2-Arylidene-4-(4-phenoxy-phenyl)but-3-en-4-olides: Synthesis, reactions and biological activity

Article abstract of DOI:10.1016/j.ejmech.2005.03.012

2-Arylidene-4-(4-phenoxy-phenyl)but-3-en-4-olides (1-17) were prepared from 3-(4-phenoxy-benzoyl)propionic acid and aromatic aldehydes. Some of the selected butenolides were reacted with ammonia and benzylamine to give corresponding 3-arylidene-5-(4-pheno

Full text of DOI:10.1016/j.ejmech.2005.03.012

European Journal of Medicinal Chemistry 40 (2005) 1394–1404
www.elsevier.com/locate/ejmech
Original article
2-Arylidene-4-(4-phenoxy-phenyl)but-3-en-4-olides:
Synthesis, reactions and biological activity
Asif Husain *, M.S.Y. Khan 1,
S.M. Hasan 2, M.M. Alam 3
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi 110 062, India
Received 29 September 2004; received in revised form 22 March 2005; accepted 23 March 2005
Available online 04 May 2005
Abstract
2-Arylidene-4-(4-phenoxy-phenyl)but-3-en-4-olides (1–17) were prepared from 3-(4-phenoxy-benzoyl)propionic acid and aromatic alde-
hydes. Some of the selected butenolides were reacted with ammonia and benzylamine to give corresponding 3-arylidene-5-(4-phenoxy-
phenyl)-2(3H)-pyrrolones (18–23) and 3-arylidene-5-(4-phenoxy-phenyl)-1-benzyl-2(3H)-pyrrolones (24–29) respectively, which were char-
1
acterized on the basis of H-, 13C-NMR, Mass spectrometric data and elemental analysis results. These compounds were tested for anti-
inflammatory and antimicrobial actions. The compounds, which showed significant anti-inflammatory activity, were screened for their analgesic
and ulcerogenic activities. Five new compounds (5, 6, 7, 25 and 26), out of 29 showed very good anti-inflammatory activity in the carrageenan
induced rat paw edema test, with significant analgesic activity in the acetic acid induced writhing test together with negligible ulcerogenic
action. Antibacterial activity against Staphylococcus aureus and Escherichia coli as well as antifungal activity against Candida albicans were
expressed as the corresponding minimum inhibitory concentration (MIC) values. Compound 21, 22 and 23 showed excellent activity against
C. albicans with MIC-10 µg/ml. Out of the above-mentioned compounds, 22 and 23 also showed good activity against S. aureus with
MIC-20 and 15 µg/ml respectively.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Butenolide; Aroylpropionic acid; Pyrrolone; Anti-inflammatory; Analgesic; Ulcerogenic; Antimicrobial activity
1. Introduction
of c-lactone ring present in the butenolide derivatives has been
further exploited for the synthesis of nitrogen heterocycles of
potential biological activity [10,11].
The butenolide system as present in many cardiac glyco-
sides shows strong oral cardiotonic activity [1]. Physiologi-
cal activity of the natural lactones is known ever since santo-
nin was used as an important anthelmintic and ascaricidal
agent [2,3]. Besides the whole group of butenolide antibiot-
ics [4], this moiety has been found to have some interesting
activities [5–9] such as anticonvulsant, anti-inflammatory,
analgesic, antitumor, antiviral, anticancer etc. The reactivity
3-(4-Phenoxy-benzoyl) propionic acid is an example of
well known aroyl propionic acid class of anti-inflammatory
drugs [12] and some of them are available in the market (fen-
bufen, bucloxic acid, furobufen etc.), they have been reported
to have comparatively more gastrointestinal side effects as
compared to other NSAIDs [13–15]. We had examined in
these laboratories the anti-inflammatory activity of a number
of 2-arylidene-4-substituted phenyl butenolides and the results
were encouraging [16,17]. 3-(4-Phenoxy-benzoyl) propionic
acid is a good anti-inflammatory agent associated with gas-
trointestinal side effects [13]. It was therefore considered
worthwhile to study various butenolide derivatives of 3-(4-
phenoxy-benzoyl) propionic acid for their anti-inflammatory
action. These butenolides were further exploited for the syn-
thesis of nitrogen heterocycles (pyrrolones). In view of the
* Corresponding author. Tel.: +91 11 2605 9681/688x5647; fax: +91 11
1698 8874; mobile: +91 989 1116086.
E-mail addresses: drasifhusain@yahoo.com (A. Husain),
msykhan@hotmail.com (M.S.Y. Khan), root@hamduni.ren.nic.in
(S.M. Hasan), hamlucky@indiatimes.com (M.M. Alam).
1 Tel.: +91 11 2605 9681/688x5890; fax: +91 11 1698 8874.
2 Tel.: +91 11 2605 9681/688x5614; fax: +91 11 1698 8874.
3 Tel.: +91 11 2605 9681/688x5660; fax: +91 11 1698 8874.
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.03.012

A. Husain et al. / European Journal of Medicinal Chemistry 40 (2005) 1394–1404
1395
reported antimicrobial activity of butenolides and pyrrolo-
nes, these compounds were also tested for their antibacterial
and antifungal activity against some selected microbes.
could be assigned to the ring bH and the olefinic hydrogen of
the arylidene substituent. However, deviations are observed
when theAr moiety is 2,6-dichlorophenyl and 9-anthracenyl.
In these cases the ring hydrogen gets shifted upfield while
the olefinic hydrogen is downfield possibly due to non-
planarity of the Ar ring. In the 13C-NMR spectral data all the
compounds showed a peak around d 98.5 that could be
assigned to the olefinic carbon (C-5). Other peaks were
observed at appropriate places.
2. Chemistry
Overall 29 new compounds 1–29 were prepared as out-
lined in Scheme 1. 2-Arylidene-4-(4-phenoxy-phenyl)but-3-
en-4-olides (1–17) were synthesized from 3-(4-phenoxy-
benzoyl) propionic acid by reacting with aromatic aldehydes
in presence of triethylamine in acetic anhydride. The required
3-(4-phenoxy-benzoyl) propionic acid was prepared by con-
densing diphenyl ether with succinic anhydride in presence
of anhydrous aluminum chloride following Friedel-Craft’s
acylation reaction conditions. The 3-arylidene-5-(4-phenoxy-
phenyl)-2(3H)-pyrrolones (18–23) were prepared by
reacting butenolides with ammonia in absolute ethanol.
The 3-arylidene-5-(4-phenoxy-phenyl)-1-benzyl-2(3H)-
pyrrolones (24–29) were synthesized by reacting appropriate
butenolides with benzylamine in dry benzene to give
c-ketobenzylamides, which were then lactamized in 6 N HCl
to give the corresponding N-benzylpyrrolones. Calculations
of d values using incremental parameters for the hydrogen
(semicyclic double bond) seems to suggest (E)-configuration.
The structures assigned to the compounds 1–29 were sup-
ported by the results of elemental analysis as well as 1H- and
13C-NMR and Mass spectral data (Scheme 1).
The fragmentation pattern observed on electron impact
mass spectrum can be summarized as follows:
The 2-arylidene-4-(4-phenoxy-phenyl)but-3-en-4-olides
gave M+ peak in reasonable intensities. The major fragment
appears to be C6H5–O–C6H4–C≡O+ arising from the hetero-
cyclic oxygen and c-carbon with its substituent. Subse-
+
quently it loses CO to give C6H5–O–C6H4 . There appeared
a peak at m/z 77 that corresponds to C6H5+ Occasionally the
aryl ring of the arylidene moiety also appeared as Ar+. In the
case of pyrrolones, the major fragmentation is through C6H5–
O–C6H4–C≡N+H, which is followed by loss of HCN to give
+
C6H5–O–C6H4 .
In case of N-benzylpyrrolones, loss of 91 mass units cor-
responding to benzyl moiety from the molecular ion is
observed along with peaks at m/z 91, 77. Other pathway is
via C6H5–O–C6H4–C≡N+H arising from C-2 and its substitu-
ent, which appears to be novel. This also loses HCN to give
+
C6H5–O–C6H4 .
In case of aryl groups having chloro-substituent(s), the
molecular ion peak or their fragments having halogen(s)
appeared as cluster of peaks.
1
In the H-NMR spectral data all the compounds showed
two singlets of one proton each around d 6.5 and d 7.4 which
Scheme 1
.

1396
A. Husain et al. / European Journal of Medicinal Chemistry 40 (2005) 1394–1404
3. Pharmacological results and discussion
showed high severity index of 1.97. The results indicate that
compounds are almost devoid of ulcerogenic action. Results
are presented in Table 2.
3.1. Anti-inflammatory activity
3.4. Antimicrobial activity
All the compounds were evaluated for in-vivo anti-
inflammatory activity. Pedal inflammation in albino rats was
induced by carrageenan in rat hind paw and the edema vol-
ume was measured by mercury displacement in a plethysmo-
graph. Carrageenan induced rat paw oedema method [18] was
employed for evaluating the anti-inflammatory activity of the
compounds at a dose level of 20 mg/kg b.w. in albino rats
(weighing 100–120 g) using indomethacin as a standard drug
for comparison. The percentage inhibition of inflammation
was calculated by applying Newbould formula [19].
The activity showed that compound 26 exhibited maxi-
mum anti-inflammatory activity (58.06%) and its activity was
comparable with the standard drug indomethacin (64.51%)
at a dose of 20 mg/kg P.O. Compound 5, 6, 13 and 25 showed
good activity (45.16–51.61%). Results are presented in
Table 1.
Structure activity relationship showed that substitution of
oxygen atom of butenolide ring with NH (pyrrolones) resulted
in marked decrease in activity, while substitution of oxygen
atom with benzylamine moiety (N-benzylpyrrolones) mark-
edly increased the activity. Compounds having trimethoxyl
function at 3,4,5-position of arylidene moiety were found to
have better anti-inflammatory activity as compared to those
having one, two or no methoxyl functions. Substitution of
one or more –OCOCH3 group in arylidene moiety was also
found to increase the activity.
The antimicrobial studies were carried out on the synthe-
sized compounds against the microorganism viz. Staphylo-
coccus aureus, Escherichia coli and Candida albicans in meat
peptone agar medium at a concentration of 100 µg/ml by cup
plate method. Compounds inhibiting growth of one or more
of the above microorganisms were further tested for mini-
mum inhibitory concentration (MIC). The test was carried
out according to the turbidity method [22].
Compound 21, 22 and 23 showed excellent activity against
C. albicans with MIC-10 µg/ml. Out of the above-mentioned
compounds, 22 and 23 also showed good activity against S.
aureus with MIC-20 and 15 µg/ml respectively. An analysis
of results showed that these compounds were having better
activity against C. albicans in comparison to S. aureus and
E. coli. Introduction of nitrogen in place of oxygen atom (pyr-
rolones) in the butenolide ring enhanced antimicrobial action.
A solution of the compounds was prepared in dimethyl-
formamide (DMF) and a series of doubling dilutions pre-
pared with sterile pipettes. To each of a series of sterile stop-
pered test tubes a standard volume of nutrient broth medium
was added. A control tube containing no antimicrobial agent
was included. The inoculum consisting of an overnight broth
culture of microorganisms was added to separate tubes. The
tubes were incubated at 37° for 24 h and examined for tur-
bidity. The tubes with highest dilution showing no turbidity
was the MIC. Results are presented in Table 1.
3.2. Analgesic activity
4. Experimental protocols
The analgesic activity of the synthesized compounds 4, 5,
6, 7, 12, 13, 24, 25, 26 and 27 was evaluated by acetic acid
induced writhing test [20]. The activity showed that com-
pound 6 exhibited maximum analgesic activity (58.79%) and
its activity was comparable with the standard drug ibuprofen
(62.33%) at a dose of 20 mg/kg P.O. Compound 5, 7 and 26
showed good activity (51.33–53.17%). Results are presented
in Table 2. Analysis of results showed that substitution of
oxygen atom of butenolide ring with benzylamine moiety
(N-benzylpyrrolones) resulted in decrease in activity. Substi-
tution of one or more –OCOCH3 group in arylidene moiety
was also found to increase the activity. Compounds having
trimethoxyl function at 3,4,5-position of arylidene moiety
were found to have better analgesic activity as compared to
those having one, two or no methoxyl functions.
4.1. Chemistry
Melting points (m.p.) were taken in open capillary tubes
and are uncorrected. Microanalysis of the compounds was
done on Perkin–Elmer model 240 analyzer and the values
were found within 0.4% of the theoretical values. 1H- and
13C-NMR spectra were recorded on Varian E-360 MHz or
Bruker spectropsin DPX-300 MHz; chemical shifts (d) are
reported in parts per million (ppm) downfield from tetram-
ethylsilane (TMS), which was used as an internal standard.
The splitting pattern abbreviations are as follows: s, singlet;
d, doublet; dd, double doublet; t, triplet; q, quartet; m, mul-
tiplet. Mass spectra were recorded on a Jeol JMS-D 300 instru-
ment fitted with a JMS 2000 data system at 70 eV. Spectral
data are consistent with assigned structures. The progress of
the reactions was monitored on TLC, which was performed
on silica gel (Merck No. 5554). Dry solvents were used
throughout.
3.3. Acute ulcerogenesis
The compounds, which showed significant anti-
inflammatory activity, were screened for their ulcerogenic
activity. The test was performed according to Cioli et al. [21].
The tested compounds showed ulcerogenic activity ranging
from 0.16 to 0.76, whereas the standard drug ibuprofen
4.1.1. Preparation of 3-(4-phenoxy-benzoyl) propionic acid
Succinic anhydride (10 g, 10 mmol) was reacted with
diphenyl ether (17 g, 10 mmol) in presence of anhydrous alu-

A. Husain et al. / European Journal of Medicinal Chemistry 40 (2005) 1394–1404
1397
Table 1
Antimicrobial and anti-inflammatory activity of the compounds 1–2 9
Compound
Ar
Antimicrobial activity
(MIC *)
Anti-inflammatory activity
(% inhibition in rat paw edema)
S. aureus E. coli
C. albicans
Normal paw
volume
(x)
Paw oedema 5 h
after carrageenan
(a)
% Inhibition
(1 – a – x/b – y) ×
100 of edema
1
2
–
–
–
–
>100
0.68 0.03
0.92 0.03
22.58
–
0.67 0.03
0.92 0.02
19.35
3
4
5
–
–
–
–
>100
–
0.69 0.02
0.68 0.03
0.70 0.02
0.92 0.02
0.89 0.04
0.87 0.03
25.80
32.25
45.16
–
>100
>100
6
7
–
–
–
–
–
–
0.72 0.03
0.70 0.02
0.88 0.03
0.90 0.05
48.38
35.48
8
9
>100
50
–
–
>100
50
0.67 0.04
0.69 0.03
0.90 0.04
0.91 0.03
25.80
29.03
10
>100
–
>100
0.68 0.03
0.92 0.05
22.58
11
12
50
–
>100
–
25
0.72 0.02
0.69 0.03
0.95 0.03
0.90 0.04
25.80
32.25
>100
13
–
–
–
0.71 0.02
0.88 0.03
45.16
(continued on next page)

1398
A. Husain et al. / European Journal of Medicinal Chemistry 40 (2005) 1394–1404
Table 1
(continued)
Compound
Ar
Antimicrobial activity
(MIC *)
Anti-inflammatory activity
(% inhibition in rat paw edema)
S. aureus E. coli
C. albicans
Normal paw
volume
(x)
Paw oedema 5 h
after carrageenan
(a)
% Inhibition
(1 – a – x/b – y) ×
100 of edema
14
15
50
–
>100
–
50
0.68 0.03
0.95 0.04
12.90
>100
0.68 0.03
0.90 0.03
29.03
16
>100
–
–
0.72 0.03
0.97 0.04
19.35
17
18
19
–
–
–
0.68 0.04
0.73 0.02
0.69 0.03
0.91 0.04
0.98 0.03
0.91 0.03
25.80
19.35
29.03
>100
–
>100
–
50
>100
20
50
>100
>100
0.67 0.02
0.90 0.04
25.80
21
22
25
20
50
50
10
10
0.68 0.04
0.66 0.05
0.96 0.02
0.93 0.04
09.67
12.90
23
15
25
10
0.69 0.03
0.97 0.05
09.67
24
25
>100
–
–
–
>100
–
0.70 0.02
0.71 0.03
0.90 0.05
0.86 0.03
35.48
51.61
26
–
–
–
0.74 0.02
0.87 0.03
58.06
(continued on next page)

A. Husain et al. / European Journal of Medicinal Chemistry 40 (2005) 1394–1404
1399
Table 1
(continued)
Compound
Ar
Antimicrobial activity
(MIC *)
Anti-inflammatory activity
(% inhibition in rat paw edema)
S. aureus E. coli
C. albicans
Normal paw
volume
(x)
Paw oedema 5 h
after carrageenan
(a)
% Inhibition
(1 – a – x/b – y) ×
100 of edema
27
–
–
>100
0.69 0.03
0.90 0.04
32.25
25.80
28
29
>100
50
>100
>100
>100
25
0.68 0.04
0.67 0.03
0.91 0.04
0.91 0.05
22.58
64.51
Indomethacin
Control
0.70 0.03
0.81 0.03
0.68 0.02 (y)
0.99 0.03 (b)
* = in µg/ml; – = insignificant activity.
minum chloride (15 g, 11.25 mmol) in dry nitrobenzene
(50 ml). The reaction mixture was refluxed for 2 h and excess
nitrobenzene was removed by steam distillation. It was puri-
fied by dissolving in sodium hydroxide solution, filtering, fol-
lowed by addition of hydrochloric acid. The solid mass so
obtained was filtered, washed with cold water, dried and crys-
tallized from acetone to give 9.6 g (65%) of the desired com-
pound as a colorless solid, m.p. 172 °C which gave efferves-
cence with sodium bicarbonate solution, 1H-NMR (CDCl3) d
2.80 and 3.27 (t each, 2 × CH2), 7.17 (m, 2H, H-2,6, phenyl),
7.22 (m, 1H, H-4, phenyl), 7.41 (m, 2H, H-3,5, phenyl),
6.98 and 7.97 (d each, 2 × A2B2 p-substituted phenyl).
ice in small portions while stirring. A solid mass separated
out, which was filtered, washed with water and crystallized
from a mixture of methanol/chloroform (1:1) to give 1–17.
4.1.2.1. 2-Benzylidene-4-(4-phenoxy-phenyl)but-3-en-4-
1
olides (1). Yield: 58%, m.p. 122 °C. H-NMR (CDCl3) d
6.85 (s, 1H, butenolide ring), 7.03 and 7.72 (d, each, 2 ×A2B2,
p-disubstituted phenyl), 7.05 (m, 4H, H-2,6, 2 × phenyl), 7.18
(m, 2H, H-4, 2 × phenyl), 7.37 (s, 1H, olefinic H), 7.42 (m,
4H, H-3,5, 2 × phenyl). 13C-NMR (CDCl3) d 170.5 (C-1),
125.6 (C-2), 118.8 (C-3), 128.2 (C-4), 96.7 (C-5), 129.1 (C-6),
118.2 (C-7,11), 130.1 (C-8,10), 154.9 (C-9), 153.4 (C-12),
131.8 (C-13,17), 119.6 (C-14,16), 124.3 (C-15), 129.4 (C-1′),
126.9 (C-2′,6′), 129.8 (C-3′,5′), 131.2 (C-4′). MS: m/z 340
(M+), 197, 169, 77. Anal. C23H16O3 (C, H).
4.1.2. General procedure for the synthesis of 2-arylidene-
4-(4-phenoxy-phenyl)but-3-en-4-olides (1–17)
A solution of 3-(4-phenoxy-benzoyl) propionic acid
(0.71 g, 3 mmol) and aromatic aldehyde (equimolar, 3 mmol)
in acetic anhydride (15 ml) with triethylamine (3–4 drops)
was refluxed for 4 h under anhydrous conditions. After
completion of reaction, the contents were poured into crushed
4.1.2.2. 2-(2-Methoxybenzylidene)-4-(4-phenoxy-phenyl)but-
3-en-4-olides (2). Yield: 54%, m.p. 118 °C. 1H-NMR (CDCl3)
d 3.90 (s, 3H, OCH3), 6.80 (s, 1H, butenolide ring), 6.94 (m,
1H, H-3, arylidene ring), 7.02 and 7.71 (d, each, 2 × A2B2,
p-disubstituted phenyl), 7.05 (m, 2H, H-2,6, phenyl), 7.18
(m, 1H, H-4, phenyl), 7.39 (m, 2H, H-4,5, arylidene ring),
7.42 (m, 2H, H-3,5, phenyl), 7.67 (dd, 1H, H-6, arylidene
ring), 7.83 (s, 1H, olefinic H). 13C-NMR (CDCl3) d 171.0
(C-1), 125.3 (C-2), 118.9 (C-3), 128.1 (C-4), 96.9 (C-5), 128.8
(C-6), 118.5 (C-7, 11), 130.6 (C-8,10), 155.5 (C-9), 153.8
(C-12), 132.2 (C-13,17), 119.4 (C-14,16), 124.1 (C-15,6′),
129.6 (C-1′), 155.1 (C-2′), 127.2 (C-3′), 130.2 (C-4′), 128.3
(C-5′), 56.4 (–OCH3). MS: m/z 370 (M+), 197, 169, 77. Anal.
C24H18O4 (C, H).
Table 2
Analgesic and ulcerogenic activity of the compounds 4–7, 12, 13, 24–27
Compound Analgesic activity (%
protection)
Ulcerogenic activity
(severity index)
0.16
4
5
6
7
12
13
24
25
26
27
Control
Ibuprofen
40.12
51.33
58.79
53.17
37.63
34.37
40.12
45.80
51.33
37.63
–
0.45
0.76
0.75
0.45
0.20
0.20
0.16
4.1.2.3. 2-(3-Methoxybenzylidene)-4-(4-phenoxy-phenyl)but-
0.45
1
0.20
3-en-4-olides (3). Yield: 52%, m.p. 104–106 °C. H-NMR
0.00
(CDCl3) d 3.87 (s, 3H, OCH3), 6.97 (m, 1H, H-4, arylidene
ring), 6.83 (s, 1H, butenolide ring), 7.03 and 7.73 (d, each, 2
62.33
1.97

1400
A. Husain et al. / European Journal of Medicinal Chemistry 40 (2005) 1394–1404
× A2B2, p-disubstituted phenyl), 7.16 (m, 6H, 2 × phenyl),
7.37 (s, 1H, olefinic H), 7.39 (m, 2H, H-3,5, phenyl). 13C-
NMR (CDCl3) d 170.9 (C-1), 126.1 (C-2), 119.1 (C-3), 128.5
(C-4), 97.3 (C-5), 129.2 (C-6), 118.1 (C-7,11), 130.2 (C-8,10),
155.9 (C-9), 153.1 (C-12), 133.1 (C-13,17), 119.6 (C-14,16),
124.3 (C-15,6′), 129.6 (C-1′), 127.1 (C-2′), 153.2 (C-3′), 127.6
(C-4′), 128.9 (C-5′), 55.5 (–OCH3). MS: m/z 370 (M+), 197,
169, 77. Anal. C24H18O4 (C, H).
ring), 7.18 (m, 1H, H-4, phenyl), 7.38 (s, 1H, olefinic H),
7.40 (m, 3H, H-2,5,6, arylidene ring), 7.66 (m, 2H, H-3,5,
phenyl). 13C-NMR (CDCl3) d 169.1 (C-1), 125.8 (C-2), 118.1
(C-3), 128.7 (C-4,5′), 97.3 (C-5), 129.1 (C-6,1′), 118.6
(C-7,11), 130.3 (C-8,10), 156.6 (C-9), 153.4 (C-12), 132.5
(C-13,17), 119.3 (C-14,16), 124.2 (C-15), 127.6 (C-2′), 158.3
(C-3′), 129.9 (C-4′), 124.5 (C-6′), 20.2 (–OAc). MS: m/z 398
(M+), 197, 77. Anal. C25H18O5 (C, H).
4.1.2.4. 2-(3,4-Dimethoxybenzylidene)-4-(4-phenoxy-
phenyl)but-3-en-4-olides (4). Yield: 61%, m.p. 112–114 °C.
1H-NMR (CDCl3) d 3.96 (s, 6H, 2 × OCH3), 6.82 (s, 1H,
butenolide ring), 6.95 (d, 1H, H-5, arylidene ring), 7.04 and
7.73 (d, each, 2 ×A2B2, p-disubstituted phenyl), 7.06 (m, 2H,
H-2,6, phenyl), 7.11 (d, 1H, H-2, arylidene ring), 7.18 (m,
1H, H-4, phenyl), 7.30 (dd, 1H, H-6, arylidene ring), 7.35 (s,
1H, olefinic H), 7.42 (m, 2H, H-3,5, phenyl). 13C-NMR
(CDCl3) d 172.1 (C-1), 126.1 (C-2), 119.3 (C-3), 128.8 (C-4),
98.1 (C-5), 129.1 (C-6,1′), 118.3 (C-7,11), 130.6 (C-8,10),
156.4 (C-9), 153.4 (C-12), 132.8 (C-13,17), 119.7 (C-14,16),
124.5 (C-15), 126.9 (C-2′), 135.2 (C-3′), 130.1 (C-4′), 129.6
(C-5′), 127.2 (C-6′) 54.6 (–OCH3). MS: m/z 400 (M+), 197,
169, 77. Anal. C25H20O5 (C, H).
4.1.2.8. 2-(4-Chlorobenzylidene)-4-(4-phenoxy-phenyl)but-
3-en-4-olides (8). Yield: 67%, m.p. 156–158 °C. H-NMR
1
(CDCl3) d 6.80 (s, 1H, butenolide ring), 7.04 and 7.76 (d,
each, 2 × A2B2, p-disubstituted phenyl), 7.06 (m, 2H, H-2,6,
phenyl), 7.19 (m, 1H, H-4, phenyl), 7.34 (s, 1H, olefinic H),
7.40 (m, 2H, H-3,5, phenyl), 7.42 and 7.56 (d, each, 2 ×A2B2,
arylidene ring). 13C-NMR (CDCl3) d 170.3 (C-1), 125.8 (C-2),
118.8 (C-3), 128.3 (C-4), 98.4 (C-5), 129.2 (C-6,1′), 118.2
(C-7,11), 130.1 (C-8,10), 156.4 (C-9), 153.3 (C-12), 132.7
(C-13,17), 119.5 (C-14,16), 124.5 (C-15), 126.8 (C-2′,6′),
129.6 (C-3′,5′), 135.6 (C-4′). MS: m/z 374 (M+), 197, 77.
Anal. C23H15O3Cl (C, H, Cl).
4.1.2.9. 2-(2,4-Dichlorobenzylidene)-4-(4-phenoxy-phenyl)-
but-3-en-4-olides (9). Yield: 56%, m.p. 198–200 °C. 1H-NMR
(CDCl3) d 6.81 (s, 1H, butenolide ring), 7.08 and 7.64 (d,
each, 2 × A2B2, p-disubstituted phenyl), 7.4 (m, 5H, phenyl),
7.68 (m, 4H, H-3,5,6, arylidene ring + olefinic H). 13C-NMR
(CDCl3) d 170.7 (C-1), 125.7 (C-2), 119.2 (C-3), 128.6 (C-4),
98.9 (C-5), 129.4 (C-6,5′), 118.1 (C-7,11), 130.1 (C-8,10),
155.9 (C-9), 153.5 (C-12), 132.3 (C-13,17), 119.5 (C-14,16),
124.3 (C-15), 129.9 (C-1′), 134.9 (C-2′), 127.1 (C-3′), 136.6
(C-4′), 126.9 (C-6′). MS: m/z 409 (M+), 374, 197, 77. Anal.
C23H14O3Cl2 (C, H, Cl).
4.1.2.5. 2-(3,4,5-Trimethoxybenzylidene)-4-(4-phenoxy-
phenyl)but-3-en-4-olides (5). Yield: 65%, m.p. 122–124 °C.
1H-NMR (CDCl3) d 3.93 (s, 9H, 3 × OCH3), 6.76 (s, 1H,
butenolide ring), 6.84 (s, 2H, H-2,6, arylidene ring), 7.04 and
7.76 (d, each, 2 ×A2B2, p-disubstituted phenyl), 7.07 (m, 2H,
H-2,6, phenyl), 7.18 (m, 1H, H-4, phenyl), 7.32 (s, 1H, ole-
finic H), 7.39 (m, 2H, H-3,5, phenyl). 13C-NMR (CDCl3) d
170.8 (C-1), 127.5 (C-2), 118.6 (C-3), 128.8 (C-4), 99.2 (C-5),
129.1 (C-6), 118.1 (C-7,11), 130.2 (C-8,10), 155.8 (C-9),
153.1 (C-12), 131.9 (C-13,17), 119.6 (C-14,16), 124.2 (C-15),
129.4 (C-1′), 129.9 (C-2′,6′), 135.1 (C-3′), 134.7 (C-4′), 130.7
(C-5′), 54.1 (–OCH3). MS: m/z 430 (M+), 197, 169, 77. Anal.
C26H22O6 (C, H).
4.1.2.10. 2-(2,6-Dichlorobenzylidene)-4-(4-phenoxy-phenyl)-
1
but-3-en-4-olides (10). Yield: 66%, m.p. 106 °C. H-NMR
(CDCl3) d 6.21 (s, 1H, butenolide ring), 7.0 and 7.66 (d, each,
2 × A2B2, p-disubstituted phenyl), 7.04 (m, 2H, H-3,5,
arylidene ring), 7.18 (t, 1H, H-4, phenyl), 7.27 (m, 1H, H-4,
arylidene ring), 7.28 (m, 2H, H-2,6, phenyl), 7.42 (s, 1H, ole-
finic H). 13C-NMR (CDCl3) d 171.3 (C-1), 127.5 (C-2), 118.7
(C-3), 128.8 (C-4,5′), 98.3 (C-5), 129.2 (C-6), 118.3 (C-7,11),
130.6 (C-8,10), 156.4 (C-9), 153.1 (C-12), 132.8 (C-13,17),
119.6 (C-14,16), 124.8 (C-15), 129.8 (C-1′), 135.1 (C-2′),
128.2 (C-3′), 130.3 (C-4′), 136.9 (C-6′). MS: m/z 409 (M+),
374, 197, 77. Anal. C23H14O3Cl2 (C, H, Cl).
4.1.2.6. 2-(2-Acetoxybenzylidene)-4-(4-phenoxy-phenyl)but-
3-en-4-olides (6). Yield: 60%, m.p. 142 °C. 1H-NMR (CDCl3)
d 2.35 (s, 3H, OCOCH3), 6.81 (s, 1H, butenolide ring),
7.03 and 7.71 (d, each, 2 × A2B2, p-disubstituted phenyl),
7.06 (m, 2H, H-2,6, phenyl), 7.36 (m, 3H, H-3,4,5, arylidene
ring), 7.37 (s, 1H, olefinic H), 7.39 (m, 2H, H-3,5, phenyl).
13C-NMR (CDCl3) d 168.5 (C-1), 126.7 (C-2), 118.6 (C-3),
128.2 (C-4), 97.7 (C-5), 129.0 (C-6,3′), 118.1 (C-7,11), 130.3
(C-8,10), 155.9 (C-9), 153.8 (C-12), 133.1 (C-13,17), 119.8
(C-14,16), 124.3 (C-15), 127.8 (C-1′), 157.2 (C-2′), 130.8
(C-4′), 128.8 (C-5′), 123.2 (C-6′), 20.6 (–OAc). MS: m/z 398
(M+), 197, 77. Anal. C25H18O5 (C, H).
4.1.2.11. 2-(3-Nitrobenzylidene)-4-(4-phenoxy-phenyl)but-3-
en-4-olides (11). Yield: 62%, m.p. 194 °C. 1H-NMR (CDCl3)
d 6.04 (s, 1H, butenolide ring), 7.08 and 7.54 (d, each, 2 ×
A2B2, p-disubstituted phenyl), 7.09 (m, 2H, H-2,6, phenyl),
7.21 (t, 1H, H-4, phenyl), 7.38 (s, 1H, olefinic H), 7.41 (m,
1H, H-5, arylidene ring), 7.66 (m, 2H, H-3,5, phenyl), 7.88
(dd, 1H, H-6, arylidene ring), 8.24 (dd, 1H, H-4, arylidene
ring), 8.40 (d, 1H, H-2, arylidene ring). 13C-NMR (CDCl3) d
166.5 (C-1), 125.9 (C-2), 118.1 (C-3), 129.1 (C-4), 98.3 (C-5),
4.1.2.7. 2-(3-Acetoxybenzylidene)-4-(4-phenoxy-phenyl)but-
1
3-en-4-olides (7). Yield: 62%, m.p. 146–148 °C. H-NMR
(CDCl3) d 2.37 (s, 3H, OCOCH3), 6.83 (s, 1H, butenolide
ring), 7.08 and 7.76 (d, each, 2 × A2B2, p-disubstituted phe-
nyl), 7.07 (m, 2H, H-2,6, phenyl), 7.16 (m, 1H, H-4, arylidene

A. Husain et al. / European Journal of Medicinal Chemistry 40 (2005) 1394–1404
1401
129.5 (C-6,1′), 117.8 (C-7,11), 130.3 (C-8,10), 157.2 (C-9),
152.4 (C-12), 133.7 (C-13,17), 119.8 (C-14,16), 123.9
(C-15,6′), 127.2 (C-2′), 131.2 (C-3′), 127.6 (C-4′), 128.6
(C-5′). MS: m/z 385 (M+), 197, 77. Anal. C23H15O5N (C, H,
N).
olefinic H), 7.40 (m, 2H, H-3,5, phenyl). 13C-NMR (CDCl3)
d 173.6 (C-1), 126.1 (C-2), 119.3 (C-3), 128.8 (C-4), 98.1
(C-5), 129.1 (C-6,1′), 118.3 (C-7,11), 130.6 (C-8,10), 156.4
(C-9), 153.4 (C-12), 132.8 (C-13,17), 119.8 (C-14,16), 124.5
(C-15), 126.7 (C-2′), 135.4 (C-3′), 130.3 (C-4′), 129.7 (C-5′),
127.1 (C-6′), 43.6 (–CH2–). MS: m/z 384 (M+), 197, 77.Anal.
C24H16O5 (C, H).
4.1.2.12. 2-(4-Acetoxy-3-methoxybenzylidene)-4-(4-phenoxy-
phenyl)but-3-en-4-olides (12). Yield: 60%, m.p. 204 °C.
1H-NMR (CDCl3) d 2.34 (s, 3H, OCOCH3), 3.90 (s, 3H,
OCH3), 6.78 (s, 1H, butenolide ring), 7.04 and 7.71 (d, each,
2 ×A2B2, p-disubstituted phenyl), 7.06 (d, 1H, H-5, arylidene
ring), 7.14 (m, 2H, H-2,6, phenyl), 7.19 (t, 1H, H-4, phenyl),
7.26 (m, 2H, H-2,6, arylidene ring), 7.38 (m, 2H, H-3,5, phe-
nyl), 7.39 (s, 1H, olefinic H). 13C-NMR (CDCl3) d 171.3
(C-1), 126.1 (C-2), 119.5 (C-3), 128.3 (C-4), 98.5 (C-5), 129.2
(C-6,4′), 118.3 (C-7,11), 130.7 (C-8,10), 156.4 (C-9), 153.4
(C-12), 132.3 (C-13,17), 119.8 (C-14,16), 124.8 (C-15), 129.9
(C-1′), 127.6 (C-2′), 133.6 (C-3′), 156.1 (C-5′), 125.6 (C-6′),
20.6 (OAc), 55.9 (–OCH3). MS: m/z 428 (M+), 386, 197, 77.
Anal. C26H20O6 (C, H).
4.1.2.16. 2-(9-Anthrylidene)-4-(4-phenoxy-phenyl)but-3-en-
4-olides (16). Yield: 58%, m.p. 128 °C. 1H-NMR (CDCl3) d
5.96 (s, 1H, butenolide ring), 6.94 and 7.56 (d, each, 2 ×A2B2,
p-disubstituted phenyl), 7.0 (m, 2H, H-2,6, phenyl), 7.15 (m,
1H, H-4, phenyl), 7.33 (m, 2H, H-3,5, phenyl), 7.51 (m, 4H,
H-2,3,6,7, anthryl), 8.05 (m, 4H, H-1,4,5,8, anthryl), 8.36 (s,
1H, olefinic H), 8.4 (s, 1H, H-10, anthryl). 13C-NMR (CDCl3)
d 174.3 (C-1), 125.8 (C-2), 118.9 (C-3), 128.1 (C-4), 99.7
(C-5), 129.3 (C-6,1′), 118.2 (C-7,11), 130.1 (C-8,10), 154.9
(C-9), 153.4 (C-12), 131.8 (C-13,17), 119.6 (C-14,16), 125.1
(C-15), 128.9 (C-2′,14′), 119.7 (C-3′,13′), 127.2 (C-
4′,5′,11′,12′), 126.2 (C-6′,8′,10′), 125.8 (C-7′,9′). MS: m/z 440
(M+), 197, 177, 77. Anal. C31H20O3 (C, H).
4.1.2.13. 2-(4-Acetoxy-3-ethoxybenzylidene)-4-(4-phenoxy-
phenyl)but-3-en-4-olides (13). Yield: 62%, m.p. 168 °C.
1H-NMR (CDCl3) d 1.45 (t, 3H, OCH2CH3), 2.34 (s, 3H,
OCOCH3), 4.11 (q, 2H, OCH2CH3), 6.90 (s, 1H, butenolide
ring), 7.15 (m, 2H, H-5,6, arylidene ring), 7.29 (m, 3H, H-2,6,
phenyl + H-2 arylidene ring), 7.41 (s, 1H, olefinic H), 7.47
(m, 1H, H-4, phenyl), 7.64 (m, 2H, H-3,5, phenyl), 7.68 and
7.82 (d, each, 2 × A2B2, p-disubstituted phenyl). 13C-NMR
(CDCl3) d 173.5 (C-1), 125.7 (C-2), 118.8 (C-3), 128.4 (C-4),
100.1 (C-5), 129.1 (C-6,4′), 118.4 (C-7,11), 130.5 (C-8,10),
155.8 (C-9), 153.2 (C-12), 133.3 (C-13,17), 119.5 (C-14,16),
124.8 (C-15), 129.6 (C-1′), 127.9 (C-2′), 132.8 (C-3′), 157.7
(C-5′), 126.2 (C-6′), 20.2 (OAc), 56.3 (–OC2H5). MS: m/z
442 (M+), 197, 77. Anal. C27H22O6 (C, H).
4.1.2.17. 2-(Cinnamoylidene)-4-(4-phenoxy-phenyl)but-3-en-
4-olides (17). Yield: 54%, m.p. 166 °C. 1H-NMR (CDCl3) d
6.48 (s, 1H, butenolide ring), 7.06 and 7.70 (d, each, 2 ×A2B2,
p-disubstituted phenyl), 7.16 (m, 2H, H-2,6, phenyl), 7.19
(m, 1H, H-4, phenyl), 7.43 (m, 2H, H-3,5, phenyl), 7.65 (m,
7H, arylidene ring + 2 olefinic protons). 13C-NMR (CDCl3)
d 172.0 (C-1), 125.5 (C-2), 118.5 (C-3), 128.7 (C-4), 98.6
(C-5), 129.1 (C-6), 118.3 (C-7,11), 130.1 (C-8,10), 154.7
(C-9), 153.1 (C-12), 131.9 (C-13,17), 120.2 (C-14,16), 124.3
(C-15), 100.3 (C-18), 129.8 (C-1′), 127.3 (C-2′,6′), 129.4
(C-3′,5′), 131.2 (C-4′). MS: m/z 366 (M+), 197, 77. Anal.
C25H18O3 (C, H).
4.1.3. General procedure for the synthesis of 3-arylidene-
5-(4-phenoxy-phenyl)-2(3H)-pyrrolones (18–23)
Dry ammonia gas was passed into anhydrous ethanolic
solution of butenolide (1.0 gm) for 1 h at room temperature,
ethanol was distilled off under reduced pressure and the solid
mass so obtained, was crystallized from methanol/acetone to
give 18–23.
4.1.2.14. 2-(2-Thienylidene)-4-(4-phenoxy-phenyl)but-3-en-
4-olides (14). Yield: 61%, m.p. 138 °C. 1H-NMR (CDCl3) d
6.83 (s, 1H, butenolide ring), 7.04 and 7.70 (d, each, 2 ×A2B2,
p-disubstituted phenyl), 7.05 (m, 2H, H-2,6, phenyl), 7.15
(m, 1H, H-5, thienyl), 7.18 (m, 1H, H-4, phenyl), 7.39 (m,
2H, H-3,5, phenyl), 7.40 (s, 1H, olefinic H), 7.56 (m, 1H,
H-3, thienyl), 7.59 (m, 1H, H-4, thienyl). 13C-NMR (CDCl3)
d 170.5 (C-1), 125.9 (C-2), 117.7 (C-3), 128.7 (C-4), 96.7
(C-5), 129.3 (C-6), 118.2 (C-7,11), 130.6 (C-8,10), 157.3
(C-9), 154.2 (C-12), 131.9 (C-13,17), 119.7 (C-14,16), 124.9
(C-15), 130.1 (C-1′), 118.7 (C-2′,3′), 128.3 (C-4′). MS: m/z
346 (M+), 197, 77. Anal. C21H14O3S (C, H, S).
4.1.3.1. 3-Benzylidene-5-(4-phenoxy-phenyl)-2(3H)-pyrrolones
(18). Yield: 65%, m.p. 164–166 °C. 1H-NMR (CDCl3) d 6.99
(s, 1H, pyrrolone ring), 7.04 and 7.70 (d, each, 2 × A2B2,
p-disubstituted phenyl), 7.05 (m, 2H, H-2,6, phenyl), 7.18
(m, 1H, H-4, phenyl), 7.39 (m, 2H, H-3,5, phenyl), 7.46 (m,
3H, H-3,4,5, arylidene ring), 7.62 (m, 2H, H-2,6, arylidene
ring), 7.63 (s, 1H, olefinic), 8.02 (s, 1H, NH). 13C-NMR
(CDCl3) d 167.8 (C-1), 125.5 (C-2), 118.3 (C-3), 127.8 (C-4),
98.7 (C-5), 129.4 (C-6,1′), 119.1 (C-7,11), 130.2 (C-8,10),
157.5 (C-9), 150.8 (C-12), 134.1 (C-13,17), 119.5 (C-14,16),
124.4 (C-15), 127.1 (C-2′,6′), 129.8 (C-3′,5′), 131.4 (C-4′).
MS: m/z 339 (M+), 153, 77. Anal. C23H17NO2 (C, H, N).
4.1.2.15. 2-(3,4-Methylenedioxybenzylidene)-4-(4-phenoxy-
phenyl)but-3-en-4-olides (15). Yield: 58%, m.p. 146 °C.
1H-NMR (CDCl3) d 6.07 (s, 2H, OCH2O), 6.80 (s, 1H,
butenolide ring), 6.90 (d, 1H, H-5, arylidene ring), 7.04 and
7.1 (d, each, 2 × A2B2, p-disubstituted phenyl), 7.09 (d, 1H,
H-2, arylidene ring), 7.15 (m, 3H, H-2,6 phenyl + H-
6 arylidene ring), 7.18 (m, 1H, H-4, phenyl), 7.31 (s, 1H,

1402
A. Husain et al. / European Journal of Medicinal Chemistry 40 (2005) 1394–1404
4.1.3.2. 3-(2-Hydroxybenzylidene)-5-(4-phenoxy-phenyl)-
2(3H)-pyrrolones (19). Yield: 62%, m.p. 210 °C. H-NMR
4.1.3.6. 3-(2-Thienylidene-5-(4-phenoxy-phenyl)-2(3H)-
pyrrolones (23). Yield: 68%, m.p. 216 °C. 1H-NMR (CDCl3)
d 6.97 (s, 1H, pyrrolone ring), 7.15 (m, 2H, H-3,4, thienyl),
7.47 and 7.85 (d, each, 2 × A2B2, p-disubstituted phenyl),
7.40 (m, 2H, H-3,5, phenyl), 7.65 (m, 4H, H-2,4,6 phenyl + H-
5 thienyl), 7.68 (s, 1H, olefinic), 8.18 (s, 1H, NH). 13C-NMR
(CDCl3) d 168.5 (C-1), 126.1 (C-2), 118.3 (C-3), 128.5
(C-4,4′), 96.7 (C-5), 129.3 (C-6), 118.8 (C-7,11), 130.1
(C-8,10), 156.9 (C-9), 153.2 (C-12), 132.1 (C-13,17), 119.6
(C-14,16), 124.7 (C-15), 130.9 (C-1′), 119.2 (C-2′,3′). MS:
m/z 345 (M+), 196, 77. Anal. C21H15NO2S (C, H, N, S).
1
(CDCl3) d 6.88 (s, 1H, pyrrolone ring), 6.91 (m, 2H, H-3,5,
arylidene ring), 7.03 and 7.71 (d, each, 2 × A2B2,
p-disubstituted phenyl), 7.06 (m, 2H, H-2,6, phenyl), 7.16
(m, 1H, H-4, phenyl), 7.20 (t, 1H, H-4, arylidene ring), 7.20
(t, 1H, H-4, arylidene ring), 7.39 (m, 2H, H-3,5, phenyl), 7.46
(m, 3H, H-3,4,5, arylidene ring), 7.62 (m, 2H, H-2,6, arylidene
ring), 7.63 (s, 1H, olefinic), 8.02 (s, 1H, NH). 13C-NMR
(CDCl3) d 166.4 (C-1), 126.1 (C-2), 117.9 (C-3), 128.5
(C-4,5′), 96.9 (C-5), 129.1 (C-6,3′), 117.6 (C-7,11), 130.1
(C-8,10), 155.4 (C-9), 152.1 (C-12), 132.6 (C-13,17), 119.8
(C-14,16), 124.2 (C-15), 127.5 (C-1′), 158.3 (C-2′), 131.1
(C-4′), 123.6 (C-6′). MS: m/z 354 (M-1), 196, 77. Anal.
C23H17NO3 (C, H, N).
4.1.4. General procedure for the synthesis 3-arylidene-5-
(4-phenoxy-phenyl)-1-benzyl-2(3H)-pyrrolones (24–29)
Synthesis of these compounds involved the following two
steps:
4.1.3.3. 3-(3-Hydroxybenzylidene)-5-(4-phenoxy-phenyl)-
2(3H)-pyrrolones (20). Yield: 65%, m.p. 202 °C. H-NMR
• Synthesis of c-ketobenzylamide.
1
Butenolide (3 mmol) and benzylamine (4 mmol) were
refluxed in dry benzene for 2 h. On completion of reac-
tion, excess benzene was distilled off and a solid mass so
obtained was washed with petroleum ether and dried. The
compound obtained was used without crystallization.
• Lactamization of c-ketobenzylamide.
c-Ketobenzylamide (3 mmol) was refluxed in 6 N hydro-
chloric acid (20 ml) for 1 h. The contents were then cooled
and a solid mass so obtained was collected, washed with
water and crystallized from methanol to give 24–29.
(CDCl3) d 6.91 (s, 1H, pyrrolone ring), 7.04 and 7.68 (d, each,
2 ×A2B2, p-disubstituted phenyl), 7.20 (m, 3H, H-2,4,6, phe-
nyl), 7.21 (m, 1H, H-5, arylidene ring), 7.37 (m, 2H, H-3,5,
phenyl), 7.92 (dd, 1H, H-6, arylidene ring), 8.05 (m, 1H, H-4,
arylidene ring), 8.18 (d, 1H, H-2, arylidene ring), 7.74 (s,
1H, olefinic), 8.63 (s, 1H, NH). 13C-NMR (CDCl3) d 170.3
(C-1), 125.2 (C-2), 118.8 (C-3), 128.9 (C-4), 99.1 (C-5), 128.5
(C-6,5′), 118.2 (C-7,11), 131.4 (C-8,10), 155.8 (C-9), 152.7
(C-12), 132.1 (C-13,17), 119.8 (C-14,16), 125.2 (C-15), 129.4
(C-1′), 127.9 (C-2′), 158.6 (C-3′), 130.3 (C-4′), 124.1 (C-6′),
MS: m/z 354 (M-1), 196, 77. Anal. C23H17NO3 (C, H, N).
4.1.4.1. 3-(4-Chlorobenzylidene)-5-(4-phenoxy-phenyl)-1-
benzyl-2(3H)-pyrrolones (24). Yield: 48%, m.p. 108 °C.
1H-NMR (CDCl3) d 4.85 (s, 2H, CH2), 6.17 (s, 1H, pyrrolone
ring), 6.96 and 7.59 (d, each, 2 × A2B2, p-disubstituted phe-
nyl), 7.20 and 7.43 (d, each, 2 × A2B2, arylidene ring), 7.25
(m, 6H, H-3,4,5 phenyl + H-3,4,5 benzyl), 7.39 (s, 1H, ole-
finic), 7.40 (m, 4H, H-2,6 phenyl + H-2,6 benzyl). 13C-NMR
(CDCl3) d 175.5 (C-1), 126.4 (C-2), 116.8 (C-3), 127.5 (C-4),
99.2 (C-5), 129.5 (C-6,1′), 118.8 (C-7,11,14,16), 130.7
(C-8,10), 155.1 (C-9), 153.7 (C-12), 132.3 (C-13,17), 123.6
(C-15), 126.9 (C-2′,6′), 129.1 (C-3′,5′), 133.6 (C-4′), 44.6
(C-1″), 132.6 (C-2″), 127.1 (C-3″,7″), 128.8 (C-4″), 119.3
(C-5″), 128.2 (C-6″). MS: m/z 463 (M+), 196, 91, 77. Anal.
C30H22NO2Cl (C, H, N, Cl).
4.1.3.4. 3-(4-Chlorobenzylidene-5-(4-phenoxy-phenyl)-2(3H)-
pyrrolones (21). Yield: 68%, m.p. 240 °C. 1H-NMR (CDCl3)
d 6.42 (s, 1H, pyrrolone ring), 7.06 and 7.58 (d, each, 2 ×
A2B2, p-disubstituted phenyl), 7.20 (m, 3H, H-2,4,6, phe-
nyl), 7.32 (s, 1H, olefinic), 7.37 (m, 2H, H-3,5, phenyl),
7.41 and 7.50 (d, each, 2 × A2B2, arylidene ring), 8.2 (s, 1H,
NH). 13C-NMR (CDCl3) d 172.0 (C-1), 125.9 (C-2), 117.7
(C-3), 127.6 (C-4), 97.8 (C-5), 129.1 (C-6,1′), 118.3 (C-7,11),
130.2 (C-8,10), 155.7 (C-9), 154.8 (C-12), 131.9 (C-13,17),
118.6 (C-14,16), 124.1 (C-15), 126.3 (C-2′,6′), 129.4 (C-3′,5′),
136.2 (C-4′). MS: m/z 373 (M+), 196, 77.Anal. C23H16NO2Cl
(C, H, N, Cl).
4.1.3.5. 3-(3-Nitrobenzylidene-5-(4-phenoxy-phenyl)-2(3H)-
pyrrolones (22). Yield: 66%, m.p. 226 °C. 1H-NMR (CDCl3)
d 6.44 (s, 1H, pyrrolone ring), 7.08 and 7.55 (d, each, 2 ×
A2B2, p-disubstituted phenyl), 7.19 (m, 1H, H-5, phenyl), 7.40
(m, 3H, H-2,4,6, phenyl), 7.50 (s, 1H, olefinic), 7.62 (m, 2H,
H-3,5, phenyl), 7.90 (dd, 1H, H-6, arylidene ring), 8.20 (m,
1H, H-4, arylidene ring), 8.51 (d, 1H, H-2, arylidene ring),
8.60 (s, 1H, NH). 13C-NMR (CDCl3) d 174.2 (C-1), 125.7
(C-2), 118.1 (C-3), 129.7 (C-4), 98.0 (C-5), 129.2 (C-6,1′),
117.8 (C-7,11), 130.5 (C-8,10), 157.1 (C-9), 151.4 (C-12),
134.2 (C-13,17), 119.8 (C-14,16), 123.5 (C-15), 127.8 (C-2′),
131.5 (C-3′), 127.2 (C-4′), 128.2 (C-5′), 124.2 (C-6′). MS:
m/z 383 (M-1), 337, 196, 77. Anal. C23H17N2O4 (C, H, N).
4.1.4.2. 3-(3,4-Dimethoxybenzylidene)-5-(4-phenoxy-phenyl)-
1-benzyl-2(3H)-pyrrolones (25). Yield: 65%, m.p. 132 °C.
1H-NMR (CDCl3) d 3.90 (s, 6H, 2 × –OCH3), 4.89 (s, 2H,
CH2), 6.20 (s, 1H, pyrrolone ring), 6.92 (d, 1H, H-5, arylidene
ring), 6.93 and 7.61 (d, each, 2 × A2B2, p-disubstituted phe-
nyl), 7.02–7.32 (m, 7H, 5H of benzyl + H-2,6 arylidene ring),
7.46 (m, 3H, H-3,4,5, phenyl), 7.49 (s, 1H, olefinic), 7.59 (m,
2H, H-2,6, phenyl). 13C-NMR (CDCl3) d 170.8 (C-1), 126.2
(C-2), 119.1 (C-3,5″), 128.3 (C-4,4″), 97.6 (C-5), 128.7
(C-6,6″), 118.6 (C-7,11), 130.8 (C-8,10), 155.1 (C-9), 152.5
(C-12), 133.2 (C-13,17), 119.5 (C-14,16), 125.1 (C-15), 129.1
(C-1′), 127.1 (C-2′,6′), 134.8 (C-3′), 130.5 (C-4′), 129.6
(C-5′), 44.2 (C-1″), 132.6 (C-2″), 127.4 (C-3″,7″), 53.9

A. Husain et al. / European Journal of Medicinal Chemistry 40 (2005) 1394–1404
1403
(–OCH3). MS: m/z 489 (M+), 196, 91, 77. Anal. C32H27NO4
(C, H, N).
1H, NH). 13C-NMR (CDCl3) d 169.5 (C-1), 126.3 (C-2), 118.3
(C-3), 128.5 (C-4,4″), 97.3 (C-5), 129.6 (C-6), 118.8 (C-7,11),
131.1 (C-8,10), 156.6 (C-9), 153.8 (C-12), 132.3 (C-13,17),
119.3 (C-14,16), 124.2 (C-15), 130.2 (C-1′), 117.5 (C-2′,3′),
128.1 (C-4′,6″), 44.6 (C-1″), 130.8 (C-2″), 127.9 (C-3″,7″),
119.7 (C-5″). MS: m/z 435 (M+), 196, 77.Anal. C28H21NO2S
(C, H, N, S).
4.1.4.3. 3-(3,4,5-Trimethoxybenzylidene)-5-(4-phenoxy-
phenyl)-1-benzyl-2(3H)-pyrrolones (26). Yield: 62%, m.p.
142 °C. 1H-NMR (CDCl3) d 3.90 (s, 9H, 3×–OCH3), 4.88 (s,
2H, CH2), 6.23 (s, 1H, pyrrolone ring), 6.90 (s, 2H, H-2,6,
arylidene ring), 6.87 and 7.60 (d, each, 2 × A2B2,
p-disubstituted phenyl), 7.11 (m, 2H, H-2,6, benzyl), 7.27 (m,
4H, H-3,4,5 phenyl + 1H olefinic), 7.44 (m, 3H, H-3,4,5, phe-
nyl), 7.60 (m, 2H, H-2,6, phenyl). 13C-NMR (CDCl3) d 168.5
(C-1), 127.8 (C-2), 118.1 (C-3), 128.6 (C-4), 100.1 (C-5),
128.7 (C-6), 118.8 (C-7,11), 130.7 (C-8,10,2′,6′), 155.2 (C-9),
154.6 (C-12), 132.5 (C-13,17), 119.8 (C-14,16), 124.3 (C-15),
129.3 (C-1′), 134.4 (C-3′), 135.1 (C-4′), 130.3 (C-5′), 45.4
(C-1″), 131.8 (C-2″), 127.3 (C-3″,7″), 128.1 (C-4″), 119.4
(C-5″), 128.7 (C-6″), 54.3 (–OCH3). MS: m/z 519 (M+), 196,
91, 77. Anal. C33H29NO5 (C, H, N).
4.2. Pharmacology
4.2.1. Anti-inflammatory activity
Freshly prepared suspension of carrageenan (0.05 ml of
1% solution in 0.9% saline) was injected under the planter
aponeurosis of the right paw of rats. Animals were divided in
groups with six animals in each group. The dose adminis-
tered was 20 mg/kg body weight. Stock solution containing
4 mg/ml of the drug was prepared and administered orally
0.5 ml/100 g body weight of the animal. One group was kept
as a control and the animals of other groups were pretreated
with test drugs given orally 30 min before carrageenan injec-
tion. The foot volume was measured before and 3 h after car-
rageenan injection by plethysmograph. The percentage inhi-
bition of inflammation was calculated by applying Newbould
formula [19]. Indomethacin was used as standard drug for
comparison.
4.1.4.4. 3-(3,4-Methylenedioxybenzylidene)-5-(4-phenoxy-
phenyl)-1-benzyl-2(3H)-pyrrolones (27). Yield: 60%, m.p.
170–172 °C. 1H-NMR (CDCl3) d 4.85 (s, 2H, CH2), 6.02 (s,
2H, –OCH2O–), 6.10 (s, 1H, pyrrolone ring), 6.85 (d, 1H,
H-5, arylidene ring), 6.92 and 7.26 (d, each, 2 × A2B2,
p-disubstituted phenyl), 7.10 (m, 7H, 5H, phenyl + H-
2,6 arylidene), 7.25 (m, 5H, benzyl), 7.60 (s, 1H, olefinic).
13C-NMR (CDCl3) d 169.5 (C-1), 126.1 (C-2), 119.8 (C-3,5″),
128.2 (C-4,4″), 97.8 (C-5), 129.5 (C-6,1′), 118.6 (C-7,11),
130.7 (C-8,10), 155.8 (C-9), 153.7 (C-12), 132.4 (C-13,17),
119.2 (C-14,16), 124.9 (C-15), 126.8 (C-2′), 134.8 (C-3′),
130.1 (C-4′), 129.2 (C-5′), 127.3 (C-6′,3″,7″), 43.3 (C-1″),
132.1 (C-2″), 128.6 (C-6″), 45.6 (–CH2–). MS: m/z 473 (M+),
196, 91, 77. Anal. C31H23NO4 (C, H, N).
4.2.2. Analgesic activity
Analgesic activity was carried out by acetic acid induced
writhing method [20] in swiss albino mice (25–30 g) of either
sex. A 1% aqueous acetic acid solution (i.p. injection in a
volume of 0.1 ml) was used as writhing induced agent. In
each group six mice were kept. Mice were kept individually
in the test cage, before acetic acid injection and habituated
for 30 min. Screening of analgesic activity was performed
after p.o. administration of test drugs at a dose of 20 mg/kg.
The compounds, which exhibited good anti-inflammatory
activity comparable to that of indomethacin, were screened
for analgesic activity. All compounds were dissolved in 1%
CMC solution. One group was kept as control and received
p.o. administration of 1% CMC. Ibuprofen was used as ref-
erence drug. After 1 h of drug administration 0.10 ml of 1%
acetic acid solution was given to mice intraperitoneally.
Stretching movements consisting of arching of the back, elon-
gation of body and extension of hind limbs were counted for
5–15 min of acetic acid injection. The analgesic activity was
expressed in terms of % inhibition. % Analgesic activity = (n
– n′/n) × 100 where n = mean number of writhes of control
group and n′ = mean number of writhes of test group. Statis-
tical analysis was done using Student’s t-test. The percent
protection in mice brought about by administration of the
drugs is shown in Table 2.
4.1.4.5. 3-(3-Nitrobenzylidene)-5-(4-phenoxy-phenyl)-1-
benzyl-2(3H)-pyrrolones (28). Yield: 63%, m.p. 116 °C.
1H-NMR (CDCl3) d 4.87 (s, 2H, CH2), 6.20 (s, 1H, pyrrolone
ring), 6.97 and 7.28 (d, each, 2 × A2B2, p-disubstituted phe-
nyl), 7.05 (m, 4H, H-2,6 phenyl + H-2,6 benzyl), 7.25 (m,
5H, H-3,5 phenyl + H-3,4,5 benzyl), 7.47 (s, 1H, olefinic),
7.60 (t, 1H, H-5, arylidene), 7.9 (d, 1H, H-4, arylidene), 8.2
(dd, 1H, H-6, arylidene), 8.5 (t, 1H, H-2, arylidene). 13C-
NMR (CDCl3) d 168.1 (C-1), 126.5 (C-2), 118.9 (C-3,5″),
129.2 (C-4,4″), 99.6 (C-5), 129.6 (C-6,1′), 117.9 (C-7,11),
130.5 (C-8,10), 156.4 (C-9), 152.7 (C-12), 134.8 (C-13,17),
119.5 (C-14,16), 124.4 (C-15), 127.6 (C-2′,4′), 131.7 (C-
3′,2″), 128.6 (C-5′,6″), 123.5 (C-6′), 44.8 (C-1″), 127.3
(C-3″,7″). MS: m/z 474 (M+), 446, 428, 383, 196, 91. Anal.
C30H22N2O4 (C, H, N).
4.1.4.6. 3-(2-Thienylidene)-5-(4-phenoxy-phenyl)-1-benzyl-
1
2(3H)-pyrrolones (29). Yield: 58%, m.p. 156 °C. H-NMR
4.2.3. Acute ulcerogenesis
(CDCl3) d 6.97 (s, 1H, pyrrolone ring), 7.15 (m, 2H, H-3,4,
thienyl), 7.47 and 7.85 (d, each, 2 × A2B2, p-disubstituted
phenyl), 7.40 (m, 2H, H-3,5, phenyl), 7.65 (m, 4H,
H-2,4,6 phenyl + H-5 thienyl), 7.68 (s, 1H, olefinic), 8.18 (s,
Acute ulcerogenesis test was done according to Cioli et al.
[21]. Albino rats (150–200 g) were divided into different
groups consisting of six animals in each group. Ulcerogenic

1404
A. Husain et al. / European Journal of Medicinal Chemistry 40 (2005) 1394–1404
activity evaluated after p.o. administration of test com-
pounds or ibuprofen at the dose of 50 mg/kg. Control rats
received p.o. administration of vehicle (suspension of 1%
methyl cellulose). Food but not water was removed 24 h before
administration of the test compounds. After the drug treat-
ment, the rats were fed normal diet for 17 h and then sacri-
ficed. The stomach was removed and opened along the greater
curvature, washed with distilled water and cleaned gently by
dipping in saline. The gastric mucosa of the rats was exam-
ined by means of a 4× binocular magnifier. The lesions were
counted and divided into large (greater than 2 mm in diam-
eter), small (1–2 mm) and punctiform (less than 1 mm). For
each stomach the severity of mucosal damage was assessed
according to the following scoring system: 0—no lesions or
upto five punctiform lesions; 1—more than five punctiform
lesions; 2—one to five small ulcers; 3—more than five small
ulcers or one large ulcer; 4—more than one large ulcer.
The mean score of each treated group minus the mean score
of the control group was considered the ’severity index’ of
gastric damage.
viding facilities to carry out this work. One of the authors
(A.H.) is thankful to Hamdard National Foundation (HNF),
New Delhi for the award of senior research fellowship.
References
[1] A.A. Avetisyan, G.G. Tokmadzhyan, Chem. Heterocycl. Compd. 23
(1987) 595–598.
[2] K.H. Lee, S.H. Kim, C. Piantadosi, J. Pharm. Sci. 63 (1976) 1163–
1165.
[3] A. Gringuaz, Introduction to Medicinal Chemistry, Wiley-VCH, New
York, 1997 (pp. 305).
[4] S.C. Harvey, Ramington’s Pharmaceutical Science, Mack Publishing
Company, Pennsylvania, 1985 (pp. 1189).
[5] W.E. Klunk, D.F. Covey, J.A. Ferrendelli, Mol. Pharmacol. 22 (2)
(1982) 431–443.
[6] J.D. Couquelet, J.M. Couquelet, M. Payard, F. Fauran, A. Thibault,
Ann. Pharm. Fr. 36 (1978) 51–60.
[7] N.D. Heinkel, J.A. Minatelli, J. Pharm. Sci. 70 (1) (1981) 84–86.
[8] C.K. Lau, C. Brideau, C.C. Chan, S. Charleson, W.A. Cromlish,
D. Ethier, J.Y. Gauthier, R. Gordon, J. Guay, S. Kargman, C.S. Li,
P. Prasit, D. Riendeau, M. Therien, D.M. Visco, L. Xu, Biorg. Med.
Chem. Lett. 15 (1999) 3187–3192.
[9] W.I. Awad, A.I. Hashem, K. El-Badry, Ind. J. Chem. 13 (1975)
1139–1141.
4.2.4. Antimicrobial activity
The bacterial strains gram positive (S. aureus; NCTC-
6571), gram negative (E. coli; ATCC-25922) and yeast (C.
albicans) were used. The test was carried out according to
the turbidity method [22]. A solution of the compounds was
prepared in dimethylformamide (DMF) and a series of dou-
bling dilutions prepared with sterile pipettes. To each of a
series of sterile stoppered test tubes a standard volume of nutri-
ent broth medium was added. A control tube containing no
antimicrobial agent was included. The inoculum consisting
of an overnight broth culture of microorganisms was added
to separate tubes. The tubes were incubated at 37° for 24 h
and examined for turbidity. The tube with highest dilution
showing no turbidity was MIC.
[10] S.A. Khattab, M. Hosny, Ind. J. Chem. 19B (1980) 1038–1043.
[11] S.M. El-Kousy, A.M. El-Torgoman, A.A. El-Basiounyl, A.I. Hashem,
Pharmazie 43 (1988) 80–81.
[12] in: B. Testa, P. Jenner (Eds.), Drug Metabolism, Chemical and Bio-
chemical Aspect, Marcel Dekker Inc., New York, 1976.
[13] A. Husain, Ph.D. Thesis, Jamia Hamdard University, New Delhi,
2000.
[14] C. Kohler, E. Tolman, W. Wooding, L. Ellenbogen, Thromb. Res. 20
(1) (1980) 123–135.
[15] C. Kohler, E. Tolman, W. Wooding, L. Ellenbogen, Arzneimittelfors-
chung 30 (4A) (1980) 702–707.
[16] M.S.Y. Khan, A. Husain, S. Sharma, Ind. J. Chem. 41B (2002) 2160–
2171.
[17] A. Husain, S.M. Hasan, S. Lal, M. Mumtaz Alam, Ind. J. Hetrocycl.
Chem. 14 (2004) 163–164.
[18] C.A. Winter, E.A. Risley, G.W. Nuss, Proc. Soc. Exp. Biol. 111 (1962)
544–547.
[19] B.B. Newbould, Br. J. Pharmacol. 21 (1963) 127–136.
[20] E. Seigmund, R. Cadmus, G. Lu, Proc. Soc. Exp. Biol. 95 (1957)
729–733.
Acknowledgements
[21] V. Cioli, S. Putzolu, V. Rossi, P. Sorza Barcellona, C. Corradino,
Toxicol. Appl. Pharmacol. 50 (1979) 283–289.
[22] in: R. Cruickshank, J.P. Dugid, D.P. Marmion, R.H.A. Swain (Eds.),
Medical Microbiology, vol. 2, Churchill, London, 1975.
The authors are thankful to (late) Hakim Abdul Hameed
Sahib (Founder, Chancellor of Jamia Hamdard) and Mr. A.
Mueed (President, Hamdard National Foundation) for pro-