.98,
55.02 ppm; FAB-MS: m/z = 311 (M ? H).
4-[(6-Chloro-1,2-dihydro-2-oxoquinolin-4-yl)methoxy]-3-
methoxybenzaldehyde (3b, C18H14ClNO4)
2-Cyano-3-[4-[(1,2-dihydro-2-oxoquinolin-4-yl)methoxy]-
phenyl]-2-propenoic acid ethyl ester (4a, C22H18N2O4)
Yield: 86%; colorless crystals (acetic acid); m.p.:
264–266 °C; IR (KBr):vꢀ = 3,431 (N–H stretching), 2,221
Yield: 72%; colorless crystals (ethanol); m.p.: 216–218 °C;
IR(KBr):vꢀ = 3,440 (N–Hstretching), 1,688 (C=Ostretching,
123

New acrylic acid ethyl esters of quinolinone
1083
(C:N stretching), 1,722 (C=O stretching, ester), 1,659
1H, =CH ethylenic), 8.48 (s, 1H, NH) ppm; 13C NMR
(75 MHz, CDCl3): d = 166.10, 162.45, 158.60, 155.18,
154.28, 136.89, 133.48, 132.86, 130.34, 129.32, 128.68,
127.33, 125.65, 118.40, 116.35, 116.20, 114.40, 114.15,
108.10, 65.28, 60.82, 16.18 ppm; FAB-MS: m/z = 390
(M ? H).
(C=O stretching, amide) cm-1 1H NMR (300 MHz,
;
CDCl3): d = 1.40–1.45 (t, 3H, CH3-ester), 4.32–4.38 (q,
2H, CH2-ester), 5.51 (s, 2H, C4-CH2), 7.19–8.10 (m, 9H,
Ar–H), 7.70 (s, 1H, =CH ethylenic), 8.44 (s, 1H, NH) ppm;
13C NMR (75 MHz, CDCl3): d = 166.56, 162.40, 158.68,
156.34, 154.28, 136.89, 133.48, 132.86, 130.30, 129.32,
128.18, 126.33, 125.65, 119.40, 116.30, 116.21, 114.47,
114.30, 108.10, 65.98, 63.02, 15.30 ppm; FAB-MS:
m/z = 375 (M ? H).
General procedure for the preparation of compounds
5a–5d
A mixture of substituted 4-[(4-formyl-2-methoxyphen
oxy)methyl]quinolin-2(1H)-one 3a–3d (4.0 mmol), ethyl
cyanoactate (4.0 mmol), and a catalytic amount of piperi-
dine in 20 cm3 ethanol was stirred for 6 h at room
temperature and left overnight. The resulting yellow liquid
was poured onto crushed ice. The yellow solid obtained
was filtered off, washed with excess of cold water, dried,
and crystallized from a suitable solvent.
2-Cyano-3-[4-[(6-chloro-1,2-dihydro-2-oxoquinolin-4-yl)-
methoxy]phenyl]-2-propenoic acid ethyl ester
(4b, C22H17ClN2O4)
Yield: 81%; colorless crystals (acetic acid); m.p.: 290–292
°C; IR (KBr):vꢀ = 3,413 (N–H stretching), 2,221 (C:N
stretching), 1,727 (C=O stretching, ester), 1,659 (C=O
;
stretching, amide) cm-1 1H NMR (300 MHz, CDCl3):
d = 1.42–1.47 (t, 3H, CH3-ester), 4.43–4.50 (q, 2H, CH2-
ester), 5.58 (s, 2H, C4-CH2), 7.20–8.10 (m, 8H, Ar–H),
7.69 (s, 1H, =CH ethylenic), 8.40 (s, 1H, NH) ppm; 13C
NMR (75 MHz, CDCl3): d = 165.55, 161.42, 159.60,
155.38, 154.28, 136.89, 133.48, 132.86, 130.39, 129.32,
128.68, 127.33, 125.65, 118.40, 116.30, 116.22, 114.47,
114.30, 109.10, 66.18, 62.12, 15.28 ppm; FAB-MS: m/z =
409 (M ? H).
2-Cyano-3-[4-[(1,2-dihydro-2-oxoquinolin-4-yl)methoxy]-
3-methoxyphenyl]-2-propenoic acid ethyl ester
(5a, C23H20N2O5)
Yield: 80%; colorless crystals (ethanol ? dioxan); m.p.:
230–232 °C; IR (KBr):vꢀ = 3,431 (N–H stretching), 2,209
(C:N stretching), 1,715 (C=O stretching, ester), 1,661
(C=O stretching, amide) cm-1 1H NMR (300 MHz,
;
CDCl3 ? CF3COOH): d = 1.40–1.45 (t, 3H, CH3-ester),
4.38–4.48 (q, 2H, CH2-ester), 5.54 (s, 2H, C4-CH2),
7.02–8.26 (m, 8H, Ar–H), 7.76 (s, 1H, =CH ethylenic),
12.45 (s, 1H, NH) ppm; 13C NMR (75 MHz, CDCl3
? CF3COOH): d = 168.56, 164.40, 159.68, 157.34,
155.28, 138.89, 135.48, 133.86, 131.30, 129.32, 128.18,
126.40, 125.65, 120.40, 116.30, 116.21, 115.47, 114.30,
109.19, 66.18, 62.20, 55.08, 17.33 ppm; FAB-MS:
m/z = 405 (M ? H).
2-Cyano-3-[4-[(7-chloro-1,2-dihydro-2-oxoquinolin-4-yl)-
methoxy]phenyl]-2-propenoic acid ethyl ester
(4c, C22H17ClN2O4)
Yield: 82%; colorless crystals (acetic acid); m.p.:
299–300 °C; IR (KBr):vꢀ = 3,420 (N–H stretching), 2,226
(C:N stretching), 1,725 (C=O stretching, ester), 1,662
(C=O stretching, amide) cm-1 1H NMR (300 MHz,
;
DMSO-d6): d = 1.41–1.48 (t, 3H, CH3-ester), 4.45–4.52
(q, 2H, CH2-ester), 5.50 (s, 2H, C4-CH2), 6.68–8.08 (m,
8H, Ar–H), 8.20 (s, 1H, =CH ethylenic), 11.80 (s, 1H, NH)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 166.15, 162.52,
159.60, 154.38, 154.18, 136.89, 133.48, 132.86, 130.39,
129.32, 128.68, 127.33, 125.65, 119.40, 117.30, 116.20,
114.47, 114.00, 109.10, 65.98, 62.32, 16.08 ppm;
FAB-MS: m/z = 409 (M ? H).
2-Cyano-3-[4-[(6-chloro-1,2-dihydro-2-oxoquinolin-4-
yl)methoxy]-3-methoxyphenyl]-2-propenoic acid ethyl
ester (5b, C23H19ClN2O5)
Yield: 78%; colorless crystals (acetic acid); m.p.:
240–242 °C; IR (KBr):vꢀ = 3,422 (N–H stretching), 2,227
(C:N stretching), 1,715 (C=O stretching, ester), 1,672
(C=O stretching, amide) cm-1 1H NMR (300 MHz,
;
2-Cyano-3-[4-[(1,2-dihydro-8-methyl-2-oxoquinolin-4-yl)-
methoxy]phenyl]-2-propenoic acid ethyl ester
(4d, C23H20N2O4)
CDCl3 ? CF3COOH): d = 1.42–1.48 (t, 3H, CH3-ester),
4.36–4.45 (q, 2H, CH2-ester), 3.78 (s, 3H, OCH3), 5.50 (s,
2H, C4-CH2), 7.02–8.10 (m, 7H, Ar–H), 7.78 (s,
1H, = CH ethylenic), 12.48 (s, 1H, NH) ppm; 13C NMR
(75 MHz, CDCl3 ? CF3COOH): d = 167.70, 165.47,
158.65, 156.34, 154.28, 139.89, 134.48, 133.86, 130.30,
129.32, 128.18, 126.40, 125.55, 120.40, 117.30, 116.21,
115.47, 114.30, 108.11, 67.18, 61.20, 54.80, 18.13 ppm;
FAB-MS: m/z = 440 (M ? H).
Yield: 84%; colorless crystals (acetic acid); m.p.:
278–280 °C; IR (KBr):vꢀ = 3,434 (N–H stretching), 2,228
(C:N stretching), 1,728 (C=O stretching, ester), 1,659
(C=O stretching, amide) cm-1 1H NMR (300 MHz,
;
CDCl3): d = 1.42–1.48 (t, 3H, CH3-ester), 2.48 (s, 3H,
C8-CH3 of quinolinone), 4.40–4.48 (q, 2H, CH2-ester),
5.52 (s, 2H, C4-CH2), 7.10–8.02 (m, 8H, Ar–H), 7.72 (s,
123

1084
R. G. Kalkhambkar et al.
2-Cyano-3-[4-[(7-chloro-1,2-dihydro-2-oxoquinolin-4-yl)-
methoxy]-3-methoxyphenyl]-2-propenoic acid ethyl ester
(5c, C23H19ClN2O5)
CDCl3): d = 1.45–1.48 (t, 3H, CH3-ester), 2.45 (s, 3H,
CH3-acetyl), 4.41–4.50 (q, 2H, CH2-ester), 5.65 (s, 2H, C4-
CH2), 7.20–8.10 (m, 9H, Ar–H), 7.76 (s, 1H, =CH
ethylenic), 8.46 (s, 1H, NH) ppm; 13C NMR (75 MHz,
CDCl3): d = 167.56, 163.40, 159.68, 157.34, 155.18,
138.89, 135.48, 132.86, 131.30, 129.32, 128.18, 126.40,
125.66, 120.40, 116.30, 116.20, 115.47, 114.30, 108.20,
67.18, 63.20, 24.48, 15.33 ppm; FAB-MS: m/z = 392
(M ? H).
Yield: 80%; colorless crystals (acetic acid); m.p.:
280–282 °C; IR (KBr):vꢀ = 3,428 (N–H stretching), 2,229
(C:N stretching), 1,712 (C=O stretching, ester), 1,665
(C=O stretching, amide) cm-1 1H NMR (300 MHz,
;
DMSO-d6): d = 1.40–1.48 (t, 3H, CH3-ester), 4.38–4.45
(q, 2H, CH2-ester), 3.78 (s, 3H, OCH3), 5.52 (s, 2H, C4-
CH2), 6.88–8.02 (m, 7H, Ar–H), 8.20 (s, 1H, =CH
ethylenic), 11.78 (s, 1H, NH) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 168.78, 165.40, 157.69, 156.40, 154.30,
138.88, 134.48, 133.86, 130.30, 129.20, 128.20, 126.40,
125.55, 121.48, 118.33, 116.20, 115.47, 114.30, 107.70,
66.80, 62.40, 55.87, 17.33 ppm; FAB-MS: m/z = 440
(M ? H).
2-[4-[(6-Chloro-1,2-dihydro-2-oxoquinolin-4-yl)methoxy]-
phenylmethylene]-3-oxobutanoic acid ethyl ester
(6b, C23H20ClNO5)
Yield: 76%; colorless crystals (acetic acid); m.p.:
230–232 °C; IR (KBr):vꢀ = 3,413 (N–H stretching), 1,722
(C=O stretching, ester), 1,692 (C=O stretching, ester),
1,660 (C=O stretching, amide) cm-1; 1H NMR (300 MHz,
CDCl3): d = 1.45–1.50 (t, 3H, CH3-ester), 2.48 (s, 3H,
CH3-acetyl), 4.43–4.50 (q, 2H, CH2-ester), 5.38 (s, 2H, C4-
CH2), 7.18–8.15 (m, 8H, Ar–H), 7.80 (s, 1H, =CH
ethylenic), 8.40 (s, 1H, NH) ppm; 13C NMR (75 MHz,
CDCl3): d = 166.59, 162.70, 158.88, 156.44, 155.18,
138.89, 136.48, 133.88, 130.20, 129.32, 128.18, 126.40,
125.66, 120.40, 117.40, 116.20, 115.47, 114.30, 109.22,
66.88, 62.10, 23.58, 16.13 ppm; FAB-MS: m/z = 426
(M ? H).
2-Cyano-3-[4-[(1,2-dihydro-8-methyl-2-oxoquinolin-4-yl)-
methoxy]-3-methoxyphenyl]-2-propenoic acid ethyl ester
(5d, C24H22N2O5)
Yield: 80%; colorless crystals (acetic acid); m.p.:
258–260 °C; IR (KBr):vꢀ = 3,434 (N–H stretching), 2,210
(C:N stretching), 1,710 (C=O stretching, ester), 1,659
(C=O stretching, amide) cm-1;1H NMR (300 MHz,
DMSO-d6): d = 1.42–1.49 (t, 3H, CH3-ester), 2.48 (s,
3H, C8-CH3 of quinolinone), 4.40–4.46 (q, 2H, CH2-ester),
3.82 (s, 3H, OCH3), 5.58 (s, 2H, C4-CH2), 6.90–8.20 (m,
7H, Ar–H), 8.28 (s, 1H, =CH ethylenic), 11.80 (s, 1H, NH)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 167.79, 164.48,
158.61, 157.44, 155.36, 138.88, 135.48, 133.46, 130.20,
129.20, 128.45, 127.40, 124.55, 122.48, 118.33, 116.20,
115.47, 114.30, 108.60, 66.70, 63.40, 56.57, 20.30,
18.33 ppm; FAB-MS: m/z = 419 (M ? H).
2-[4-[(7-Chloro-1,2-dihydro-2-oxoquinolin-4-yl)methoxy]-
phenylmethylene]-3-oxobutanoic acid ethyl ester
(6c, C23H20ClNO5)
Yield: 72%; colorless crystals (acetic acid); m.p.:
220–222 °C; IR (KBr):vꢀ = 3,420 (N–H stretching), 1,725
(C=O stretching, ester), 1,678 (C=O stretching, ester),
1,662 (C=O stretching, amide) cm-1; 1H NMR (300 MHz,
DMSO-d6): d = 1.38–1.47 (t, 3H, CH3-ester), 2.50 (s, 3H,
CH3-acetyl), 4.40–4.48 (q, 2H, CH2-ester), 5.52 (s, 2H, C4-
CH2), 6.68–7.98 (m, 8H, Ar–H), 8.10 (s, 1H, =CH
ethylenic), 11.78 (s, 1H, NH) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 167.19, 163.40, 159.18, 156.44, 155.18,
137.89, 136.48, 135.88, 131.25, 129.32, 128.38, 126.40,
125.66, 122.40, 117.40, 116.20, 115.47, 114.30, 107.20,
67.58, 63.15, 24.58, 15.53 ppm; FAB-MS: m/z = 426
(M ? H).
General procedure for the preparation of compounds
6a–6d
A mixture of substituted 4-[(4-formylphenoxy)methyl]quin-
olin-2(1H)-one 2a–2d (4.0 mmol), ethyl acetoacetate
(4.0 mmol), and a catalytic amount of piperidine in 20 cm3
ethanol was stirred for 6 h at room temperature and left
overnight. The resulting yellow liquid was poured to crushed
ice. Theyellowcoloredsolidobtainedwasfilteredoff, washed
with excess of cold water, dried, and crystallized from a
suitable solvent.
2-[4-[(1,2-Dihydro-8-methyl-2-oxoquinolin-4-yl)methoxy]-
phenylmethylene]-3-oxobutanoic acid ethyl ester
(6d, C24H23NO5)
2-[4-[(1,2-Dihydro-2-oxoquinolin-4-yl)methoxy]phenyl-
methylene]-3-oxobutanoic acid ethyl ester
(6a, C23H21NO5)
Yield: 78%; colorless crystals (acetic acid); m.p.:
260–262 °C; IR (KBr):vꢀ = 3,434 (N–H stretching), 1,724
(C=O stretching, ester), 1,688 (C=O stretching, ester),
1,655 (C=O stretching, amide) cm-1; 1H NMR (300 MHz,
CDCl3): d = 1.45–1.49 (t, 3H, CH3-ester), 2.45 (s, 3H,
CH3-acetyl), 2.52 (s, 3H, C8-CH3 of quinolinone),
Yield: 80%; colorless crystals (acetic acid); m.p.:
288–290 °C; IR (KBr):vꢀ = 3,431 (N–H stretching), 1,720
(C=O stretching, ester), 1,680 (C=O stretching, ester),
1,658 (C=O stretching, amide) cm-1; 1H NMR (300 MHz,
123

New acrylic acid ethyl esters of quinolinone
1085
4.42–4.50 (q, 2H, CH2-ester), 5.54 (s, 2H, C4-CH2),
7.10–8.10 (m, 8H, Ar–H), 7.78 (s, 1H, =CH ethylenic),
8.48 (s, 1H, NH) ppm; 13C NMR (75 MHz, CDCl3):
d = 166.19, 163.50, 157.48, 155.14, 154.10, 138.89,
136.48, 133.88, 131.20, 129.32, 128.18, 126.40, 125.66,
121.40, 118.40, 116.20, 115.17, 114.30, 108.20, 67.18,
63.60, 25.18, 20.12, 15.17 ppm; FAB-MS: m/z = 406
(M ? H).
2-[[4-[(7-Chloro-1,2-dihydro-2-oxoquinolin-4-yl)methoxy]-
3-methoxyphenyl]methylene]-3-oxobutanoic acid ethyl ester
(7c, C24H22ClNO6)
Yield: 80%; colorless crystals (acetic acid); m.p.:
277–279 °C; IR (KBr):vꢀ = 3,433 (N–H stretching), 1,724
(C=O stretching, ester), 1,690 (C=O stretching, ester),
1,663 (C=O stretching, amide) cm-1; 1H NMR (300 MHz,
DMSO-d6): d = 1.38–1.42 (t, 3H, CH3-ester), 2.45 (s, 3H,
CH3-acetyl), 4.40–4.48 (q, 2H, CH2-ester), 3.88 (s, 3H,
OCH3), 5.68 (s, 2H, C4-CH2), 6.78–8.03 (m, 7H, Ar–H),
8.10 (s, 1H, =CH ethylenic), 11.81 (s, 1H, NH) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 167.90, 163.84, 158.81,
157.74, 156.78, 139.19, 135.48, 133.86, 130.30, 129.22,
128.18, 127.10, 125.66, 120.40, 117.50, 116.80, 115.47,
114.30, 109.20, 67.10, 62.30, 54.18, 24.18, 17.40 ppm;
FAB-MS: m/z = 456 (M ? H).
General procedure for the preparation of compounds
7a–7d
A mixture of substituted 4-[(4-formyl-2-methoxyphenoxy)-
methyl]quinolin-2(1H)-one 3a–3d (4.0 mmol), ethyl aceto-
acetate (4.0 mmol), and a catalytic amount of piperidine in
20 cm3 ethanol was stirred for 6 h at room temperature and
left overnight. The resulting yellow liquid was poured onto
crushed ice. The yellow solid obtained was filtered off,
washed with excess of cold water, dried, and crystallized from
a suitable solvent.
2-[[4-[(1,2-Dihydro-8-methyl-2-oxoquinolin-4-yl)methoxy]-
3-methoxyphenyl]methylene]-3-oxobutanoic acid ethyl ester
(7d, C25H25NO6)
Yield: 82%; colorless crystals (acetic acid); m.p.:
250–252 °C; IR (KBr): vꢀ = 3,442 (N–H stretching), 1,722
(C=O stretching, ester), 1,682 (C=O stretching, ester),
1,662 (C=O stretching, amide) cm-1; 1H NMR (300 MHz,
DMSO-d6): d = 1.41–1.50 (t, 3H, CH3-ester), 2.40 (s, 3H,
CH3-acetyl), 2.51 (s, 3H, C8-CH3 of quinolinone),
4.40–4.48 (q, 2H, CH2-ester), 3.84 (s, 3H, OCH3), 5.52
(s, 2H, C4-CH2), 6.75–8.10 (m, 7H, Ar–H), 8.15 (s, 1H,
=CH ethylenic), 11.72 (s, 1H, NH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 168.10, 162.14, 158.81,
157.74, 156.78, 139.19, 135.44, 133.66, 130.30, 129.22,
128.18, 127.10, 125.66, 120.40, 118.50, 116.80, 115.47,
114.30, 108.27, 68.11, 63.44, 54.18, 24.10, 20.43,
18.30 ppm; FAB-MS: m/z = 436 (M ? H).
2-[[4-[(1,2-Dihydro-2-oxoquinolin-4-yl)methoxy]-3-
methoxyphenyl]methylene]-3-oxobutanoic acid
ethyl ester (7a, C24H23NO6)
Yield: 83%; colorless crystals (ethanol ? dioxan); m.p.:
192–194 °C; IR (KBr):vꢀ = 3,430 (N–H stretching), 1,724
(C=O stretching, ester), 1,660 (C=O stretching, amide)
1
cm-1; H NMR (300 MHz, DMSO-d6): d = 1.40–1.48 (t,
3H, CH3-ester), 2.42 (s, 3H, CH3-acetyl), 4.40–4.47 (q, 2H,
CH2-ester), 3.78 (s, 3H, OCH3), 5.50 (s, 2H, C4-CH2),
6.69–7.90 (m, 8H, Ar–H), 8.15 (s, 1H, =CH ethylenic), 11.78
(s, 1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6): d =
168.56, 164.40, 158.68, 157.34, 155.18, 138.89, 135.48,
133.86, 131.30, 129.32, 128.18, 126.40, 125.66, 120.40,
116.30, 116.20, 115.47, 114.30, 109.20, 67.18, 62.20, 54.28,
24.48, 18.33 ppm; FAB-MS: m/z = 422 (M ? H).
Antimicrobial assay
2-[[4-[(6-Chloro-1,2-dihydro-2-oxoquinolin-4-yl)methoxy]-
3-methoxyphenyl]methylene]-3-oxobutanoic acid ethyl ester
(7b, C24H22ClNO6)
The in vitro antimicrobial activity of the test compounds
was examined against the two bacterial microorganisms
E. coli (gram negative) and B. cirrhosis (gram positive) and
the two fungal microorganisms A. niger and R. bataticola.
DMF was used as a solvent control, and the reference drugs
used were norfloxacin and griseofulvin. The tests were
carried out by the cup-plate method [16–18], at a concen-
tration of 100, 50, and 25 lg cm-3. The zone of inhibition
was measured in millimeters after 48 h of incubation at
37 °C. The percentage inhibition of test compounds was
calculated by relating the zone of inhibition of the test
compound (ZOItest compound) to those of the standard
(ZOIstandard, taken as 100%) and control (ZOIcontrol) as
Yield: 78%; colorless crystals (acetic acid); m.p.:
240–242 °C; IR (KBr):vꢀ = 3,434 (N–H stretching), 1,720
(C=O stretching, ester), 1,680 (C=O stretching, ester),
1,658 (C=O stretching, amide) cm-1; 1H NMR (300 MHz,
DMSO-d6): d = 1.42–1.50 (t, 3H, CH3-ester), 2.48 (s, 3H,
CH3-acetyl), 4.40–4.48 (q, 2H, CH2-ester), 3.80 (s, 3H,
OCH3), 5.48 (s, 2H, C4-CH2), 6.80–8.00 (m, 7H, Ar–H),
8.08 (s, 1H, =CH ethylenic), 11.65 (s, 1H, NH) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 168.60, 164.44, 158.61,
157.34, 156.28, 138.89, 135.48, 133.86, 131.30, 129.22,
128.18, 127.10, 125.66, 120.40, 116.50, 116.20, 115.47,
114.30, 108.20, 68.10, 63.30, 55.18, 25.18, 18.30 ppm;
FAB-MS: m/z = 456 (M ? H).
follows: % inhibition = (ZOItest
(ZOIstandard - ZOIcontrol) 9 100%.
- ZOIcontrol)/
compound
123

1086
R. G. Kalkhambkar et al.
Acknowledgments The authors thank the University Sophisticated
Instrument Center, KUD for IR, 1H NMR, and 13C NMR. Thanks are
also due to SAIF-CDRI Lucknow for ESI–MS Data. One of the
authors (RGK) is grateful to Karnatak University and Karanatak
Science College Dharwad for the University Research Studentship.
GA and YTJ acknowledge the financial support provided by the
second stage of the BK21 program. The authors wish to thank the
reviewers for useful suggestions.
Acute toxicity
Groups of six albino mice weighing 20–25 g were fasted
overnight and treated per orally and i.p. with the test
compounds [19]. The dose was varied from 1,000 to
100 mg kg-1 body weights. The animals were observed for
24 h for any signs of acute toxicity such as increased or
decreased motor activity, tremors, convulsion, sedation,
lacrimation, etc. No mortality of the animals was observed
even after 24 h. Hence the LD50 cutoff value of the test
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123