Aminocarbonyl arylvinylbenzamides as gastric sparing anti-inflammatory agents

Article abstract of DOI:10.1002/ardp.201000096

Some (E/Z)-aminocarbonyl arylvinylbenzamides (B1-B15) were synthesized, evaluated for anti-inflammatory activity and ulcerogenic tendency, and their effect on gastro-intestinal motility in the rats was studied. These benzamides comprising of aliphatic unsaturated region situated between two amide linkages were synthesized by nucleophilic ring opening of appropriate azlactones (AZ1-AZ4) by suitable amines. The characterization of newly synthesized benzamides was performed by IR, ¹H- and ¹³C-NMR, mass and elemental analysis. Amongst the tested compounds, benzamide B1, B2, B4, B5, and B13 were able to produce comparable or superior anti-inflammatory activity at 10 and 20 mg/kg p.o. dose with respect to standard diclofenac in carrageenan induced rat paw edema model with lessened propensity to cause gastro-intestinal hypermotility and were found to have nil tendencies to generate gastric ulcers. A series of N-[(E/Z)-2-(4-substituted/unsubstitutedphenyl)-1-{[arylamino] carbonyl} vinyl]benzamides (B1-B15) was synthesized by utilizing easily accessible starting material 4-substituted/unsubstituted benzylidene-2- phenyloxazol-5-one (AZ1-AZ4) and subjected to anti-inflammatory activity, gastrointestinal motility, and gastric damage studies in rats. Copyright

Full text of DOI:10.1002/ardp.201000096

292
Arch. Pharm. Chem. Life Sci. 2011, 11, 292–300
Full Paper
Aminocarbonyl Arylvinylbenzamides as Gastric Sparing
Anti-inflammatory Agents
Saurabh C. Khadse1, Gokul S. Talele2, and Surendra S. Agrawal1
1 Department of Pharmaceutical Chemistry, R.C. Patel Institute of Pharmaceutical, Education and Research,
Maharashtra, India
2 Nashik Gramin Shikshan Prasarak Mandal’s College of Pharmacy, Maharashtra, India
Some (E/Z)-aminocarbonyl arylvinylbenzamides (B1–B15) were synthesized, evaluated for anti-
inflammatory activity and ulcerogenic tendency, and their effect on gastro-intestinal motility in
the rats was studied. These benzamides comprising of aliphatic unsaturated region situated between
two amide linkages were synthesized by nucleophilic ring opening of appropriate azlactones
(AZ1–AZ4) by suitable amines. The characterization of newly synthesized benzamides was
1
performed by IR, H- and 13C-NMR, mass and elemental analysis. Amongst the tested compounds,
benzamide B1, B2, B4, B5, and B13 were able to produce comparable or superior anti-inflammatory
activity at 10 and 20 mg/kg p.o. dose with respect to standard diclofenac in carrageenan induced rat
paw edema model with lessened propensity to cause gastro-intestinal hypermotility and were found
to have nil tendencies to generate gastric ulcers.
Keywords: Aminocarbonyl arylvinylbenzamides / Gastro-intestinal hypermotility / Ulcerogenic tendency
Received: March 31, 2010; Revised: June 2, 2010; Accepted: June 7, 2010
DOI 10.1002/ardp.201000096
Introduction
prostaglandins (PGs) production, enhance gastric motility,
resulting in an increase in mucosal permeability and mye-
loperoxidase (MPO) activity, and eventually, gastric lesions
[6]. So evaluation of GI motility becomes important para-
meter while developing new anti-inflammatory agents.
The biological versatility of amides is well known, as many
compounds have been reported with the said structural
feature exhibiting sufficiently potent activity against several
ailments, viz. convulsions [7], psychosis [8], infectious diseases
due to microbes and helminthes [9], pain and inflammatory
disorders [10] and gastric motility dysfunction [11], all
these disorders cause concern to greater percent of popula-
tion worldwide.
Conventional anti-inflammatory drugs suffer from ulcero-
genic tendency, which has been the long-standing problem
for researchers, resulting in either withdrawal of therapy or
death of patients suffering from rheumatism, arthritis and
similar disorders due to gastrointestinal toxicity [1, 2]. On the
other hand, compounds which were introduced in market as
non-ulcerogenic anti-inflammatory drugs (COX-2 inhibitors)
have been withdrawn from the international market because
of the threat of causing cardiovascular and central nervous
systems side effects, associated with their long term use [3, 4].
Hence, search for potent and GI-sparing compounds with
ability to inhibit inflammatory responses is still under
progress.
Several benzamides have been reported to possess anti-
inflammatory activity, moreover, parsalmide a benzamide
derivative consisting of unsaturated region with anti-inflam-
matory property, is claimed to be a preferential COX-1 inhibi-
tor without ulcerogenic tendency [10]. Organic residues like
thiazole, morpholine and substituted phenyl ring has been
established to impart drug-like character to the molecule for
the modulations of inflammation [12, 13]. Required topolog-
ical characteristics for anti-inflammatory activity can be
acquired if desirable pharmacophoric features are incorpor-
ated within the molecule. Hence, it was attempted to
In the recent years, some reports have specified the role of
gastric hypermotility caused by NSAIDs in the development
of gastrointestinal lesions [5]. NSAIDs, at a dose that inhibits
Correspondence: Saurabh C. Khadse, R.C. Patel Institute of
Pharmaceutical Education & Research, Karvand Naka, Shirpur,
Dist.-Dhule, Maharashtra-425 405, India.
E-mail: khadse_s@rediffmail.com
Fax: þ91-2563255189
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Arch. Pharm. Chem. Life Sci. 2011, 11, 292–300
Aminocarbonyl Arylvinylbenzamides as Anti-inflammatory Agents
293
assemble fragments like heterocyclic residue, substituted
phenyl ring and unsaturated region around the amidic
linkage.
vibration band at v ¼ 1800–1760 cmꢀ1 and absence of any
band assignable for carboxylic -OH or amidic -NH function
supports the formation of an oxazolone (azlactone) cyclic
system. In contrast the IR spectrum of benzamides (B1–
B15) reveals the presence of carbonyl stretching band at
v ¼ 1665–1640 cmꢀ1 and amidic –NH function at v ¼
3280–3215 cmꢀ1 region. 1H-NMR spectra of all benzamide
compounds excluding compounds B1, B4, and B13 exhibit
two signals in singlet for two amidic protons at d ¼ 9–13.70
and compounds B1, B4, and B13 show a singlet for one amidic
proton at d ¼ 9.40–9.50. 13C-NMR spectra of oxazolones show
absorption of lactone carbonyl carbon at d ¼ 160.24–166.47
while imine carbon has got absorbed within d 157.20 to
161.12 ppm. All benzamides show two signals in singlet
for two amidic carbons at d ¼ 165.55–167.26. This spectral
data adequately supports the ring opening of oxazolone to
form title compounds with amidic -NH functions.
The significance of 5(4H)-oxazolones as intermediate in
organic synthesis is well documented, as these compounds
are flexible reagents for the synthesis of a-keto and arylacetic
acids, a-amino acids and peptides [14, 15]. It is well known
that ring opening of easily accessible 4-substituted-2-phenyl-
oxazol-5-one by nucleophillic attack leads to the formation of
benzamidic compounds [16, 17]. These facts prompted us to
synthesize some benzamides consisting of such structural
features beneficial for producing anti-inflammatory activity.
Results and discussion
Chemistry
In the present work, arylideneoxazolones (AZ1–AZ4) were
synthesized by the reaction of aromatic aldehydes and ben-
zoylglycine in acetic anhydride in the presence of sodium
acetate [18]. Subsequently, these oxazolones were subjected
to ring opening by the nucleophilic attack of amines having
labile hydrogen atoms to get the title compounds amino-
carbonyl arylvinylbenzamides (B1–B15, Scheme 1, Table 1).
All the synthesized compounds were characterized by their
physical properties and spectral data. The purity and hom-
ogeneity of synthesized compounds were confirmed by
single-spot TLC. Spectral analysis (IR, 1H-NMR and MS) of
the compounds adequately supported the structures of the
synthesized compounds. The IR spectrum of azlactones
shows presence of strong lactone carbonyl stretching
Pharmacology
Anti-inflammatory activity of the synthesized benzamides
(B1–B15) was determined by carrageenan induced rat paw
edema method [19]. Compounds which were found to be
most active in the rat paw edema test were subjected to
gastrointestinal toxicity studies. For all in-vivo tests diclofenac
was used as a reference compound.
The % inhibition of paw edema by compounds B1, B2, B4,
B5, and B13 was found to be far better than other benzamides
when administered at 10 and 20 mg/kg dose. Among the
most active compounds, B4 have shown better anti-inflam-
matory activity than standard diclofenac, whereas other
Scheme 1.
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Arch. Pharm. Chem. Life Sci. 2011, 11, 292–300
Table 1. Chemical structures, melting points and percent yields of benzamide compounds.
Compounds
B1
Ar
R
M.p. (8C)
Yield (%)
170–172
73
N
O
N
B2
B3
213–216
209–212
81
53
NH
S
CH
Cl
3
NH
B4
B5
187–190
220–223
79
88
Cl
Cl
N
O
N
NH
S
CH
Cl
3
B6
217–220
56
Cl
NH
B7
B8
245–248
242–245
76
49
NH
NH
F
CH3
CH3
Cl
CH3
N
CH3
CH3
N
B9
240–242
256–258
194–196
41
55
78
N
NH
CH3
S
CH3
B10
B11
NH
F
N
CH3
N
F
NH
S
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Arch. Pharm. Chem. Life Sci. 2011, 11, 292–300
Table 1. (continued )
Aminocarbonyl Arylvinylbenzamides as Anti-inflammatory Agents
295
Compounds
Ar
R
M.p. (8C)
Yield (%)
CH
3
B12
210–213
60
F
NH
Cl
O
B13
B14
B15
183–185
210–212
225–227
80
88
83
F
F
N
NH
OCH
OCH
3
3
Cl
NH
Table 2. Anti-inflammatory activity of benzamide compounds using carrageenan induced paw edema in rats.
Compounda)
Dose
(mg/kg)
% Inhibition of edemab),c)
1 h
2 h
3 h
4 h
5 h
6 h
Diclofenac
10
20
10
20
10
20
10
10
20
10
20
10
20
10
20
10
20
10
10
20
10
20
10
20
10
20
10
10
25.30 ꢁ 1.636
35.33 ꢁ 2.121
31.25 ꢁ 2.029
33.11 ꢁ 2.784
24.44 ꢁ 2.408
33.3 ꢁ 1.755
10.40 ꢁ 1.689
35.67 ꢁ 2.356
35.45 ꢁ 1.578
26.62 ꢁ 2.320
30.77 ꢁ 1.342
20.30 ꢁ 1.757
21.21 ꢁ 2.345
23.28 ꢁ 1.470
26.22 ꢁ 2.397
12.70 ꢁ 1.166
11.67 ꢁ 1.169
16.36 ꢁ 2.550
17.70 ꢁ 2.825
19.34 ꢁ 1.638
19.81 ꢁ 1.614
25.55 ꢁ 2.165
15.28 ꢁ 1.224
15.67 ꢁ 0.665
27.46 ꢁ 3.212
26.32 ꢁ 2.739
16.53 ꢁ 2.683
19.44 ꢁ 1.590
48.70 ꢁ 2.119
53.67 ꢁ 1.521
46.35 ꢁ 2.242
48.43 ꢁ 1.480
46.91 ꢁ 3.644
50.78 ꢁ 0.946
16.66 ꢁ 2.458
53.66 ꢁ 1.690
58.10 ꢁ 2.374
41.41 ꢁ 2.851
43.56 ꢁ 3.116
30.66 ꢁ 2.457
29.43 ꢁ 2.532
33.87 ꢁ 2.492
30.67 ꢁ 2.459
17.05 ꢁ 1.514
18.22 ꢁ 1.745
18.77 ꢁ 2.347
21.01 ꢁ 2.584
20.43 ꢁ 1.834
32.19 ꢁ 2.161
40.22 ꢁ 1.816
25.25 ꢁ 2.094
27.24 ꢁ 1.794
51.34 ꢁ 2.573
48.77 ꢁ 2.490
24.65 ꢁ 1.235
24.12 ꢁ 1.522
32.06 ꢁ 2.081
40.38 ꢁ 1.836
39.43 ꢁ 2.876
38.34 ꢁ 2.635
22.34 ꢁ 2.635
33.41 ꢁ 0.911
15.22 ꢁ 2.291
40.23 ꢁ 1.463
45.77 ꢁ 2.311
42.69 ꢁ 2.508
40.56 ꢁ 1.397
26.24 ꢁ 2.291
25.77 ꢁ 3.376
30.07 ꢁ 2.624
30.05 ꢁ 2.332
18.48 ꢁ 1.178
18.19 ꢁ 1.561
17.66 ꢁ 2.593
20.36 ꢁ 2.328
21.15 ꢁ 1.023
21.26 ꢁ 2.064
24.67 ꢁ 1.573
20.65 ꢁ 0.879
20.89 ꢁ 1.324
41.11 ꢁ 0.702
36.28 ꢁ 1.394
22.21 ꢁ 1.738
25.77 ꢁ 1.789
26.74 ꢁ 2.362
35.55 ꢁ 2.465
39.21 ꢁ 2.726
35.93 ꢁ 3.033
23.30 ꢁ 2.285
30.74 ꢁ 2.171
13.42 ꢁ 2.111
38.77 ꢁ 3.127
36.17 ꢁ 1.872
26.77ꢁ 0.988
29.81 ꢁ 2.212
20.42 ꢁ 3.119
21.24 ꢁ 2.659
24.38 ꢁ 1.947
23. 33 ꢁ 2.478
16.83 ꢁ 1.799
17.89 ꢁ 2.126
14.88 ꢁ 1.555
18.93 ꢁ 2.541
17.54 ꢁ 0.965
29.81 ꢁ 2.2
28.16 ꢁ 2.930
30.47 ꢁ 2.332
29.60 ꢁ 2.623
30.30 ꢁ 2.814
22.09 ꢁ 2.588
27.68 ꢁ 2.896
11.53 ꢁ 2.155
24.34 ꢁ 1.234
24.98 ꢁ 1.588
31.80 ꢁ 2.725
30.56 ꢁ 2.652
29.53 ꢁ 3.055
26.66 ꢁ 2.769
23.29 ꢁ 1.863
22.59 ꢁ 2.120
16.09 ꢁ 1.164
17.77 ꢁ 1.847
14.66 ꢁ 2.223
19.37 ꢁ 1.734
20.22 ꢁ 1.170
28.81 ꢁ 2.347
28 ꢁ 1.778
23.38 ꢁ 1.602
26.51 ꢁ 0.919
22.95 ꢁ 0.812
27.30 ꢁ 3.961
23.24 ꢁ 2.260
28.37 ꢁ 1.977
9.31 ꢁ 2.254
22.21 ꢁ 1.709
22.33 ꢁ 1.659
27.36 ꢁ 1.850
31.61 ꢁ 2.243
19.36 ꢁ 3.284
17.88 ꢁ 1.471
17.17 ꢁ 0.851
18.34 ꢁ 2.747
9. 69 ꢁ 1.153
12.56 ꢁ 1.894
13.33 ꢁ 1.502
13.77 ꢁ 0.854
15.12 ꢁ 1.025
22.32 ꢁ 1.421
23.43 ꢁ 0.836
16.16 ꢁ 1.232
17.17 ꢁ 0.941
20.22 ꢁ 1.478
18.65 ꢁ 1.543
10 ꢁ 0.892
B1
B2
B3
B4
B5
B6
B7
B8
B9
B10
B11
B12
B13
28.58 ꢁ 1.745
17.90 ꢁ 1.556
19.11 ꢁ 0.691
32.49 ꢁ 0.872
31.88 ꢁ 1.483
21.56 ꢁ 2.156
20.22 ꢁ 1.483
16.97 ꢁ 0.887
17.45 ꢁ 1.224
25.25 ꢁ 2.391
24.01 ꢁ 1.482
15.23 ꢁ 1.352
18.77 ꢁ 2.473
B14
B15
14.57 ꢁ 2.273
a)
Reference standard diclofenac and test compounds were administered orally to rats.b) Activity is expressed as % inhibition of paw
volume over control rats.c) All values are expressed as mean ꢁ SEM (n ¼ 6).
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Table 3. Effect of benzamides on GI motility and ulcerogenic
activity in rats.
Ulcerogenic
Distance
covered
activityc)
Treatmenta),b)
% Motilityc)
by charcoalc)
Lesion score
in mm
Controld)
Diclofenac
B1
B4
B5
B13
35.5 ꢁ 1.6
54.75 ꢁ 3.1
41.41 ꢁ 2
39 ꢁ 1.7
59.71 ꢁ 1.2
83.93 ꢁ 3.5ꢂꢂ
72.96 ꢁ 1.3ꢂ
69.05 ꢁ 1.2
65 ꢁ 0.81ꢂ
Nil
7 ꢁ 0.3
Nil
Nil
Nil
41.67 ꢁ 2.1
49.2 ꢁ 1.8
71.3 ꢁ 1.22ꢂꢂ
Nil
a)
A single oral dose of diclofenac and test compounds (100 mg/kg)
1 h prior to the administration of charcoal suspension to
determine GI motility. b) Dose of diclofenac and test compounds
c)
(100 mg/kg) for evaluating ulcerogenic activity. All values are
expressed as mean ꢁ SEM (n ¼ꢂ6 for both activities). d) Control is
Figure 1. Anti-inflammatory activity of diclofenac and benzamides
ꢂꢂ
0.5% carboxymethylcellulose. p < 0.05, p < 0.01.
at a 10 mg/kg dose in carrageenan-induced paw edema in rats.
rats. For the evaluation of GI hypermotility, test and refer-
ence compounds were subjected to charcoal meal method
[20], in which motility produced by the compounds was
measured as percent motility and were compared with the
control. The % motility produced by test compounds was
lesser than percent motility induced by diclofenac. When
same test compounds were subjected ulcerogenic activity
by acute gastric damage method [10, 21], the incidence of
gastric lesions were also found to be nil. For an evaluation of
anti-inflammatory activity, benzamide compounds were
administered in 10 and 20 mg/kg dose equivalent to the dose
of standard diclofenac in mg/kg. No death or abnormal
behavior of animals was observed in the group of animals
which were subjected to anti-inflammatory activity up to
15 days after the completion of study.
benzamides failed to produce desired inhibition of edema
when compared with standard (Table 2, Fig. 1)
While evaluating gastrointestinal toxicity profile we had
our focus on the importance of gastrointestinal hypermotil-
ity induced by NSAIDs, which is said to trigger the pathogenic
events leading to gastrointestinal lesions. The GI motility
(Fig. 2) and ulcerogenic activity of the compounds B1, B4,
B5, and B13 (Table 3) were assessed in vivo on albino Wistar
Conclusion
In conclusion, the preliminary results indicate that the syn-
thesized compounds consisting of heterocyclic residues such
as morpholine and thiazole, halogen substituted/unsubsti-
tuted phenyl ring and unsaturated region around the amide
linkages possess moderate to significant anti-inflammatory
property. When activity produced by benzamides containing
morpholine structural feature (B1, B4, and B13) was com-
pared with the activity produced by benzamides containing
thiazole structural feature (B2, B5, B9, and B11), it was found
that the former group produced greater anti-inflammatory
activity than the later group. Especially, halogen substituted
phenyl ring present in benzamides with morpholine struc-
tural feature are more active than other compounds in the
group. Interestingly, benzamides possessing fluoro substi-
tution on the phenyl ring (B11, B12, and B13) were not able
Figure 2. Representative images of rat intestine showing distance
covered by charcoal meal (indicated by arrow) following oral admin-
istration of diclofenac and test compounds at a 100 mg/kg dose.
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Arch. Pharm. Chem. Life Sci. 2011, 11, 292–300
Aminocarbonyl Arylvinylbenzamides as Anti-inflammatory Agents
297
160.85, 137.64, 129.17, 128.98, 128.51, 127.86, 127.49, 127.09,
126.67, 126.41, 113.74. CHN calcd. for C16H11NO2: C, 77.1; H, 4.45;
N, 5.62. Found: C, 77.05; H, 4.39; N, 5.52.
to produce enhanced anti-inflammatory activity than the
chloro substituted benzamides (B4, B5, and B6). On the other
hand presence of electron releasing groups like dimethyl-
amino, methyl, and methoxy on the phenyl ring around the
region of the amide linkages (in compounds B8, B9, B10, B14,
and B15) results in sharp decline in activity. Role of aliphatic
unsaturated region for the activity is unclear as all the com-
pounds have unsaturated region in their structure, although
it must be having further impact on delocalization of elec-
trons in the benzamide structure. Gastrointestinal motility
produce by the test compounds in the rats was found to be
less than motility produced in diclofenac treated rats, sub-
sequently tested benzamides were also found to be non-
ulcerogenic. Therefore, our study further indicates the
relationship between GI hypermotility and ulcerogenic
tendency of NSAIDs. So, this experimental result provides
further opportunity for several manipulations in the same
scaffold to improve the investigational outcome.
(Z/E)-4-(4-Chlorobenzylidene)-2-phenyl-1,3-oxazol-5(4H)-
one (AZ2)
M.p.: 190–1928C (58%, toulene, yellow crystalline); Rf: 0.58
(benzene/ethylacetate (4.9:0.1)). IR (KBr) cmꢀ1: 1796 (C O),
–
–
–
–
–
–
1649 (C N), 1765 (C C), 3065–3050 (Ar C–H), 3030 (olef. C–H),
1290 (C–O), 740 (C–Cl). 1H-NMR: (CDCl3): d (ppm) ¼ 7.44–7.95
(10H, m, 9 arom. H þ 1 olefinic CH). 13C-NMR: (CDCl3): d
(ppm) ¼ 166.47, 161.10, 142.10, 137.25, 132.47, 129.52, 129.16,
128.62, 128.55, 127.84, 126.77, 114.14. CHN calcd.
for C16H10ClNO2: C, 67.74; H, 3.55; N, 4.94. Found: C, 67.70; H,
3.66; N, 4.90.
(Z/E)-4-[4-(Dimethylamino)benzylidene]-2-phenyl-1,3-
oxazol-5(4H)-one (AZ3)
M.p.: 210–2128C (65%, acetonitrile, blood red crystalline); Rf: 0.71
(benzene/ethylacetate (4.9:0.1)). IR (KBr) cmꢀ1: 1783 (C O), 1644
–
–
–
–
–
–
(C N), 1760 (C C), 3080–3050 (Ar C–H), 3044 (olef. C–H), 1297
(C–O), 2906–2820 (aliph. C–H). 1H-NMR: (CDCl3): d (ppm) ¼ 3.05
(6H, s, –N(CH3)2), 6.70–7.95 (10H, m, 9 arom. H þ 1 olefinic CH).
13C-NMR: (CDCl3): d (ppm) ¼ 160.24, 157.20, 150.64, 130.51,
129.17, 127.49, 127.16, 126.67, 126.01, 124.92, 113.59, 111.95,
41.11. CHN calcd. for C18H16N2O2: C, 73.95; H, 5.52; N, 9.58.
Found: C, 73.98; H, 5.49; N, 9.56.
Experimental
Chemistry
All the chemicals used in this work were of laboratory grade and
were purchased from E. Merck Ltd., India, and Loba Chemical
Ltd., India. The melting points reported here-in are uncorrected
and were determined in open capillaries using Thiele’s melting
point apparatus. The yields of arylideneoxazolones (AZ1–AZ4)
are mentioned in braces along with respective melting points
and solvent used for crystallization. The melting points and
percent yield of the benzamides are specified in the Table 1.
Purity of the compounds was ascertained by single-spot TLC-
reports, which was developed using pre-coated Silica gel G plates.
IR spectra were recorded using KBr discs on Shimadzu 8400-S
FTIR and elemental analysis were carried out using FLASH EA
1112 CHN analyzer (Thermo Finnigan, Italy) and found within
ꢁ0.4 of theoretical values. The 1H-NMR spectra of synthesized
compounds were obtained using Mercury Plus 300 MHz NMR
Spectrometer, at IIT Powai, Mumbai while 13C-NMR spectra of the
compounds were recorded using Joel-FT-NMR spectrometer at
Institute of Science, Mumbai and the obtained chemical shifts
are reported in d ppm. Mass spectra of the compounds were
analyzed on VARIAN-500 mass spectrometer at IIT Powai,
Mumbai and JEOL SX 102/DA-600 mass spectrometer at CDRI,
Lucknow.
(Z/E)-4-(4-Fluorobenzylidene)-2-phenyl-1,3-oxazol-5(4H)-
one (AZ4)
M.p.: 168–1708C (80%, toulene, yellow crystalline); Rf: 0.54
(benzene/ethylacetate (4.9:0.1)). IR (KBr) cmꢀ1: 1800 (C O),
–
–
–
–
–
–
1650 (C N), 1772 (C C), 3070–3040 (Ar C–H), 3037 (olef. C–H),
1291 (C–O), 760 (C–F). 1H-NMR: (CDCl3): d (ppm) ¼ 7.18–7.95
(10H, m, 9 arom. H þ 1 olefinic CH). 13C-NMR: (CDCl3): d
(ppm) ¼ 166.47, 161.12, 160.05, 133.14, 132.47, 130.10, 129.16,
128.62, 128.55, 127.84, 126.77, 114.25. CHN calcd.
for C16H10FNO2: C, 71.91; H, 3.77; N, 5.24. Found: C, 71.94; H,
3.75; N, 5.20.
General procedure for the synthesis of benzamides
(B1–B15)
Equimolar quantity of arylideneoxazolones (AZ1, AZ2, and AZ4)
and appropriate amines in dry toluene were refluxed for about
2 h and allowed to cool overnight to obtain solid precipitate. The
precipitated solid was washed with 0.5 N HCl and then crystal-
lized with ethanol/DMF mixture (9:1) to get white crystalline
benzamides. Reaction of AZ3 with excess of amines was carried
out in dioxane (reflux for 4 to 6 h) to overcome the resistance of
AZ3 to react with amines due to less electrophilic nature of C-5.
Purity of these compounds was ascertained by single-spot TLC
(benzene/ethylacetate, 1:1)
Synthesis of arylideneoxazolones (AZ1–AZ4)
Azlactones (AZ1–AZ4) were conventionally synthesized by follow-
ing reported procedure [18].
(Z/E)-4-Benzylidene-2-phenyl-1,3-oxazol-5(4H)-one
(AZ1)
N-[(Z/E)-1-(Morpholin-4-yl) carbonyl-2-
phenylvinyl]benzamide (B1)
M.p.: 165–1678C (61%, benzene, yellow crystalline); Rf: 0.62
[benzene/ethylacetate (4.9:0.1)]. IR (KBr) cmꢀ1: 1793 (C O),
–
IR (KBr) cmꢀ1: 1658.8 (C O), 3215.4 (N–H), 1635.6 (C C), 3055–
–
–
–
–
1647 (C N), 1768 (C C), 3068–3058 (Ar C–H), 3039 (olef. C–H),
–
3022 (Ar C-H), 2999.4 (olef. C–H), 2885–2850 (aliph. C–H). 1H-NMR:
(DMSO-d6): d (ppm) ¼ 9.40 (1H, s, amide NH), 3.60 (4H, t, –CH2
morpholine), 2.95 (4H, t, –CH2 morpholine), 7.30–8.00
–
–
–
–
1296 (C–O). 1H-NMR: (CDCl3): d (ppm) ¼ 7.32–7.93 (11H, m, 10
arom. H þ 1 olefinic CH). 13C-NMR: (CDCl3): d (ppm) ¼ 165.75,
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(11H, m,10 arom. H þ 1 olefinic CH). 13C-NMR: (DMSO-d6): d
(ppm) ¼ 167.04, 165.75, 136.43, 134.25, 132.47, 129.52, 129.16,
128.62, 128.55, 127.84, 126.77, 115.29, 65.75, 45.11. MS: m/z
336 Mþ; CHN calcd. for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33.
Found: C, 71.38; H, 5.98; N, 8.35.
132.25, 131.77, 130.27, 129.16, 128.62, 128.55, 127.87, 126.77,
125.25, 123.80, 120.00, 115.29, 20.89. MS: m/z 424.12 Mþ; CHN
calcd. for C23H18Cl2N2O2: C, 64.95; H, 4.23; N, 6.59. Found: C,
64.96; H, 4.21; N, 6.60.
N-[(Z/E)-2-(4-Chlorophenyl)-1-{[(4-
fluorophenyl)amino]carbonyl}vinyl]benzamide (B7)
N-{(Z/E)-2-Phenyl-1-[(1,3-thiazol-2-yl)
aminocarbonyl]vinyl}benzamide (B2)
IR (KBr) cmꢀ1: 1645 (C O), 3215 (N–H), 1600 (C C), 3070-3050 (Ar
–
–
–
–
1
IR (KBr) cmꢀ1: 1643.41 (C O), 3273.31 (N–H), 1635.69 (C C),
C–H), 2990 (olef. C–H). H-NMR: (DMSO-d6): d (ppm)¼ 9.65, 10.60
(2H, s, s, amide -NH), 6.80–8.00 (14H, m, 13 arom. H þ 1 olefinic
CH). 13C-NMR: (DMSO-d6): d (ppm) ¼ 167.25, 166.05, 160.05,
138.15, 133.11, 133.00, 132.25, 131.77, 130.27, 129.16, 128.62,
128.55, 127.87, 126.77, 120.00, 115.29. MS: m/z 394.13 Mþ. CHN
calcd. for C22H14ClFN2O2: C, 66.92; H, 4.08; N, 7.10. Found: C,
66.90; H, 4.11; N, 7.12.
–
–
–
–
3072–3051 (Ar C–H), 2972.4 (olef. C–H). 1H-NMR: (DMSO-d6): d
(ppm) ¼ 9.74, 13.63 (2H, s, s, amide –NH), 7.20–8.04 (13H, m,
12 arom. H þ 1 olefinic CH). 13C-NMR: (DMSO-d6):
d
(ppm) ¼ 167.16, 165.75, 165.25, 134.25, 133.62, 132.66, 132.29,
129.52, 129.16, 128.62, 128.43, 127.86, 127.16, 115.29, 113.35.
MS: m/z 349.09 Mþ; CHN calcd. for C19H15N3O2S: C, 65.30; H, 4.32;
N, 12.00. Found: C, 64.98; H, 4.20; N, 12.04.
N-{(Z/E)-1-{[(3,5-Dimethylphenyl)amino]carbonyl}-2-[4-
(dimethylamino) phenyl]vinyl}benzamide (B8)
N-[(Z/E)-1-{[(3-Chloro-5-methylphenyl)amino]carbonyl}-2-
phenylvinyl]benzamide (B3)
IR (KBr) cmꢀ1: 1660.77 (C O), 3227 (N–H), 1601.93 (C C), 3072–
–
–
–
–
IR (KBr) cmꢀ1: 1652 (C O), 3232 (N–H), 1622 (C C), 3065–3040 (Ar
3060 (Ar C–H), 3000 (olef. C–H), 2930–2900 (aliph. C–H). 1H-NMR:
(DMSO-d6): d (ppm) ¼ 9.75, 9.90 (2H, s, s, amide –NH), 3.05 (6H, s,
N(CH3)2), 2.34 (6H, s, –CH3), 6.71–8.07 (13H, m, 12 arom. H þ 1
olefinic CH). 13C-NMR: (DMSO-d6): d (ppm) ¼ 167.10, 165.55,
150.64, 138.65, 134.17, 130.51, 129.17, 127.49, 127.10, 126.67,
126.11, 124.92, 123.22, 122.00, 115.01, 111.95, 41.11, 20.75. MS:
m/z 413.20 Mþ; CHN calcd. for C26H27N3O2: C, 75.50; H, 6.60; N,
10.16. Found: C, 75.52; H, 6.56; N, 10.20.
–
–
–
–
1
C–H), 2985 (olef. C–H), 2870–2830 (aliph. C–H). H-NMR: (DMSO-
d6): d (ppm) ¼ 9.60, 10.40 (2H, s, s, amide –NH), 2.34 (3H, s, –CH3),
6.70–8.00 (14H, m, 13 arom. H þ 1 olefinic CH). 13C-NMR: (DMSO-
d6): d (ppm) ¼ 167.25, 166.05, 136.19, 134.19, 133.22, 132.90,
132.20, 131.77, 129.16, 129.10, 128.62, 128.55, 127.84, 126.77,
125.25, 123.80, 120.00, 115.29, 20.89. MS: m/z 390.11 Mþ. CHN
calcd. for C23H19ClN2O2: C, 70.68; H, 4.90; N, 7.17. Found: C,
70.71; H, 4.89; N, 7.19.
N-{(Z/E)-2-[4-(Dimethylamino)phenyl]-1-[(1,3-thiazol-2-yl)
aminocarbonyl]vinyl} benzamide (B9)
N-[(Z/E)-2-(4-Chlorophenyl)-1-(morpholin-4-yl)
carbonylvinyl]benzamide (B4)
IR (KBr) cmꢀ1: 1660 (C O), 3230 (N-H), 1600 (C C), 3072–3060 (Ar
–
–
–
–
1
IR (KBr) cmꢀ1: 1648 (C O), 3222 (N–H), 1625.5 (C C), 3060–3030
C–H), 3000 (olef. C–H), 2930–2900 (aliph. C–H). H-NMR: (DMSO-
d6): d (ppm) ¼ 9.60, 13.55 (2H, s, s, amide -NH), 3.05 (6H, s,
N(CH3)2), 6.70–8.00 (12H, m, 11 arom. H þ 1 olefinic CH). 13C-
NMR: (DMSO-d6): d (ppm) ¼ 167.07, 165.49, 165.25, 150.64,
134.25, 130.51, 129.17, 127.49, 127.16, 126.67, 126.11, 124.92,
115.01, 113.59, 111.95, 41.11. MS: m/z 392.13 Mþ; CHN calcd.
for C21H20N4O2S: C,64.27; H, 5.14; N, 14.28. Found: C, 64.28; H,
5.12; N, 14.30.
–
–
–
–
(Ar C–H), 2990.4 (olef. C–H), 2885–2850 (aliph. C–H). 1H-NMR:
(DMSO-d6): d (ppm) ¼ 9.50 (1H, s, amide NH), 3.60 (4H, t, –CH2
morpholine), 3.00 (4H, t, –CH2 morpholine), 7.40–8.05 (10H, m, 9
arom. H þ 1 olefinic CH). 13C-NMR: (DMSO-d6): d (ppm) ¼ 167.04,
165.75, 137.25, 134.26, 132.75, 129.52, 129.16, 128.62, 128.55,
127.84, 126.77, 115.29, 65.75, 45.11. MS: m/z 370 Mþ; CHN calcd.
for C20H19ClN2O3: C, 64.79; H, 5.17; N, 7.50. Found: C, 64.82; H,
5.18; N, 7.67.
N-{(Z/E)-1-{[(4-Fluorophenyl)amino]carbonyl}-2-[4-
(dimethylamino) phenyl] vinyl} benzamide (B10)
N-{(Z/E)-2-(4-Chlorophenyl)-1-[(1,3-thiazol-2-yl)
aminocarbonyl]vinyl} benzamide (B5)
IR (KBr) cmꢀ1: 1648 (C O), 3220(N–H), 1610 (C C), 3070–3050 (Ar
–
–
–
–
1
IR (KBr) cmꢀ1: 1646 (C O), 3250 (N–H), 1620 (C C), 3070–3040 (Ar
C–H), 2995 (olef. C–H), 2930–2900 (aliph. C–H). H-NMR: (DMSO-
d6): d (ppm) ¼ 9.65, 10.40 (2H, s, s, amide -NH), 3.00 (6H, s,
N(CH3)2), 6.70–8.00 (14H, m, 13 arom. H þ 1 olefinic CH).
13C NMR: (DMSO-d6): d (ppm) ¼ 167.10, 165.55, 160.05, 150.64,
138.49, 134.17, 130.51, 129.17, 127.49, 127.10, 126.67, 126.02,
124.92, 120.12, 115.01, 111.95, 41.11. MS: m/z 403.13 Mþ; CHN
calcd. for C24H22FN3O2: C,71.45; H, 5.50; N, 10.42. Found: C,
71.42; H, 5.53; N, 10.44.
–
–
–
–
C–H), 2990 (olef. C–H), 734.19 (Ar C–Cl). 1H-NMR: (DMSO-d6): d
(ppm) ¼ 9.63, 13.50 (2H, s, s, amide –NH), 7.30–8.00 (12H, m, 11
arom. H þ 1 olefinic CH). 13C-NMR: (DMSO-d6): d (ppm) ¼ 167.16,
165.75, 165.25, 134.86, 133.62, 132.66, 132.29, 129.52, 129.16,
128.62, 128.43, 127.86, 127.16, 115.29, 113.35. MS: m/z 383 Mþ;
CHN calcd. for C19H14ClN3O2S: C, 59.40; H, 3.68; N, 10.95. Found:
C, 59.34; H, 3.66; N, 10.98.
N-[(Z/E)-1-{[(3-Chloro-5-methylphenyl)amino]carbonyl}-2-
(4-chlorophenyl) vinyl]benzamide (B6)
N-{(Z/E)-2-(4-Fluorophenyl)-1-[(1,3-thiazol-2-yl)
aminocarbonyl]vinyl}benzamide (B11)
IR (KBr) cmꢀ1: 1652 (C O), 3230 (N-H), 1622 (C C), 3065–3040 (Ar
IR (KBr) cmꢀ1: 1646.16 (C O), 3260 (N–H), 1600.97 (C C), 3070–
–
–
–
–
–
–
–
–
1
C–H), 2985 (olef. C–H), 2870–2830 (aliph. C–H). H-NMR: (DMSO-
d6): d (ppm) ¼ 9.60, 10.40 (2H, s, s, amide –NH), 2.34 (3H, s, –CH3),
7.16–8.00 (13H, m, 12 arom. H þ 1 olefinic CH). 13C-NMR: (DMSO-
d6): d (ppm) ¼ 167.25, 166.05, 140.40, 137.05, 133.22, 132.90,
3056 (Ar C–H), 2998 (olef. C–H). 1H-NMR: (DMSO-d6):
d
(ppm) ¼ 9.75, 13.65 (2H, s, s, amide -NH), 7.30–8.05 (12H, m,
11 arom. H þ 1 olefinic CH). 13C-NMR: (DMSO-d6):
d
(ppm) ¼ 167.16, 165.75, 165.25, 160.05, 133.16, 132.29, 129.52,
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Arch. Pharm. Chem. Life Sci. 2011, 11, 292–300
Aminocarbonyl Arylvinylbenzamides as Anti-inflammatory Agents
299
129.78, 128.62, 128.43, 127.86, 127.45, 118.22, 115.29, 113.35.
MS: m/z 367.1 Mþ; CHN calcd. for C19H14FN3O2S: C, 62.10; H, 3.82;
N, 11.42. Found: C, 62.08; H, 3.84; N, 11.46.
IAEC/2008-09/29) constituted for the purpose of control
and supervision of experimental animals by Ministry of
Environment and Forests, Government of India, New Delhi.
N-[(Z/E)-1-{[(3-Chloro-5-methylphenyl)amino]carbonyl}-2-
(4-fluorophenyl) vinyl] benzamide (B12)
Anti-inflammatory activity
Anti-inflammatory activity of the synthesized benzamides was
determined by carrageenan induced rat paw edema method [19].
Inflammation was induced by injecting 0.1 mL of 1% carra-
geenan sodium salt (Sigma) subcutaneously in the sub-plantar
region of the rat right hind paw. Standard and test compounds
were administered to the respective group orally and vehicle (1%
CMC in distilled water) to control groups, 30 min before carra-
geenan injection. The hind paw volume was measured plethys-
mometrically (UGO Basile-7140) after the carrageenan injection,
at hourly intervals for 6 h and percent inhibition was calculated
using the following formula:
IR (KBr) cmꢀ1: 1652 (C O), 3230 (N–H), 1622 (C C), 3065–3040 (Ar
–
–
–
–
1
C–H), 2985 (olef. C–H), 2870–2830 (aliph. C–H). H-NMR: (DMSO-
d6): d (ppm) ¼ 9.45, 10.30 (2H, s, s, amide –NH), 2.30 (3H, s,–CH3),
7.00–8.00 (13H, m, 12 arom. H þ 1 olefinic CH). 13C-NMR: (DMSO-
d6): d (ppm) ¼ 167.25, 166.05, 160.05, 137.86, 133.25, 133.16,
132.27, 131.77, 130.27, 129.16, 128.62, 128.55, 127.87, 126.77,
125.25, 123.80, 120.00, 115.30, 20.89. MS: m/z 408.08 Mþ; CHN
calcd. for C23H18ClFN2O2: C, 67.56; H, 4.44; N, 6.85. Found: C,
67.60; H, 4.40; N, 6.82.
N-[(Z/E)-2-(4-Fluorophenyl)-1-(morpholin-4-
yl)carbonylvinyl]benzamide (B13)
% of inhibition of edema ¼ ð1ꢀVt=VcÞ ꢃ 100 (1)
where Vt and Vc are the volume of edema in paw of rats in the
drug treated and control group respectively.
IR (KBr) cmꢀ1: 1650 (C O), 3225 (N–H), 1628 (C C), 3060–3030 (Ar
–
–
–
–
1
C–H), 2993 (olef. C–H), 2880–2850 (aliph. C–H). H-NMR: (DMSO-
d6): d (ppm) ¼ 9.50 (1H, s, amide NH), 3.66 (4H, t, -CH2 morpho-
line), 2.90 (4H, t, -CH2 morpholine), 7.40–8.00 (10H, m, 9 arom.
H þ 1 olefinic CH). 13C-NMR: (DMSO-d6): d (ppm) ¼ 167.04,
165.75, 160.05, 134.52, 132.75, 130.15, 129.16, 128.62, 128.55,
127.84, 126.77, 115.29, 65.75, 45.11. MS: m/z 354.10 Mþ; CHN
calcd. for C20H19FN2O3: C, 67.79; H, 5.40; N, 7.91. Found: C, 67.76;
H, 5.38; N, 7.94.
GI motility
The percent motility was evaluated in vivo on albino Wistar rats of
either sex, weighing 150–200 g, determining the influence of the
products on the gastrointestinal motility after ingesting a char-
coal meal, according to the reported method [20]. This method
involved the administration of a charcoal meal to the rats after
18 h fast, through the oral feeding probe, 1 h after the admin-
istration of the test compounds (100 mg/kg). Animals were sac-
rificed by cervical dislocation 20 min after administration of the
charcoal meal to remove the stomach and the small intestine.
The small intestine was uncoiled without stretching it to
measure the distance covered by the charcoal, and the total
length of the small intestine. The percent motility was calculated
by applying the following formula:
N-[(Z/E)-2-(4-Fluorophenyl)-1-{[(4-
methoxyphenyl)amino]carbonyl}vinyl]benzamide (14)
IR (KBr) cmꢀ1: 1651.12 (C O), 3220.2 (N–H), 1601.9 (C C), 3090–
–
–
–
–
3070 (Ar C–H), 3001 (olef. C–H), 2870–2830 (aliph. C–H). 1H-NMR:
(DMSO-d6): d (ppm) ¼ 9.80, 10.50 (2H, s, s, amide –NH), 3.80 (3H, s,
OCH3), 6.90–8.00 (14H, m, 13 arom. H þ 1 olefinic CH). 13C-NMR:
(DMSO-d6): d (ppm) ¼ 167.26, 166.00, 160.05, 153.97, 133.00,
132.25, 130.15, 129.77, 129.16, 128.62, 128.35, 127.87, 121.88,
115.29, 115.10, 114.16, 52.51. MS: m/z 390.13 Mþ; CHN calcd.
for C23H19FN2O3: C, 70.76; H, 4.91; N, 7.18. Found: C, 70.88; H,
4.99; N, 7.04.
% motility ¼ C=SI ꢃ 100 (2)
where C is the distance (cm) covered by the charcoal and SI means
the total length of the small intestine (cm).
N-[(Z/E)-2-(4-chlorophenyl)-1-{[(4-
methoxyphenyl)amino]carbonyl}vinyl]benzamide(15)
Ulcerogenic activity
Ulcerogenic activity was evaluated by acute gastric damage
method [10, 21]. Rats weighing 150–200 g were deprived of food,
but not water, for 18 h and were then given group wise diclo-
fenac and the compounds to be examined orally at the dose of
100 mg/kg. A further group was treated with an equal volume of
the vehicle. Each group was made up of six rats. The rats were
killed after 6 h of dosing and the stomach was excised and
opened by an incision along the greater curvature. The
extent of macroscopic damage was determined by an observer
unaware of the treatments that the rats received. The method
involved measuring the length of the lesions in millimeters and
then summing the length of all lesions observed in each
stomach.
IR (KBr) cmꢀ1: 1652 (C O), 3221 (N–H), 1602.3 (C C), 3070–3040
–
–
–
–
(Ar C–H), 2985 (olef. C–H), 2865–2830 (aliph. C–H). 1H-NMR:
(DMSO-d6): d (ppm) ¼ 9.75, 10.55 (2H, s, s, amide -NH), 2.34
(3H, s, –CH3), 7.16–8.00 (13H, m, 12 arom. H þ 1 olefinic CH).
13C-NMR: (DMSO-d6): d (ppm) ¼ 167.26, 166.00, 153.97, 139.87,
133.16, 132.25, 130.15, 129.57, 129.16, 128.62, 127.95, 127.86,
122.10, 115.29, 115.10, 114.16, 52.51. MS: m/z 406.17 Mþ; CHN
calcd. for C23H19ClN2O3: C, 67.90; H, 4.71; N, 6.89. Found: C,
67.93; H, 4.69; N, 6.91.
Animal studies
Wistar albino rats of both sexes, weighing 150–200 g were sub-
jected to all the pharmacological testing. Animals were main-
tained under standard conditions during the course of
experimentation. The employed experimental protocols were
as per the ethical principles and guidelines, and approved by
Institutional Animal Ethical Committee (resolution no. -RCPIPER/
Statistical analysis
Statistical analysis was performed by using Graph Pad Prism 4
software. Data was analyzed by one way variance (ANOVA) fol-
lowed by Dunnett’s test. Data are presented as arithmetic
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300
S. C. Khadse et al.
Arch. Pharm. Chem. Life Sci. 2011, 11, 292–300
mean ꢁ SEM, where a p value of <0.05 was considered as sta-
[10] G. Caliendo, V. Santagada, E. Perissutti, B. Severino, F.
Fiorino, T. D. Warner, J. L. Wallace, D. R. Ifa, E. Antunes,
G. Cirino, G. Nucci, Eur. J. Med. Chem. 2001, 36, 517–
530.
tistically significant.
The authors wish to thank, Management, R.C. Patel Institute of
Pharmaceutical Education and Research, Shirpur, for providing
necessary laboratory facilities. Words of gratitude are also expressed for
IIT Powai, Mumbai and CDRI, Lucknow for providing NMR and Mass
spectra of the compounds
[11] H. Harada, H. Yamazaki, Y. Toyotomi, H. Tateishi, Y. Mine,
N. Yoshida, S. Kato, Bioorg. Med. Chem. Lett. 2002, 12, 967–
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The authors have declared no conflict of interest.
[13] A. S. Michaellidou, D. Hadjipavlou-Litina, Chem. Rev. 2005,
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ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com