Synthesis of 2-(aryl)-5-(arylidene)-4-thiazolidinone derivatives with potential analgesic and anti-inflammatory activity

Article abstract of DOI:10.1007/s00044-011-9679-0

A series of novel N-[5-(arylidene)-2-(aryl)-4-oxo-thiazolidin-3-yl]-4- biphenylcarboxamide derivatives was synthesized and evaluated for analgesic and anti-inflammatory activity. In this study, biphenyl-4-carboxylic acid hydrazide was converted to the corresponding aryl hydrazones using aryl aldehydes in the presence of catalytic amount of glacial acetic acid. The aryl hydrazones on reaction with thioglycolic acid in the presence of anhydrous zinc chloride yielded N-[2-(aryl)-4-oxo-thiazolidin-3-yl]-4-biphenylcarboxamide which further on reaction with aromatic aldehydes in the presence of anhydrous sodium acetate and glacial acetic acid furnished the title compounds. All compound exhibited anti-inflammatory activity at the dose 10 mg/kg. The structures of all these newly synthesized compounds were confirmed by their elemental analyses (C, H, N) and spectral data (IR and ¹H NMR). Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9679-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1652–1659
DOI 10.1007/s00044-011-9679-0
ORIGINAL RESEARCH
Synthesis of 2-(aryl)-5-(arylidene)-4-thiazolidinone derivatives
with potential analgesic and anti-inflammatory activity
•
Aakash Deep Sandeep Jain Prabodh Chander Sharma
•
•
•
Priyanka Phogat Manav Malhotra
Received: 13 January 2011 / Accepted: 21 May 2011 / Published online: 4 June 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of novel N-[5-(arylidene)-2-(aryl)-4-
oxo-thiazolidin-3-yl]-4-biphenylcarboxamide derivatives was
synthesized and evaluated for analgesic and anti-inflam-
matory activity. In this study, biphenyl-4-carboxylic acid
hydrazide was converted to the corresponding aryl hydra-
zones using aryl aldehydes in the presence of catalytic
amount of glacial acetic acid. The aryl hydrazones on
reaction with thioglycolic acid in the presence of anhy-
drous zinc chloride yielded N-[2-(aryl)-4-oxo-thiazolidin-
3-yl]-4-biphenylcarboxamide which further on reaction
with aromatic aldehydes in the presence of anhydrous
sodium acetate and glacial acetic acid furnished the title
compounds. All compound exhibited anti-inflammatory
activity at the dose 10 mg/kg. The structures of all these
newly synthesized compounds were confirmed by their
Keywords Synthesis ꢀ 4-Thiazolidinone ꢀ Analgesic ꢀ
Anti-inflammatory activity
Introduction
One of the main objectives of organic and medicinal
chemistry is the design, synthesis, and production of mol-
ecules having a value as human therapeutic agents (Kumar
et al., 2011b). In the recent past, 4-thiazolidinone scaffold
and its derivatives have attracted considerable attention of
medicinal chemists and have become an important class of
heterocyclic compounds because of their diverse biological
activities such as anti-inflammatory (Kumar and Rajput,
2009; Ottana et al., 2005; Geronikaki et al., 2008), anal-
gesic (Tandon et al., 1985; Knutsen et al., 2007) antimy-
cobacterial (Kucukguzel et al., 2002; Srivastav et al., 2005),
antimicrobial (Ozkirimli et al., 2009; Bondock et al., 2007;
Madhukar et al., 2009; Fuloria et al., 2009), antiarrhythmic
(Amr et al., 2009), anti-HIV activity (Kucukguzel et al.,
2006; Barreca et al., 2001), and anticonvulsant (Shiradkar
et al., 2007). An essential component in drug designing
program is the syntheses of novel molecules, with better
activity with lesser side effects. These observations pro-
moted us to synthesize a new series of 4-thiazolidinones.
Thus, as a part of our ongoing research endeavors to
search biologically active heterocyclic compounds con-
taining sulfur and nitrogen atoms, we have synthesized
some novel thiazolidin-4-ones and evaluated them for their
anti-inflammatory, analgesic, and other biological activities
in our laboratories (Kumar et al., 2011a, b; Jain et al.,
2011; Sharma et al., 2011). Moreover, it has been observed
that thiazolidinone derivatives derived from biphenyl-4-
carboxylic acid have shown promising anti-inflammatory
and antibacterial activities (Deep et al., 2010, 2011). Thus,
1
elemental analyses (C, H, N) and spectral data (IR and H
NMR).
A. Deep (&)
Department of Pharmaceutical Sciences, Maharshi Dayanand
University, Rohtak, Haryana 124001, India
e-mail: aakashdeep82@gmail.com
S. Jain
Department of Pharmaceutical Sciences, Guru Jambheshwar
University of Science and Technology, Hisar 125001, India
P. C. Sharma
Institute of Pharmaceutical Sciences, Kurukshetra University,
Kurukshetra 136118, India
P. Phogat
Department of Pharmaceutical Sciences, Hindu College
of Pharmacy, Sonepat 131001, India
M. Malhotra
Department of Pharmaceutical Chemistry, ISF College
of Pharmacy, Ferozpur Road, Moga 142 001, India
123

Med Chem Res (2012) 21:1652–1659
1653
in the lights of these facts, we anticipated that the 2-(aryl)-
5-(arylidene)-4-thiazolidinone derivatines may also possess
commendable biological potential. Thus, it was decided to
undertake biological evaluation of these compounds to
determine their possible pharmacological potential. Hence,
in this study, we report the synthesis with chemical char-
acterization and anti-inflammatory and analgesic activities
of some novel thiazolidin-4-ones derived from biphenyl-4-
carboxylic acid.
which might result in detection of new potential antirheu-
matic agents. A series of compounds were prepared and
assayed in a variety of biological test for analgesic and
anti-inflammatory activity. Compounds (6a–r) were
investigated for in vivo antiinflammatory activity by car-
rageenan-induced rat paw edema method using plethys-
mometer and for in vivo analgesic activity by writhing
method. All described 4-thiazolidinone derivatives were
evaluated for anti-inflammatory activity and among them
compounds 6l and 6m showed comparatively good per-
centage of inhibition of edema than the other synthesized
compounds. Percentage inhibition observed with compound
6m bearing a para methoxy and para chloro substitution was
highest i.e., 71.83 and 57.90%, respectively, at 2 and 4-h
time interval. The second most active compound of the
series was compound 6l with 71.21% inhibition at 4 h
interval. However, at 2 h interval compound 6o with two
methoxy groups was observed to be second most active
compound of the series. Similarly, all synthesized com-
pounds were evaluated for analgesic activity. In the acetic
acid-induced writhing, the entire test compounds showed
the significant analgesic activity as compared to the stan-
dard drug. The compounds 6h and 6p bearing two electron
withdrawing groups i.e., chloro and nitro (6h) and fluoro
and chloro (6p) were found to be most potent with per-
centage protection of 46.25%. Next to these, compound 6g
bearing two nitro substitutions depicted 43.25% protection.
Results and discussion
We describe here a convenient approach for the preparation
of N-[5-(arylidene)-2-(aryl)-4-oxo-thiazolidin-3-yl]-4-bi-
phenylcarboxamide derivatives 6a–r. All compounds were
synthesized according to Scheme 1. At the first stage,
Schiff’s bases 4a–r biphenyl-4-carboxylic acid hydrazide 3
and aromatic aldehydes were prepared. Further, reaction of
these Schiff’s bases with thioglycolic acid in DMF and in
the presence of a small amount of ZnCl2 yielded the N-[2-
(aryl)-4-oxo-thiazolidin-3-yl]-4-biphenylcarboxamide
derivatives 5a–r which on further reaction with aromatic
aldehydes in the presence of sodium acetate and glacial
acetic acid yield the 2,3,5-trisubstituted-4-thiazolidinones.
The synthesized compounds were characterized on the basis
1
of their elemental analysis, IR and H NMR. IR spectra of
all compounds 6a–r showed absorption band at around
3481–3298, 1665–1634, 1648–1402 cm-1 regions, con-
1
forming the presence of NH, C=O, C–N, respectively. H
Experimental
NMR was more informative. In addition to the peak of
biphenyl-4-carboxamido moiety, other characteristic signal
were observed at d 8.07–8.00 (1H, –MH), 7.31–6.94 (s, 1H,
C=CH) and 4.98–4.32 (s, 1H, –NCHS), confirming the
structure of thiazolidine ring. The elemental analysis, val-
ues are consistent with their predicted structure. The pur-
pose of this study was to predict any molecular modification
All the chemical and solvents
All the chemicals and solvents used in this study were pro-
cured from Qualigens (Navi Mumbai, India), CDH (New
Delhi, India), and SD Fines (Mumbai, India). Melting
points were determined in open-glass capillaries on TEMPO
ROH
COOH
CH3OH
CONHNH2
COOCH3
N2H4.OH2
H2SO4
Biphenyl-4-carboxylic acid hydrazide (3)
Biphenyl-4-carboxylic acid methyl ester (2)
Biphenyl 4-carboxylic acid (1)
ArCHO
O
O
O
O
Ar'
SHCH2COOH
HN
N
CONH-N=CHAr
S
HN
N
Ar'CHO
S
Ar
Ar
2-Subsituted-4-thiazolidinone (5a-d)
2,5 Disubsituted-4-thiazolidinone (6a-r)
ArCHO and Ar'CHO are aromatic aldehydes.
Biphenyl-4-carboxylic acid hydrazone (4a-d)
Scheme 1 Synthetic pathway for the formation of the title compounds
123

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Med Chem Res (2012) 21:1652–1659
melting point apparatus and are uncorrected. The purity of the
synthesized compounds was checked by thin layer chroma-
tography (TLC). 1H NMR spectra were recorded on Bruker
Avance II 400 NMR spectrometer using TMS as internal
standard. Elemental analyses were carried out on Carlo Erba
1106 CHN Analyzer. IR spectra were recorded on Perkin
Elmer Spectrum RXI FTIR spectrophotometer in KBr phase.
refluxed for 5–7 h. After cooling, the solution was poured
on crushed ice to precipitate the product. The product was
recrystallized from rectified spirit.
N-[2-(4-Chloro-phenyl)-5-benzylidene-4-oxo-thiazolidin-
3yl]-biphenyl-4-carboxamide (6a)
White crystal yield 71%, m.p 220°C. IR (KBr, cm-1) 3477
(N–H str amide1), 3028 (C–H str aromatic), 1649 (C=O str
amide1), 1603–1484 (C=C str aromatic), 1446–1402 (C–N
str), 747–693(C–Cl).1H NMR, (DMSO) dppm 8.24–7.40
(m, 9H, Ar H), 8.04 (s, 1H, –NH), 7.62–7.53 (m, 5H, Ar0
H), 7.50–7.38 (m, 4H, Ar H), 7.31 (s, 1H, C=CH), 4.68 (s,
1H, –NCHS). Anal.: Calcd. for C29H21ClN2O2S: Calc C,
70.08; H, 4.26; N, 5.64. Found C, 70.12; H, 4.29; N, 5.67.
General procedure for synthesis of 4-thiazolidinone
derivatives
Synthesis of biphenyl-4-carboxylic acid methyl ester (2)
A mixture of (0.25 M, 50 g) biphenyl-4-carboxylic acid (1)
and excess of methanol (250 ml) with 1 ml of sulfuric acid was
refluxed for 3–4 h in RBF. The mixture was cooled; the solid
was separated by filtration and recrystallized from methanol.
N-[2-(4-Chloro-phenyl)-5-(3-nitro-benzylidene)-4-oxo-
thiazolidin-3yl]-biphenyl-4-carboxamide (6b)
Synthesis of biphenyl-4-carboxylic acid hydrazide (3)
Slightly yellow powder, yield 79%, m.p 250°C. IR (KBr,
cm-1) 3453 (N–H str amide1), 3051 (C–H str aromatic),
1657 (C=O str amide1), 1606–1484 (C=C str aromatic),
1404 (C–N str), 1544 (N–O str, NO2), 779–604(C–Cl).1H
NMR, (DMSO) dppm 8.19–7.43(m, 4H, Ar0 H), 8.02 (s,
1H, –NH), 7.65–7.57(m, 9H, Ar H), 7.53–7.40 (m, 4H, Ar
H), 7.28 (s, 1H, C=CH), 4.98 (s, 1H, –NCHS). Anal.:
Calcd. for C29H20ClN3O4S: Calc C, 64.26; H, 3.72; N,
7.75. Found C, 64.31; H, 3.69; N, 7.77.
A mixture of (0.2 M, 42.4 g) biphenyl-4-carboxylic acid
methyl ester (2) and excess of hydrazine hydrate (0.30 M,
15 ml), ethanol (250 ml) was refluxed for about 3 h and
cooled. The solid was separated by filtration and recrystallized
from ethanol to afford biphenyl-4-carboxylic acid hydrazide.
Synthesis of biphenyl-4-carboxylic acid hydrazone (4a–r)
A mixture of (0.025 M, 5.3 g) biphenyl-4-carboxylic acid
hydrazide (3) and required aromatic aldehydes (0.025 M)
was refluxed in methanol (50 ml) in the presence of a cata-
lytic amount of glacial acetic acid for about 2 h. The mixture
was cooled; the solid was separated by filtration and recrys-
tallized from methanol to give the corresponding hydrazones.
N-[2-(4-Chloro-phenyl)-5-(4-chloro-benzylidene)-4-oxo-
thiazolidin-3yl]-biphenyl-4-carboxamide (6c)
White powder, yield 81%, m.p 257°C. IR (KBr, cm-1
)
3481 (N–H str amide1), 3037 (C–H str aromatic), 1651
(C=O str amide1), 1606–1483 (C=C str aromatic),
1447–1402 (C–N str), 778–601(C–Cl).1H NMR, (DMSO)
dppm 8.21–7.44(m, 9H, Ar H), 8.02 (s, 1H, –NH),
7.62–7.55 (m, 4H, Ar0 H), 7.56–7.41 (m, 4H, Ar H), 7.13
(s, 1H, C=CH), 4.97 (s, 1H, –NCHS). Anal.: Calcd. for
C29H20Cl2N2O2S: Calc C, 65.54; H, 3.79; N, 5.27. Found
C, 65.51; H, 3.74; N, 5.29.
Synthesis of 2,3-disubstituted-4-thiazolidinone (5a–r)
A mixture of (0.015 M) biphenyl-4-carboxylic acid hydra-
zone (4a–r) and required amount of thioglycolic acid
(0.015 M, 1.40 ml) in DMF (50 ml), containing a pinch of
anhydrous ZnCl2 was refluxed for about 6 h. The reaction
mixture was cooled and poured on to crushed ice. The solid
thus obtained was filtered, washed with water, and the
product was recrystallized from rectified spirit. Synthetic
pathway for formation of title compounds is presented in
Scheme 1. Characterization data of these compounds is
provided in Table 1.
N-[2-(4-Chloro-phenyl)-5-(3-bromo-benzylidene)-4-
oxothiazolidin-3yl]-biphenyl-4-carboxamide (6d)
White cystal, yield 79%, m.p 248°C. IR (KBr, cm-1) 3410
(N–H str amide1), 3035 (C–H str aromatic), 1651 (C=O str
amide1), 1606–1473 (C=C str aromatic), 1447–1403 (C–N
str), 784–632 (C–Cl), 554–513 (C–Br).1H NMR, (DMSO)
dppm 8.31–7.42 (m, 9H, Ar H), 8.03 (s, 1H, –NH),
7.59–7.33 (m 4H, Ar0 H), 7.01 (s, 1H, C=CH), 7.41–7.19 (m
4H, Ar, H). Anal.: Calcd. for C29H20BrClN2O2S: Calc C,
60.48; H, 3.50; N, 4.86. Found C, 60.49; H, 3.48; N, 4.89.
Synthesis of 2,3,5-trisubstituted-4-thiazolidinone (6a–r)
A mixture of (0.01 M) 2,3-disubstituted-4-thiazolidinone
(5a–r) required aromatic aldehydes (0.01 M) and anhy-
drous sodium acetate in glacial acetic acid (20 ml) and
123

Med Chem Res (2012) 21:1652–1659
1655
Table 1 Characterization data of synthesized compounds
Compound no.
Ar
Ar0
Mol. formula
(mol. wt)
Yield%
M.p (°C)
Microanalysis
C
H
N
6a
6b
6c
6d
6e
6f
4-ClC6H4
C6H5–
C29H21ClN2O2S
(497.01)
71
Calc
70.08
70.12
64.26
64.31
65.54
65.51
60.48
60.49
68.37
68.32
68.62
68.66
63.04
63.09
64.26
64.31
59.39
59.41
67.03
67.01
73.15
73.17
67.03
67.07
68.37
68.34
63.05
63.08
71.24
71.28
67.63
67.65
62.26
62.28
70.57
70.61
4.26
4.29
3.72
3.69
3.79
3.74
3.50
3.48
4.40
4.44
4.17
4.21
3.65
3.67
3.72
3.74
3.44
3.47
4.31
4.36
4.91
4.94
4.31
4.33
4.40
4.44
4.06
4.02
5.01
5.05
3.91
3.94
3.60
3.61
4.54
4.57
5.64
5.67
7.75
7.77
5.27
5.29
4.86
4.89
5.32
5.31
8.28
8.23
10.14
10.18
7.75
7.71
7.17
7.13
7.82
7.78
5.69
5.65
7.82
7.84
5.32
5.36
4.90
4.94
5.36
5.39
5.44
5.41
5.01
4.99
5.49
5.52
220
79
Found
Calc
4-ClC6H4
3-NO2C6H4
4-ClC6H4
3-BrC6H4
4-OCH3C6H4
C6H5–
C29H20ClN3O4S
(542.00)
250
81
Found
Calc
4-ClC6H4
C29H20Cl2N2O2S
(531.45)
257
79
Found
Calc
4-ClC6H4
C29H20BrClN2O2S
(575.90)
248
82
Found
Calc
4-ClC6H4
C30H23ClN2O3S
(527.03)
262
83
Found
Calc
3-NO2C6H4
3-NO2C6H4
3-NO2C6H4
3-NO2C6H4
3-NO2C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-FC6H4
C29H21N3O4S
(507.56)
221
87
Found
Calc
6g
6h
6i
3-NO2C6H4
4-ClC6H4
3-BrC6H4
4-OCH3C6H4
C6H5–
C29H20N4O6S
(552.26)
225
85
Found
Calc
C29H20ClN3O4S
(542.00)
202
69
Found
Calc
C29H20BrN3O4S
(586.46)
216
71
Found
Calc
6j
C30H23N3O5S
(537.59)
230
75
Found
Calc
6k
6l
C30H24N2O3S
(592.59)
245
81
Found
Calc
3-NO2C6H4
4-ClC6H4
3-BrC6H4
4-OCH3C6H4
4-ClC6H4
3-BrC6H4
4-OCH3C6H4
C30H23N3O5S
(537.59)
238
92
Found
Calc
6m
6n
6o
6p
6q
6r
C30H23ClN2O3S
(527.03)
242
77
Found
Calc
C30H23BrN2O3S
(571.48)
235
88
Found
Calc
C31H26N2O4S
(522.61)
32
Found
Calc
C29H20ClFN2O2S
(515.00)
83
247
82
Found
Calc
4-FC6H4
C29H20BrFN2O2S
(559.45)
236
87
Found
Calc
4-FC6H4
C30H23FN2O3S
(510.58)
223
Found
N-[2-(4-Chloro-phenyl)-5-(4-methoxy-benzylidene)-4-
oxothiazolidin-3-yl]-biphenyl-4-carboxamide (6e)
3H, –OCH3). Anal.: Calcd. for C30H23ClN2O3S: Calc C,
68.37; H, 4.40; N, 5.32. Found C, 68.32; H, 4.44; N, 5.31.
Off white powder, yield 82%, m.p 262°C. IR (KBr, cm-1
)
N-[2-(3-Nitro-phenyl)-5-benzylidene-4-oxo-thiazolidin-3-
yl]-biphenyl-4-carboxamide (6f)
3469 (N–H str amide1), 3032 (C–H str aromatic), 1653
(C=O str amide1), 1605–1484 (C=C str aromatic),
1447–1404 (C–N str), 1249 (C–O–C str), 776–607 (C–Cl).
1H NMR, (DMSO) dppm 8.14–7.42 (m, 9H, Ar H), 8.02 (s,
1H, –NH), 7.45–7.22 (m, 4H, Ar H), 7.12 (s, 1H, C=CH),
7.39–6.92 (m, 4H, Ar0, H), 4.60 (s, 1H, –NCHS), 3.48 (s,
Yellow powder, yield 83%, m.p 221°C. IR (KBr, cm-1
3429 (N–H str amide1), 3028 (C–H str aromatic), 1650
(C=O str amide1), 1606–1484 C=C str aromatic),
)
1
1446–1402 (C–N str), 1549 (N–O str, NO2). H NMR,
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Med Chem Res (2012) 21:1652–1659
(DMSO) dppm 8.32–7.40 (m, 9H, Ar H), 8.04 (s, 1H,
–NH), 7.78–7.33 (m, 4H, Ar0 H), 7.45–7.26 (m, 5H, Ar H),
7.01 (s, 1H, C=CH), 4.91 (s, 1H, –NCHS). Anal.: Calcd.
for C29H21N3O4S: Calc C, 68.62; H, 4.17; N, 8.28. Found
C, 68.66; H, 4.21; N, 8.23.
1H, –NH), 7.48–7.22 (m, 4H, Ar H), 7.39–6.93 (m, 4H,
Ar0, H), 7.00 (s, 1H, C=CH) 4.65(s, 1H, –NCHS), 3.51 (s,
3H, –OCH3). Anal.: Calcd. for C30H23N3O5S: Calc C,
67.03; H, 4.31; N, 7.82. Found C, 67.01; H, 4.36; N, 7.78.
N-[5-Benzylidene-2-(4-methoxy-phenyl)-4-oxo-thiazolidin-
3-yl]-biphenyl-4-carboxamide (6k)
N-[2-(3-Nitro-phenyl)-5-(3-nitro-benzylidene)-4-oxo-
thiazolidin-3-yl]-biphenyl-4-carboxamide (6g)
White crystal, yield 75%, m.p 245°C. IR (KBr, cm-1) 3431
(N–H str amide1), 3028 (C–H str aromatic), 1634 (C=O str
amide1), 1607–1484 (C=C str aromatic), 1446–1408 (C–N
str), 1280 (C–O–C str). 1H NMR, (DMSO) dppm
8.21–7.32 (m, 9H, Ar H), 8.04 (s, 1H, –NH), 7.40–7.21 (m,
4H, Ar H), 6.94 (s, 1H, C=CH), 7.18–6.99 (m, 4H, Ar0, H),
4.62 (s, 1H, –NCHS), 3.41 (s, 3H, –OCH3). Anal.: Calcd.
for C30H24N2O3S: Calc C, 73.15; H, 4.91; N, 5.69. Found
C, 73.17; H, 4.94; N, 5.65.
Yellow crystal, yield 87%, m.p 225°C. IR (KBr, cm-1
)
3452 (N–H str amide1), 3050 (C–H str aromatic), 1657
(C=O str amide1), 1606–1483 (C=C str aromatic),
1435–1403 (C–N str), 1528(N–O str, NO2). 1H NMR,
(DMSO) dppm 8.81–7.47 (m, 4H, Ar0 H), 8.04–7.39 (m,
9H, Ar H), 8.01 (s, 1H, –NH), 7.57–7.31 (m, 4H, Ar H),
7.04 (s, 1H, C=CH), 4.61 (s, 1H, –NCHS). Anal.: Calcd.
for C29H20N4O6S: Calc C, 63.04; H, 3.65; N, 10.14. Found
C, 63.09; H, 3.67; N, 10.18.
N-[2-(4-Methoxy-phenyl)-5-(3-nitro-benzylidene)-4-oxo-
thiazolidin-3-yl]-biphenyl-4-carboxamide (6l)
N-[2-(3-Nitro-phenyl)-5-(4-chlorobenzylidene)-4-oxo-
thiazolidin-3-yl]-biphenyl-4-carboxamide (6h)
Off yellow crystal, yield 81%, m.p 238°C. IR (KBr, cm-1
)
Yellow crystal, yield 85%, m.p 202°C. IR (KBr, cm-1
)
3357 (N–H str amide1), 3052 (C–H str aromatic), 1656
(C=O str amide1), 1607–1483 (C=C str aromatic),
1446–1402 (C–N str), 1528 (N–O str, NO2), 1269–1211
3469 (N–H str amide1), 3056 (C–H str aromatic), 1654
(C=O str amide1), 1605–1484 (C=C str aromatic),
1447–1403 (C–N str), 1538 (N–O str, NO2), 608–778 (C–
1
(C–O–C str). H NMR, (DMSO) dppm 8.63–7.39 (m, 4H,
1
Cl). H NMR, (DMSO) dppm 8.25–7.47 (m, 9H, Ar H),
Ar0 H), 8.11–7.36 (m, 9H, Ar H), 8.03 (s, 1H, –NH),
7.57–7.31 (m, 4H, Ar H), 7.09 (s, 1H, C=CH), 4.51 (s, 1H,
–NCHS) 3.46 (s, 3H, –OCH3). Anal.: Calcd. for
C30H23N3O5S: C, 67.03; H, 4.31; N, 7.82. Found C, 67.07;
H, 4.33; N, 7.84.
8.00 (s, 1H, –NH), 7.52–7.46 (m 4H, Ar H), 7.50–7.28 (m,
4H, Ar0 H), 7.18 (s, 1H, C=CH), 4.72 (s, 1H, –NCHS).
Anal.: Calcd. for C29H20ClN3O4S: Calc C, 64.26; H, 3.72;
N, 7.75. Found C, 64.31; H, 3.74; N, 7.71.
N-[2-(3-Nitro-phenyl)-5-(3-bromo-benzylidene)-4-oxo-
thiazolidin-3-yl]-biphenyl-4-carboxamide (6i)
N-[5-(4-Chloro-benzylidene)-2-(4-methoxy-phenyl)-4-
oxothiazolidin-3-yl]-biphenyl-4-carboxamide (6m)
Yellow powder, yield 69%, m.p 216°C. IR (KBr, cm-1) 3361
(N–H str amide1), 3033 (C–H str aromatic), 1653 (C=O str
amide1), 1608–1484(C=C str aromatic), 1417–1402 (C–N
str), 1580–1529 (N–O str, NO2), 624–508 (C–Br). 1H NMR,
(DMSO) dppm 8.33–7.42 (m, 9H, Ar H), 8.03 (s, 1H, –NH),
7.69–7.32 (m 4H, Ar H), 7.46–7.26 (m 4H, Ar0, H) 7.11 (s,
1H, C=CH), 4.79 (s, 1H, –NCHS). Anal.: Calcd. for
C29H20BrN3O4S: Calc C, 59.39; H, 3.44; N, 7.17. Found C,
59.41; H, 3.47; N, 7.13.
Off white powder, yield 92%, m.p 242°C. IR (KBr, cm-1
)
3432 (N–H str amide1), 3036 (C–H str aromatic), 1651
(C=O str amide1), 1606–1483 (C=C str aromatic),
1447–1403(C–N str), 1268 (C–O–C str), 778–603 (C–Cl).
1H NMR, (DMSO) dppm 8.31–7.48 (m, 9H, Ar H), 8.02 (s,
1H, –NH), 7.51–7.44 (m, 4H, Ar0 H), 7.50–7.28 (m 4H, Ar
H), 7.03 (s, 1H, C=CH), 4.77 (s, 1H, –NCHS) 3.49 (s, 3H,
–OCH3). Anal.: Calcd. for C30H23ClN2O3S: Calc C, 68.37;
H, 4.40; N, 5.32. Found C, 68.34; H, 4.44; N, 5.36.
N-[5-(4-Methoxy-benzylidene)-2-(3-nitro-phenyl)-4-
oxothiazolidin-3-yl]-biphenyl-4-carboxamide (6j)
N-[5-(3-Bromo-benzylidene)-2-(4-methoxy-phenyl)-4-
oxothiazolidin-3-yl]-biphenyl-4-carboxamide (6n)
Yellow powder, yield 71%, m.p 230°C. IR (KBr, cm-1
)
White powder, yield 77%, m.p 235°C. IR (KBr, cm-1) 3408
(N–H str amide1), 3036 (C–H str aromatic), 1650 (C=O str
amide1), 1607–1473 (C=C str aromatic), 1447–1404 (C–N
str), 1279–1218(C–O–C str), 553–503(C–Br). 1H NMR,
(DMSO) dppm 8.13–7.45 (m, 9H, Ar H), 8.03 (s, 1H, –NH),
3400 (N–H str amide1), 3039 (C–H str aromatic), 1655
(C=O str amide1), 1605–1484 (C=C str aromatic), 1412
(C–N str), 1546 (N–O str, NO2), 1269–1248 (C–O–C str).
1H NMR, (DMSO) dppm 8.15–7.49 (m, 9H, Ar H), 8.02 (s,
123

Med Chem Res (2012) 21:1652–1659
1657
7.61–7.41 (m, 4H, Ar0 H), 7.12–7.09 (m 4H, Ar H), 6.98 (s,
1H, C=CH), 4.65 (s, 1H, –NCHS) 3.51 (s, 3H, –OCH3).
Anal.: Calcd. for C30H23BrN2O3S: Calc C, 63.05; H, 4.06;
N, 4.90. Found C, 63.08; H, 4.02; N, 4.94.
Ar H),), 8.05 (s, 1H, –NH), 7.52–7.25, (m, 4H, Ar0 H), 7.03
(s, 1H, C=CH), 4.33 (s, 1H, –NCHS), 3.98 (s, 3H, –OCH3).
Anal.: Calcd. for C30H23FN2O3S: Calc C, 70.57; H, 4.54;
N, 5.49. Found C, 70.61; H, 4.57; N, 5.52.
N-[5-(4-Methoxy-benzylidene)-2-(4-methoxy-phenyl)-4-
oxothiazolidin-3-yl]-biphenyl-4-carboxamide (6o)
Anti-inflammatory screening
White powder, yield 88%, m.p 232°C. IR (KBr, cm-1
3312 (N–H str amide1), 2925 (C–H str aromatic), 1651
)
All the experimental procedures and protocols used in the
study were reviewed by the Institutional Animal Ethics
Committee and were in accordance with the guidelines of
the CPCSEA, Ministry of Forests and Environment, Govt.
of India. Anti-inflammatory activity of all title compounds
was carried out by carrageenan-induced rat paw edema test.
(Winter et al., 1962). Albino rats of either sex (150–200 g)
were divided into different groups, each containing six
individuals. Animals were fasted for 12 h before experi-
ment and only water was allowed. While the first group
was a control one and received vehicle sodium CMC (0.5%
w/v) 0.5 ml per rat, the second group received diclofenac
sodium 10 mg/1 kg body mass. All the remaining groups
received orally the test compounds at the same dose. All
the suspensions for oral dose were prepared in the vehicle
mentioned above and administered in a constant volume of
0.5 ml per rat. After 1 h of the administration of the test
compound and diclofenac sodium 0.1 ml of 1% w/v sus-
pension of carrageenan was injected into the subplanatar of
left paw of control and test animals. Immediately, the paw
volume was measured using plethismometer (initial paw
volume), there after the paw volume was measured every
half an hour till 3 h. The difference between initial and
subsequent readings gave the edema volume for the cor-
responding time. The percent anti-inflammatory activity
was calculated according to the formula as given below:
(C=O str amide), 1606–1484 (C=C str aromatic), 1417(C–
1
N str), 1275–1253 (C–O–C str). H NMR, (DMSO) dppm
8.22–7.43 (m, 9H, Ar H), 8.07 (s, 1H, –NH), 7.59–7.39 (m,
4H, Ar0 H), 7.52–7.31 (m 4H, Ar H), 7.12 (s, 1H, C=CH),
4.79 (s, 1H, –NCHS) 3.51 (s, 6H, –OCH3). Anal.: Calcd.
for C31H26N2O4S: Calc C, 71.24; H, 5.01; N, 5.36. Found
C, 71.28; H, 5.05; N, 5.39.
N-[5-(4-Chloro-benzylidene)-2-(4-fluoro-phenyl)-4-
oxothiazolidin-3-yl]-biphenyl-4-carboxylic acid amide (6p)
White crystal, yield 83%, m.p 247°C. IR (KBr, cm-1) 3317
(N–H str amide1), 3035 (C–H str aromatic), 1665 (C=O str
amide1), 1606–1474 (C=C str aromatic), 1447–1411 (C–N
str), 1233 (C–F), 608–778 (C–Cl). 1H NMR, (DMSO)
dppm 8.25–7.39 (m, 9H, Ar H), 8.03 (s, 1H, –NH),
7.59–7.36 (m, 4H, Ar0 H), 7.33–7.11 (m, 4H, Ar H), 7.09
(s, 1H, C=CH), 4.58 (s, 1H, –NCHS). Anal.: Calcd. for
C29H20ClFN2O2S: Calc C, 67.63; H, 3.91; N, 5.44. Found
C, 67.65; H, 3.94; N, 5.41.
N-[5-(3-Bromo-benzylidene)-2-(4-fluoro-phenyl)-4-
oxothiazolidin-3-yl]-biphenyl-4-carboxamide (6q)
Off white crystal, yield 82%, m.p 236°C. IR (KBr, cm-1
)
Percentage of inhibition of oedema ¼ ð1 ꢁ Vt=VcÞ100;
3298 (N–H str amide1), 3037 (C–H str aromatic), 1651
(C=O str amide1), 1605–1486 (C=C str aromatic),
1448–1402 (C–N str), 1226 (C–F), 554–502(C–Br). 1H
NMR, (DMSO) dppm 8.47–7.50(m, 9H, Ar H), 8.12–7.35
(m, 4H, Ar0 H), 8.02 (s, 1H, –NH), 7.51–7.35, (m, 4H, Ar
H), 7.21 (s, 1H, C=CH), 4.32 (s, 1H, –NCHS). Anal.:
Calcd. for C29H20BrFN2O2S: Calc C, 62.26; H, 3.60; N,
5.01. Found C, 62.28.; H, 3.61; N, 4.99.
where Vt and Vc are the volume of edema in right paw of
rats in the drug treated and control group, respectively.
Analgesic activity
Writhing test
Acetic acid-induced writhing model was employed to
evaluate the analgesic activity (Kazunaga et al., 1980). The
test compounds, standard, and vehicle were administered
orally to the mice and thereafter, 30 min later 0.7% acetic
acid solution was injected intraperitoneally. Diclofenac
sodium was used as standard drug. The mice were placed in
separate boxes under observation immediately after acetic
acid injection and the numbers of abdominal constrictions
were counted over a period of 20 min.
N-[5-(4-Methoxy-benzylidene)-2-(4-fluoro-phenyl)-4-
oxothiazolidin-3-yl]-biphenyl-4-carboxamide (6r)
White crystal, yield 87%, m.p 223°C. IR (KBr, cm-1) 3366
(N–H str amide1), 3031 (C–H str aromatic), 1656 (C=O str
amide1), 1604–1483 (C=C str aromatic), 1441–1412 (C–N
str), 1221 (C–F), 1276–1251 (C–O–C str). 1H NMR,
(DMSO) dppm 8.42–7.55(m, 9H, Ar H), 8.25–7.37 (m, 4H,
123

1658
Med Chem Res (2012) 21:1652–1659
Table 2 Anti-inflammatory and analgesic activity of title compounds
Compound no.
Anti-inflammatory activity (%)
Analgesic activity
Dose (mg/kg)
Dose (mg/kg)
2 h
4 h
Mean number
of writhing SEM
Protection (%)
6a
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
48.92
45.21
46.14
44.56
45.83
38.09
39.63
39.94
38.70
37.78
45.83
47.68
57.90
46.75
49.54
43.64
41.76
45.82
54.18
55.11
56.35
55.34
54.80
53.87
47.99
51.37
49.23
50.78
48.92
68.74
71.21
71.83
69.05
70.28
52.92
52.08
53.62
79.26
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
31.83 1.07**
29 1.15**
20.43
27.50
22.93
17.93
29.60
40.85
43.35
46.25
37.50
37.93
38.35
36.25
32.10
33.35
40.43
46.25
37.50
37.93
68.50
6b
6c
30.83 1.01**
32.83 1.42**
28.16 1.49**
23.66 1.05**
22.66 1.52**
21.5 1.14**
25 1.59**
6d
6e
6f
6g
6h
6i
6j
24.83 1.32**
24.66 1.13**
25.5 1.08**
27.16 1.90**
26.66 1.24**
23.83 1.24**
21.5 1.14**
25 1.59**
6k
6l
6m
6n
6o
6p
6q
6r
24.83 1.32**
12.6 0.71**
Diclofenac sodium
Values of paw thickness are mean SEM from six animals in each group, P \ 0.05
** P \ 0.01, compared with control
The percentage protection was calculated by employing
following formula and the results have been presented in
Table 2.
structure activity relationship of these compounds to be
employed as biologically useful agents.
No :of writhes in test
% Protection ¼ 100 ꢁ
ꢂ 100:
Results of anti-inflammatory and analgesic screening
No: of writhes in control
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