Synthesis, anti-inflammatory and analgesic activities of arylidene-2-(3-chloroanilino)nicotinic acid hydrazides

Article abstract of DOI:10.1007/s00044-013-0860-5

A new series of 2-(3-chloroanilino)nicotinic acid hydrazides 12a-p were synthesized and evaluated for their anti-inflammatory and analgesic activities. Most of the compounds have shown anti-inflammatory activity with a moderate-to-excellent activity range. Among them, 3-chloro 12d and 4-methoxyphenyl derivatives 12i exhibited the most potent anti-inflammatory activity relative to niflumic acid as the reference drug (95, 87, and 81 % reductions in inflammation, respectively). The compounds with the highest anti-inflammatory activity were subjected to analgesic assay and showed moderate-to-excellent analgesic activities. The 2,4-dimethoxyphenyl derivative (12j) exhibited the highest analgesic activity relative to niflumic acid (99.6 and 68 % activity, respectively).

Full text of DOI:10.1007/s00044-013-0860-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0860-5
ORIGINAL RESEARCH
Synthesis, anti-inflammatory and analgesic activities
of arylidene-2-(3-chloroanilino)nicotinic acid hydrazides
•
Latifeh Navidpour Hamed Shafaroodi
•
•
Ghazaleh Saeedi-Motahar Abbas Shafiee
Received: 22 May 2013 / Accepted: 17 October 2013
Ó Springer Science+Business Media New York 2013
Abstract A new series of 2-(3-chloroanilino)nicotinic
acid hydrazides 12a–p were synthesized and evaluated for
their anti-inflammatory and analgesic activities. Most of
the compounds have shown anti-inflammatory activity with
a moderate-to-excellent activity range. Among them,
3-chloro 12d and 4-methoxyphenyl derivatives 12i exhib-
ited the most potent anti-inflammatory activity relative to
niflumic acid as the reference drug (95, 87, and 81 %
reductions in inflammation, respectively). The compounds
with the highest anti-inflammatory activity were subjected
to analgesic assay and showed moderate-to-excellent
analgesic activities. The 2,4-dimethoxyphenyl derivative
(12j) exhibited the highest analgesic activity relative to
niflumic acid (99.6 and 68 % activity, respectively).
prostaglandin H2 endoperoxide synthase or cyclooxygen-
ase (Vane and Botting, 1998). Its constitutive isoform,
namely COX-1, is related to homeostatic functions, such as
gastric mucosal cytoprotection, renal blood flow regula-
tion, and vascular antithrombotic activity; while its
inducible isoform, COX-2, is overexpressed under stress
conditions, although constitutive in a few tissues (Vane and
Botting, 1998; Simmons et al., 2004). Since most of the
currently available NSAIDs in the markets show greater
selectivity for COX-1 than for COX-2 (Jackson and
Hawkey, 1999), long-term usage of NSAIDs is associated
with significant side effects of gastrointestinal, bleeding,
and nephrotoxicity (Vandraas et al., 2010) which cause
some patients to abandon NSAID therapy. Therefore, the
discovery of new safer anti-inflammatory drugs represents
a challenging goal for such a research area.
Keywords Hydrazone ꢀ Anti-inflammatory ꢀ Analgesic
Some pyridine compounds such as aminopyridylmeth-
anols and aminomethyl-pyridinamines (Sondhi et al., 2002)
have been found useful as analgesic, as well as anti-
inflammatory agents, and for treating Alzheimer’s disease
(Effland and Klein, 1991). The pyridine nucleus is present
in niflumic acid (1) and flunixin (2), the two traditional
NSAIDs belonging to the class of fenamates (Fig. 1).
These drugs are derivatives of N-phenyl (or heteroaryl)
anthranilic acid, which are clinically prescribed for their
analgesic, anti-inflammatory, and anti-pyretic properties.
Unlike aspirin and most NSAIDs, the fenamates do not
affect platelet aggregation and bleeding time, but are still
endowed of most of the adverse effects induced by NSA-
IDs, particularly gastrointestinal bleeding, ulceration, and
perforation (Cocco et al., 2004).
Introduction
The nonsteroidal anti-inflammatory drugs (NSAIDs) are
widely used for treatment of pain, pyrexia, inflammation,
rheumatoid arthritis, and osteoarthritis (Bacchi et al., 2012;
Rubio-Perez and Morillas-Ruiz, 2012). NSAIDs block the
biosynthesis of prostaglandins by inhibiting enzyme
L. Navidpour (&) ꢀ A. Shafiee
Department of Medicinal Chemistry, Faculty of Pharmacy and
Drug Design and Development Research Center, Tehran
University of Medical Sciences, 14176 Tehran, Iran
e-mail: navidpur@sina.tums.ac.ir
Regarding GI damage of NSAIDs, two factors are
generally considered: local irritation by the direct contact
of carboxylic acid (–COOH) moiety of NSAIDs with GI
mucosal cells (topical effect), and decreased tissue
H. Shafaroodi ꢀ G. Saeedi-Motahar
Pharmacology and Toxicology Department, Pharmaceutical
Sciences Branch and Pharmaceutical Sciences Research Center,
Islamic Azad University, Tehran, Iran
123

Med Chem Res
prostaglandin production in tissues which attenuates the
physiological cytoprotective role of prostaglandins in
maintaining GI health and homeostasis (Smith et al., 1998;
Hawkey et al., 2000).
(3–4) improves their analgesic activity (Fig. 2) (Matheus
et al., 1991; Simmons et al., 2004; Lacerda, 2012).
Considering the above approach, in recent studies, we
have found that niflumic acid-based N-acylhydrazone
derivatives (6) show significant anti-inflammatory and
analgesic activities, comparable with niflumic acid as the
reference drug (Kheradmand et al., 2013). Hence, as a part
of our ongoing program (Almasirad et al., 2005, 2006;
Moradi et al., 2010; Kheradmand et al., 2013), we describe
herein the synthesis, and biological evaluation of a novel
diverse group of N-acylarylhydrazone derivatives of 2-(3-
chloroanilino)nicotinic acid with different substituents on
the terminal phenyl (or heteroaryl) ring as anti-inflamma-
tory and analgesic agents. Therefore, the effect of substi-
tution of trifluoromethyl (Kheradmand et al., 2013) with
chlorine group on aniline moiety, which provides slightly
less lipophilic compounds, on their anti-inflammatory and
analgesic activities was investigated.
Synthetic approaches based on chemical modification of
NSAIDs have been considered with the aim of improving
safety profile of these NSAIDs. Several studies have
described the derivatization of carboxylic acid function
with amide or N-acylarylhydrazone moieties having less
acidic amide hydrogen (Fig. 2) (Bala et al., 2013; Alm-
asirad et al., 2005; Almasirad et al., 2006). On the other
hand, some evidences suggest that the hydrazone moiety
possesses a pharmacophoric character for the inhibition of
cyclooxygenase and the presence of a N-heteroaromatic
ring having less hydrophobic character in N-acyl moiety
COOH
NH
COOH
NH
N
N
Results and discussion
CH3
CF3
2 (Flunixin)
Chemistry
CF3
1 (Niflumic acid)
The synthetic reactions leading to the substituted arylidene-
2-(3-chloroanilino)nicotinic acid hydrazides (12a–p) are
outlined in Scheme 1.
Fig. 1 Representative examples of pyridine derivatives of fenamates
CH3
N
O
O
CH3
O
H
N
N
O
O
N
N
S
N
H
NH
NH
N
H
N
H
N
N
5. LASSBio-294
3
4
O
O
Ar
N
Ar
N
NH
NH
NH
NH
H
H
N
N
Cl
CF3
6
12 (designed compounds)
Fig. 2 Representative examples of hydrazone derivatives (3–6) and designed compounds 12
123

Med Chem Res
O
O
O
C
OCH2CH3
NH
NH2
OH
NH
b
OH
a
N
N
+
N
Cl
Cl
Cl
Cl
7
8
10, 82%
9, 94%
3''
X
4''
2''
O
O
O
4
5''
Het
N
N
NH NH2
NH
NH
5
6
NH
6''
d
c
H
H
N
N
NH
N
NH
or
2'
6'
5'
Cl
11, 88%
Cl
Cl
4'
12a-p, 50-96%
Scheme 1 Reagents and conditions: a NaI 140 °C, 1 h, then 100 °C, 2 h; and b H2SO4, abs. EtOH, reflux, 72 h; c N2H4ꢀH2O, abs. EtOH, r.t.,
24 h; d Ar-CHO, abs. EtOH, HCl (2 drops), r.t., 24 h
2-(3-Chloroanilino)nicotinic acid hydrazide (11) is the
key intermediate for the production of the title compounds
12. The starting material, 2-(3-chloroanilino)nicotinic acid
(9), was prepared by the reaction of 2-chloronicotinic acid
(7) with an excess amount of 3-chloroaniline (8) in the pre-
sence of catalytic amount of sodium iodide (Hoffmann and
Faure, 1968). Esterification of 9 using general acid-catalyzed
method afforded the ethyl ester 10 (Kamal et al., 2007).
Treatment of 10 with hydrazine hydrate in absolute ethanol
generated the required hydrazide 11 (Kamal et al., 2007).
Title hydrazone compounds (12a–p) were prepared by
the condensation of hydrazide 11 with different substituted
aromatic aldehydes in absolute ethanol.
Interestingly, the compounds were shown to have dif-
ferent pharmacokinetic parameters, and hence, these
compounds have shown their maximum activity at differ-
ent time intervals. Therefore, they have been compared at
their maximum anti-inflammatory activity (Table 1, last
column).
First, the substituents on the terminal phenyl moiety,
attached to the imine functional group of title compounds
12a–p were rationally selected to acquire information
about the influence of electronic and physicochemical
parameters on pharmacological activities. The analysis of
the results revealed that the presence of any substituent,
electron-donating or electron-withdrawing, produced
compounds with similar to noticeably improved activity
relative to the unsubstituted one (12a). Moreover, intro-
duction of small lipophilic fluoro, chloro, or methoxy
substituents produced compounds with improved anti-
inflammatory activities (47–95 % reduction in inflamma-
tion), while hydrophilic hydroxyl-substituted compounds
(12f–g) have shown less to similar activities (35–48 %
reduction in inflammation) for an i.p. dose of 10 mg/kg in
comparison with 12a.
Anti-inflammatory activity
In vivo pharmacological evaluation of 12a–p was carried
out to assess their potential anti-inflammatory activity.
Qualitative structure–activity relationship data, acquired
using the carrageenan induced rat paw edema assay (Al-
Haboubi and Zeitlin, 1983), showed that this group of
arylidene-2-(3-chloroanilino)nicotinic acid hydrazides
exhibit anti-inflammatory activity with moderate-to-excel-
lent activity range (11–95 % inhibition at different time
intervals) in comparison with niflumic acid as the reference
drug (47–80 % inhibition, Table 1).
The effect of changing the position of substituents on the
phenyl ring was next investigated. In general, most of the
meta-substituted compounds (except for 12h–i) were pre-
ferred over para-substituted ones.
123

Med Chem Res
Table 1 Anti-inflammatory activities of compounds 12a–p
O
Ar
N
NH
H
N
NH
Cl
AI acticity (%)a
At 30 m
Compound
Ar
At 1 h
At 2 h
At 3 h
Max. activity
12a
12b
12c
Ph
38.30 9.41
77.92 – 4.04b
36.92 6.79
95.37 – 4.45
51.52 – 8.46
35.31 5.70
10.03 6.70
79.07 – 5.60
49.29 20.42
56.33 18.23
62.98 – 7.70
45.18 – 16.82
36.23 3.01
72.44 – 12.67
33.80 5.01
33.20 0.82
47.25 ? 3.26
38.96 4.42
67.83 3.90
47.18 – 7.57
71.94 16.32
34.42 8.38
47.94 – 5.15
35.57 – 9.14
61.21 12.16
47.05 10.33
40.66 15.38
38.51 13.17
10.52 5.26
37.38 – 7.47
45.89 19.24
30.30 4.76
47.49 13.89
81.38 1 15.62
39.35 – 7.72
55.34 11.77
30.10 5.55
59.07 9.14
33.01 7.52
39.65 9.04
24.89 10.15
54.96 8.75
87.48 – 5.04
75.76 – 4.47
28.98 12.43
25.33 10.57
32.43 2.68
23.15 12.75
48.30 7.17
49.34 – 7.39
70.85 ? 10.04
32.62 7.98
56.06 6.72
28.37 6.37
43.17 8.59
25.32 4.98
46.31 2.75
28.62 10.77
40.51 8.01
63.46 5.61
61.66 5.13
33.71 12.65
16.95 6.33
23.58 14.24
15.23 6.27
57.94 – 18.87
35.85 6.06
59.07 ? 5.78
39.35 – 7.72
77.92 – 4.04
47.18 – 7.57
95.37 – 4.45
51.52 – 8.46
47.94 – 5.15
35.57 – 9.14
79.07 – 5.60
87.48 – 5.04
75.76 – 4.47
62.98 – 7.70
45.18 – 16.82
37.38 – 7.47
72.44 – 12.67
57.94 – 18.87
49.34 – 7.39
81.38 1 15.62
3-F-C6H4
4-F-C6H4
12d
12e
3-Cl-C6H4
4-Cl-C6H4
3-OH-C6H4
4-OH-C6H4
3-OMe-C6H4
4-OMe-C6H4
2,4-(OMe)2-C6H3
3,4-(OMe)2-C6H3
3,4,5-(OMe)3-C6H2
3-Pyridyl
12f
12g
12h
12i
12j
12k
12l
12m
12n
12o
12p
Niflumic acid
a
4-Pyridyl
2-Furyl
2-Thienyl
The compounds are administered at the dose of 10 mg/kg
b
The highest anti-inflammatory activity for each compound is shown as bold
Then, substitution of phenyl moiety with any heterocy-
(95 %, relative to niflumic acid, 80 % reduction in
inflammation) than this analog from the previously pub-
lished compounds (78 %, relative to niflumic acid; 70 %
reduction in inflammation). Also, in both group of com-
pounds, meta-substitution provided compounds with higher
anti-inflammatory activity than the para ones.
cle (pyridyl, thienyl, or furyl) produced compounds with
similar to improved activities (49–72 % reduction in
inflammation).
Finally, among these analogs, (3-chlorobenzylidene)-2-
(3-chloroanilino)nicotinic acid hydrazide (12d), exhibited
the highest anti-inflammatory activity relative to niflumic
acid as the reference drug (95 and 80 % reduction in
inflammation postdrug administration, respectively).
Moreover, the analysis of the anti-inflammatory activi-
ties of 12a–p and a comparison of their activities with
previously synthesized analogs of these compounds
(Kheradmand et al., 2013) having 3-trifluoromethylanilino
moiety instead of 3-chloroanilino group have revealed that
both groups showed noticeable activity relative to niflumic
acid as the reference drug. In both groups 3-chloroben-
zylidene derivatives have shown the highest anti-inflam-
matory activity, while 12d showed more improved activity
Regarding the other analogs, the influence of substit-
uents on the anti-inflammatory activity was not similar in
these two groups. In the present analogs, hydroxyphenyl
(12f, g) or pyridyl derivatives (12m, n) had shown
weaker activities than niflumic acid, while similar sub-
stitutions in the previously published analogs provided
compounds with similar to improved activities. On the
contrary, the methoxy (12h, i) or 3-fluoro derivatives
(12b) in the present group of compounds have shown
similar to improved activities than niflumic acid, while
similar analogs in the previously published ones revealed
weaker activities.
123

Med Chem Res
potential anti-inflammatory and analgesic activities. Most
of the compounds have shown significant pharmacological
activities. In carrageenan-induced rat paw edema assay,
3-chloro derivative 12d exhibited the most potent anti-
inflammatory activity. Selected compounds were subjected
for writhing test and among them, 4-methoxy (12i) and 2,4-
dimethoxyphenyl derivatives (12j) showed the most potent
analgesic activities. Therefore, these new structures can be
considered interesting for further modification as anti-
inflammatory and analgesic agents.
Table 2 Analgesic activities of the selected 12 derivatives
Compound
R
Number of
writhinga
Inhibition (%)
CMC
48.75 5.73
20.85 3.3*
24.65 4.47*
19.65 5.04*
12b
3-F-C6H4
52.23*,b
49.43*
59.69*
12d
3-Cl-C6H4
3-OMe-C6H4
4-OMe-C6H4
2,4-(OMe)2-C6H3
4-pyridyl
12h
12i
1.33 0.88*** 97.27***
0.2 0.2*** 99.59***
4.6 1.5*** 90.56***
12j
12n
Niflumic acid
15.45 6.9**
68.31**
Experimental protocols
* P \ 0.05; ** P \ 0.01; *** P \ 0.001 compared to CMC group
a
The compounds are administered at the dose of 10 mg/kg
b
Chemistry
Analgesic activity relative to niflumic acid. *, ** and *** differed
from control (CMC) group P \ 0.05, P \ 0.01 and P \ 0.001,
respectively
Melting points were determined with a Reichert-Jung hot-
stage microscope (Reichert-Jung, Germany) and are
uncorrected. Infrared spectra were recorded on a Nicolet
Magna 550-FT spectrometer (Nicolet, Madison, WI, USA).
1H NMR and 13C NMR spectra were recorded on a Bruker
FT-500 MHz spectrometer (Bruker Bioscience, USA) in
CDCl3 or DMSO-d6 with TMS as the internal standard.
Elemental microanalyses were carried out using a Perkin-
Elmer 240-C apparatus (Perkin-Elmer, Beaconsfield, UK)
and were within 0.4 % of the theoretical values for C, H,
and N. Male NMRI mice and male Wistar rats, used in the
analgesic and anti-inflammatory screens, respectively, were
purchased from Pasteur Institute (Karaj, Iran), and exper-
iments were carried out using protocols approved by the
ethics committee of Tehran University of Medical
Sciences.
Analgesic activity
The compounds which exhibited significant anti-inflam-
matory activities comparable to that of the niflumic acid
were subjected to analgesic assay.
The analgesic activities of the compounds were studied
by using acetic acid-induced abdominal constriction test
(writhing test) (Whittle, 1964). Qualitative structure–
activity relationship data, acquired using the analgesic
assay, showed that most of the selected arylidene-2-(3-
chloroanilino)nicotinic acid hydrazides were able to reduce
the AcOH-induced constrictions with moderate-to-excel-
lent activity range (49–99.6 % inhibition) in comparison
with niflumic acid as the reference drug (68 % inhibition)
(Table 2).
Interestingly, among substituted analogs, 4-pyridyl
derivatives (12n), 4-methoxyphenyl (12i) and 2,4-dime-
thoxyphenyl (12j) exhibited the most potent analgesic
activity with 91, 97, and 99.6 % of inhibition, respectively,
relative to the reference drug niflumic acid with 68 % of
inhibition activity. This phenomenon can be explained by
possible hydrogen bond formation between the nitrogen of
4-pyridyl or C-4 methoxy substituent on the phenyl ring
with amino acids of target-binding site.
Ethyl 2-(3-chloroanilino)nicotinate (10)
2-(3-Chloroanilino)nicotinic acid 9 (24.8 g, 0.1 mol) and
H2SO4 (5 mL) were taken in absolute ethanol (300 mL)
and refluxed for 72 h. Then, the reaction mixture concen-
trated under reduced pressure; 100 mL of aqueous sodium
carbonate solution (10 %, w/v) was added to the residue,
and the ester was extracted in chloroform. Then, the sol-
vent was dried over anhydrous Na2SO4, evaporated, and
the remaining was recrystallized from ethanol to yield 10
(22.05 g) as a yellowish white solid.
The analysis of analgesic activities of the selected
compounds and comparison of their activities with the
previously published analogs (Kheradmand et al., 2013)
showed both groups as having significant analgesic activ-
ities relative to niflumic acid as the reference drug.
Yield 82 %. m.p. 46–48 °C. IR (KBr) 3431 (NH), 1690
(C=O) cm-1. 1H NMR (CDCl3) d 10.35 (bs, 1H, NH), 8.39
(dd, J = 2.0, 4.5 Hz, 1H, H6), 8.25 (dd, J = 2.0, 8.0 Hz,
0
1H, H4), 7.96 (t, J = 1.5 Hz, 1H, H2 ), 7.49 (dd, J = 1.5,
0
8.0 Hz, 1H, H4 ), 7.23 (t, J = 8.0 Hz, 1H, H5 ), 7.00 (dd,
0
Conclusion
0
J = 1.5, 8.0 Hz, 1H, H6 ), 6.75 (dd, J = 4.5, 8.0 Hz, 1H,
H5), 4.38 (q, J = 7.2 Hz, 2H, CH2), 1.41 (t, J = 7.2 Hz,
3H, CH3). 13C NMR (CDCl3) d 167.4 (C=O), 155.7 (C2),
Various substituted arylidene-2-(3-chloroanilino)nicotinic
acid hydrazides were synthesized and screened for their
0
152.9 (C6), 141.1 (C1 ), 140.1 (C4), 134.4 (C3 ), 129.7 (C5 ),
0
0
123

Med Chem Res
0
122.4 (C4 ), 120.2 (C2 ), 118.4 (C6 ), 113.8 (C5), 107.6 (C3),
0
0
Anal. Calcd. for C19H15ClN4O: C, 65.05; H, 4.31; N,
15.97. Found: C, 65.18; H, 4.50; N, 15.87.
61.4 (CH2), 14.2 (CH3).
Anal. Calcd. for C14H13ClN2O2: C, 60.77; H, 4.74; N,
10.12. Found: C, 60.58; H, 4.87; N, 10.22.
(3-Fluorobenzylidene)-2-(3-chloroanilino)nicotinic acid
hydrazide (12b)
2-(3-Chloroanilino)nicotinic acid hydrazide (11)
It was obtained as a light lemon yellow solid, yield 82 %.
m.p. 184–186 °C. IR (KBr) 3298 (NH), 1670 (C=O) cm-1
A
mixture of ethyl 2-(3-chloroanilino)nicotinate 10
.
(20.75 g, 75 mmol) and hydrazine hydrate (375 mmol) in
ethanol (200 mL) was stirred at room temperature for 24 h.
Then, the reaction mixture concentrated in vacuo and left
for overnight. The resulting crystals were filtered and re-
crystallized from ethanol to yield acid hydrazide 11
(17.3 g) as a light lemon yellow solid.
1H NMR (CDCl3) d 10.55 (bs, 1H, NH), 8.47 (s, 1H, =CH–),
8.45 (d, J = 4.6 Hz, 1H, H6), 8.28 (d, J = 7.5 Hz, 1H, H4),
0
8.09 (s, 1H, H2 ), 7.65–7.45 (m, 4H, H2 ’,5 ’,6 ’ & H4 ),
0
0
0
0
0
0
0
7.38–7.25 (m, 2H, H4 ’ & H5 ), 7.10-6.98 (m, 2H, H5 & H6 ).
13C NMR (DMSO-d6) d 164.4 (C=O), 162.9 (d, J =
00
243.99 Hz, C3 ), 154.5 (C2), 151.1 (C6), 147.7 (=CH–),
0 00
141.9 (C1 ), 138.4 (C4), 137.2 (d, J = 7.48 Hz, C5 ), 133.6
Yield 88 %. m.p. 169–171 °C. IR (KBr) 3375, 3272
(NH), 1650 (C=O) cm-1. 1H NMR (DMSO-d6) d 10.93 (bs,
1H, NH), 10.10 (bs, 1H, NH), 8.35 (d, J = 4.5 Hz, 1H,
0
00
0
00
(C3 ), 131.5 (d, J = 7.55 Hz, C6 ), 130.8 (C5 ), 124.1 (C1 ),
0
121.9 (C4 ), 119.3 (C2 ), 118.6 (C6 ), 117.5 (d, J = 21.38 Hz,
0
0
0
H6), 8.09 (s, 1H, H2 ), 8.04 (d, J = 7.5 Hz, 1H, H4), 7.38
00
00
C4 ), 114.7 (C5), 113.6 (d, J = 22.64 Hz, C2 ), 111.6 (C3).
Anal. Calcd. for C19H14ClFN4O: C, 61.88; H, 3.83; N,
15.19. Found: C, 61.67; H, 3.91; N, 15.34.
0
(d, J = 8.0 Hz, 1H, H4 ), 7.30 (t, J = 8.0 Hz, 1H, H5 ),
0
0
6.99 (d, J = 8.0 Hz, 1H, H6 ), 6.90 (dd, J = 4.5, 7.5 Hz,
1H, H5), 4.62 (bs, 2H, NH2). 13C NMR (DMSO-d6) d 167.0
0
(C=O), 154.3 (C2), 150.8 (C6), 142.2 (C1 ), 136.9 (C4),
(4-Fluorobenzylidene)-2-(3-chloroanilino)nicotinic acid
0
133.6 (C3 ), 130.8 (C5 ), 121.4 (C4 ), 118.6 (C2 ), 118.0
0
0
0
hydrazide (12c)
0
(C6 ), 114.7 (C5), 111.3 (C3).
Anal. Calcd. for C12H11ClN4O: C, 54.87; H, 4.22; N,
21.33. Found: C, 54.73; H, 4.41; N, 21.45.
It was obtained as a light lemon yellow solid, yield 88 %.
m.p. 199–200 °C. IR (KBr) 3355, 3215 (NH), 1679 (C=O)
cm-1. 1H NMR (DMSO-d6) d 12.22 (bs, 1H), 10.63 (bs, 1H),
8.51 (s, 1H, =CH–), 8.40 (d, J = 4.8 Hz, 1H, H6), 8.30 (d,
General procedure for synthesis of arylidene-2-(3-
0
J = 8.0 Hz, 1H, H4), 8.09 (s, 1H, H2 ), 7.82 (dd, J = 6.5,
chloroanilino)nicotinic acid hydrazides (12a–p)
0
0
0
8.0 Hz, 2H, H2 ’,6 ’), 7.47 (d, J = 7.2 Hz, 1H, H4 ), 7.36–7.26
0
0
0
0
A mixture of hydrazide 11 (1 mmol) and corresponding
aldehyde (1 mmol) in absolute ethanol (10 mL) in the
presence of hydrochloric acid (2 drops) as the catalyst was
stirred at room temperature for 24 h. The completion of the
reaction was monitored by TLC. Then, water was added to
the mixture, and the precipitate was filtered, washed, and
recrystallized from ethanol to give 12
(m, 3H, H5 & H3 ’,5 ’), 7.06–6.94 (m, 2H, H6 & H5). 13C
NMR (DMSO-d6) d 164.1 (C=O), 163.7 (d, J = 247.77 Hz,
00
C4 ), 154.2 (C2), 150.2 (C6), 148.1 (=CH–), 141.5 (C1 ),
0
0
138.9 (C4), 133.7 (C3 ), 131.2 (C1 ), 130.9 (C5 ), 129.9 (d,
00
0
00 00
0
0
0
J = 7.55 Hz, C2 ,6 ), 122.3 (C4 ), 119.8 (C2 ), 119.0 (C6 ),
00 00
116.4 (d, J = 21.38 Hz, C3 ,5 ), 114.6 (C5), 112.0 (C3).
Anal. Calcd. for C19H14ClFN4O: C, 61.88; H, 3.83; N,
15.19. Found: C, 62.07; H, 3.99; N, 15.08.
Benzylidene-2-(3-chloroanilino)nicotinic acid hydrazide
(12a)
(3-Chlorobenzylidene)-2-(3-chloroanilino)nicotinic acid
hydrazide (12d)
It was obtained as a light lemon yellow solid, yield 50 %.
m.p. 143-145 °C. IR (KBr) 3427, 3231 (NH), 1658 (C=O)
cm-1. 1H NMR (DMSO-d6) d 12.11 (bs, 1H, NH), 10.59 (bs,
1H, NH), 8.45 (bs, 1H, = CH–), 8.41 (d, J = 4.5 Hz, 1H,
It was obtained as a light lemon yellow solid, yield 89 %.
m.p. 198–200 °C. IR (KBr) 3443 (NH), 1671 (C=O) cm-1
.
1H NMR (DMSO-d6) d 12.37 (bs, 1H), 10.58 (bs, 1H, NH),
8.47 (s, 1H, =CH-), 8.42 (d, J = 4.7 Hz, 1H, H6), 8.28 (d,
0
H6), 8.21 (d, J = 7.5 Hz, 1H, H4), 8.12 (s, 1H, H2 ),
0
0
0
0
0
0
7.78–7.70 (m, 2H, H2 ’,6 ’), 7.52–7.40 (m, 4H, H4 , H3 ’,4 ’,5 ’),
0 0
J = 8.0 Hz, 1H, H4), 8.11 (s, 1H, H2 ), 7.82 (s, 1H, H2 ’),
0
0
0
7.72 (d, J = 7.8 Hz, 1H, H6 ’), 7.55–7.45 (m, 3H, H4 &
0
7.31 (t, J = 8.0 Hz, 1H, H5 ), 7.03–6.94 (m, 2H, H5 & H6 ).
13C NMR (DMSO-d6) d 164.4 (C=O), 154.6 (C2), 151.4 (C6),
0
4 ’,5 ’), 7.33 (t, J = 8.0 Hz, 1H, H5 ), 7.08–6.95 (m, 2H,
0
0
H
H6 & H5). 13C NMR (DMSO-d6) d 164.4 (C=O), 154.4
0
0
149.1 (=CH–), 142.1 (C1 ), 138.0 (C4), 134.5 (C3 ), 133.6
0
00
(C1 ), 130.8 (C5 ), 130.7 (C4 ), 129.4 (C2 ,6 ), 127.7 (C3 ,5 ),
0
00
00 00
00 00
0
(C2), 151.0 (C6), 147.4 (=CH–). 141.8 (C1 ), 138.4 (C4),
0
121.7 (C4 ), 119.0 (C2 ), 118.3 (C6 ), 114.6 (C5), 111.5 (C3).
0
0
00 00 0 00
136.8 (C3 ), 134.2 (C1 ), 133.6 (C3 ), 131.3 (C4 ), 130.8
123

Med Chem Res
6.86 (d, J = 9.0 Hz, 2H, H3 ’,5 ’). 13C NMR (DMSO-d6) d
0
00
(C5 ), 130.4 (C5 ), 126.9 (C2 ), 126.4 (C6 ), 122.0 (C4 ),
00
00
0
0
0
0
0
00
163.9 (C=O), 160.2 (C4 ), 154.3 (C2), 150.3 (C6), 149.6
119.4 (C2 ), 118.7 (C6 ), 114.6 (C5), 111.6 (C3).
Anal. Calcd. for C19H14Cl2N4O: C, 59.24; H, 3.66; N,
14.54. Found: C, 59.03; H, 3.82; N, 14.31.
0
(=CH–), 141.7 (C1 ), 138.4 (C4), 130.8 (C5 ), 129.5 (C2 ,6 ),
0
00 00
00
0
0
0
125.5 (C1 ), 122.1 (C4 ), 119.5 (C2 ), 118.8 (C6 ), 116.2
00 00
(C3 ,5 ), 114.6 (C5), 112.14 (C3).
(4-Chlorobenzylidene)-2-(3-chloroanilino)nicotinic acid
Anal. Calcd. for C19H15ClN4O2: C, 62.21; H, 4.12; N,
15.27. Found: C, 62.34; H, 4.19; N, 15.08.
hydrazide (12e)
It was obtained as a light lemon yellow solid, yield 90 %.
m.p. 215–216 °C. IR (KBr) 3365 (NH), 1678 (C=O) cm-1
(3-Methoxybenzylidene)-2-(3-chloroanilino)nicotinic acid
.
hydrazide (12h)
1H NMR (DMSO-d6) d 12.23 (bs, 1H, NH), 10.59 (bs, 1H,
NH), 8.48 (s, 1H, =CH–), 8.41 (d, J = 4.6 Hz, 1H, H6),
It was obtained as a light lemon yellow solid, yield 87 %.
m.p. 193–195 °C. IR (KBr) 3338, 3184 (NH), 1655 (C=O)
cm-1. 1H NMR (DMSO-d6) d 12.22 (bs, 1H, NH), 10.60 (bs,
1H, NH), 8.46 (s, 1H, =CH–), 8.41 (d, J = 4.4 Hz, 1H, H6),
0
8.26 (d, J = 8.2 Hz, 1H, H4), 8.10 (s, 1H, H2 ), 7.79 (d,
0
0
0
0
J = 8.0 Hz, 2H, H2 ’,6 ’), 7.540(d, J = 8.0 Hz, 2H, H3 ’,5 ’),
7.47 (d, J = 8.0 Hz, 1H, H4 ), 7.32 (t, J = 8.0 Hz, 1H,
H5 ), 7.05–6.96 (m, 2H, H6 & H5). 13C NMR (DMSO-d6) d
164.3 (C=O), 154.3 (C2), 150.5 (C6), 147.9 (=CH–), 141.6
0
0
0
8.26 (d, J = 7.5 Hz, 1H, H4), 8.10 (s, 1H, H2 ), 7.49 (d,
0 0
J = 8.0 Hz, 1H, H4 ), 7.40 (t, J = 8.0 Hz, 1H, H5 ),
0
00
0
(C1 ), 138.7 (C4), 135.2 (C4 ), 133.6 (C3 ), 133.5 (C2 ,6 ),
00 00
0
0
0
0
0
7.35–7.25 (m, 3H, H2 ’,5 ’,6 ’), 7.15–6.86 (m, 3H, H4 ’ & H6 &
H5), 3.82 (s, 3H, OCH3). 13C NMR (DMSO-d6) d 164.4
0
00
00 00
0
130.8 (C5 ), 129.5 (C1 ), 129.3 (C3 ,5 ), 122.2 (C4 ), 119.6
0
(C2 ), 118.9 (C5 ), 114.6 (C5), 111.9 (C3).
0
00
(C=O), 160.04 (C3 ), 154.6 (C2), 151.3 (C6), 149.0 (=CH–),
0 00 0 0
142.04 (C1 ), 138.1 (C4), 136.0 (C1 ), 133.6 (C3 ), 130.7 (C5 ),
Anal. Calcd. for C19H14Cl2N4O: C, 59.24; H, 3.66; N,
14.54. Found: C, 59.09; H, 3.43; N, 14.67.
00
00
130.5 (C5 ), 121.7 (C6 ), 120.7 (C4 ), 119.1 (C2 ), 118.4
00
0
0
00
(C6 ), 117.0 (C2 ), 114.7 (C5), 111.6 (C3), 55.7 (CH3).
Anal. Calcd. for C20H17ClN4O2: C, 63.08; H, 4.50; N,
14.71. Found: C, 63.04; H, 4.31; N, 14.51.
(3-Hydroxybenzylidene)-2-(3-chloroanilino)nicotinic acid
hydrazide (12f)
It was obtained as a yellowish gray solid, yield 90 %. m.p.
(4-Methoxybenzylidene)-2-(3-chloroanilino)nicotinic acid
145–147 °C. IR (KBr) 3485 (OH), 3385 (NH), 1676 (C=O)
hydrazide (12i)
1
cm-1. H NMR (DMSO-d6) d 12.12 (bs, 1H, NH), 10.60
(bs, 1H, NH), 8.44–8.35 (m, 2H, H6 & =CH–), 8.26 (d,
It was obtained as a lemon yellow solid, yield 95 %. m.p.
1
219–220 °C. IR (KBr) 3338 (NH), 1668 (C=O) cm-1. H
0
J = 8.0 Hz, 1H, H4), 8.10 (s, 1H, H2 ), 7.47 (d,
0
0
J = 8.0 Hz, 1H, H4 ), 7.32 (t, J = 8.0 Hz, 1H, H5 ), 7.27 (t,
NMR (DMSO-d6) d 12.15 (bs, 1H, NH), 10.65 (bs, 1H, NH),
8.42 (d, J = 4.5 Hz, 1H, H6), 8.39 (s, 1H, = CH-), 8.29 (d,
0
J = 7.2 Hz, 1H, H5 ’), 7.22 (s, 1H, H2 ’), 7.12 (d,
0
0
0
0
J = 7.5 Hz, 1H, H4), 8.10 (s, 1H, H2 ), 7.70 (d, J = 8.5 Hz,
J = 7.2 Hz, 1H, H6 ’), 7.10–6.86 (m, 2H, H6 & H5), 6.86
(d, J = 7.2 Hz, 1H, H4 ’). 13C NMR (DMSO-d6) d 163.8
0
0
2H, H2 ’,6 ’), 7.48 (d, J = 8.0 Hz, 1H, H4 ), 7.33 (t,
0
0
00
(C=O), 158.2 (C3 ), 153.9 (C2), 149.6 (C6), 149.3 (=CH–),
0 0 0
J = 8.0 Hz, 1H, H5 ), 7.04 (d, J = 8.5 Hz, 2H, H3 ’,5 ’), 7.00
0
141.1 (C1 ), 139.4 (C4), 135.8 (C1 ), 133.8 (C3 ), 131.0
00
0
0
(d, J = 8.0 Hz, 1H, H6 ), 6.98 (dd, J = 4.5, 7.5 Hz, 1H, H5),
3.82 (s, 3H, OCH3). 13C NMR (DMSO-d6) d 164.0 (C=O),
0
00
0
00
0
(C5 ), 130.4 (C5 ), 122.8 (C4 ), 120.3 (C6 ), 119.5 (C2 ),
00
119.3 (C4 ), 118.2 (C6 ), 114.5 (C5), 113.3 (C2 ), 112.5
0
00
00
161.5 (C4 ), 154.3 (C2), 150.3 (C6), 149.2 (=CH–), 141.7
0
0
0
00 00
(C1 ), 138.5 (C4), 133.6 (C3 ), 130.8 (C5 ), 129.3 (C2 ,6 ),
(C3).
00 0 0 0
127.1 (C1 ), 122.1 (C4 ), 119.5 (C2 ), 118.8 (C6 ), 114.9
Anal. Calcd. for C19H15ClN4O2: C, 62.21; H, 4.12; N,
15.27. Found: C, 62.31; H, 3.97; N, 15.40.
00 00
(C3 ,5 ), 114.6 (C5), 112.1 (C3), 55.8 (CH3).
Anal. Calcd. for C20H17ClN4O2: C, 63.08; H, 4.50; N,
14.71. Found: C, 63.18; H, 4.72; N, 14.58.
(4-Hydroxybenzylidene)-2-(3-chloroanilino)nicotinic acid
hydrazide (12g)
(2,4-Dimethoxybenzylidene)-2-(3-chloroanilino)nicotinic
It was obtained as a lemon yellow solid, yield 95 %. m.p.
acid hydrazide (12j)
159–161 °C. IR (KBr) 3459 (OH), 3385 (NH), 1664 (C=O)
1
cm-1. H NMR (DMSO-d6) d 12.05 (bs, 1H, NH), 10.70
(bs, 1H, NH), 8.40 (s, 1H, =CH–), 8.37 (d, J = 4.9 Hz, 1H,
It was obtained as a light lemon yellow solid, yield 92 %.
m.p. 202–204 °C. IR (KBr) 3320, 3195 (NH), 1625 (C=O)
cm-1. 1H NMR (DMSO-d6) d 11.95 (bs, 1H, NH), 10.72 (bs,
1H, NH), 8.71 (s, 1H, =CH–), 8.40 (d, J = 4.7 Hz, 1H, H6),
0
H6), 8.28 (d, J = 8.1 Hz, 1H, H4), 8.01 (s, 1H, H2 ), 7.58
0
(d, J = 9.0 Hz, 2H, H2 ’,6 ’), 7.49 (d, J = 8.0 Hz, 1H, H4 ),
0
0
0
7.23 (t, J = 8.0 Hz, 1H, H5 ), 7.05–6.96 (m, 2H, H6 & H5),
0
0
8.21 (d, J = 7.5 Hz, 1H, H4), 8.12 (s, 1H, H2 ), 7.83 (d,
123

Med Chem Res
0
J = 8.8 Hz, 1H, H6 ’), 7.49 (d, J = 7.9 Hz, 1H, H4 ), 7.23 (t,
0
NMR (DMSO-d6) d 12.85 (bs, 1H, NH), 10.62 (bs, 1H,
0
J = 7.9 Hz, 1H, H5 ), 7.05–6.93 (m, 2H, H6 & H5), 6.86 (m,
0
0
NH), 9.01 (s, 1H, H2 ’), 8.73 (bs, 1H, H6 ’), 8.54 (s, 1H,
0
2H, H3 ’,5 ’), 3.87 (s, 3H, OCH3), 3.84 (s, 3H, OCH3). 13C
0
0
0
=CH–), 8.59 (bs, 1H, H4 ’), 8.42 (d, J = 4.5 Hz, 1H, H6),
00
00
0
8.24 (d, J = 7.5 Hz, 1H, H4), 8.10 (s, 1H, H2 ), 7.70 (bs,
NMR (DMSO-d6) d 164.0 (C=O), 163.1 (C4 ), 159.8 (C2 ),
0
154.6 (C2), 151.2 (C6), 144.7 (=CH–), 142.1 (C1 ), 137.8
0 0
1H, H5 ’), 7.48 (d, J = 8.0 Hz, 1H, H4 ), 7.32 (t,
J = 8.0 Hz, 1H, H5 ), 7.07–6.94 (m, 2H, H6 & H5). 13C
0
0
00
0
(C4), 133.6 (C3 ), 130.7 (C5 ), 127.1 (C6 ), 121.6 (C4 ), 118.9
0
0
0
(C2 ), 118.2 (C6 ), 115.3 (C1 ), 114.6 (C5), 111.6 (C3), 107.0
0
00
NMR (DMSO-d6) d 164.8 (C=O), 154.6 (C2), 151.5 (C6),
00
00
(C5 ), 98.8 (C3 ), 55.3 (CH3), 55.9 (CH3).
00 00 0
144.2 (=CH–), 143.5 (C6 ), 142.6 (C2 ), 141.9 (C1 ), 140.9
00 0 0 00 00
(C4 ), 138.7 (C4), 133.6 (C3 ), 130.7 (C5 ), 127.2 (C3 ,5 ),
Anal. Calcd. for C21H19ClN4O3: C, 61.39; H, 4.66; N,
13.64. Found: C, 61.50; H, 4.51; N, 13.73.
0
0
0
121.9 (C4 ), 119.3 (C2 ), 118.6 (C6 ), 114.6 (C5), 110.0 (C3).
Anal. Calcd. for C18H14ClN5O: C, 61.46; H, 4.01; N,
19.91. Found: C, 61.27; H, 3.88; N, 20.04.
(3,4-Dimethoxybenzylidene)-2-(3-chloroanilino)nicotinic
acid hydrazide (12k)
(Pyridin-4-ylmethylene)-2-(3-chloroanilino)nicotinic acid
It was obtained as a light lemon yellow solid, yield 96 %.
m.p. 214–215 °C. IR (KBr) 3320, 3200 (NH), 1650 (C=O)
cm-1. 1H NMR (DMSO-d6) d 12.05 (bs, 1H, NH), 10.60 (bs,
1H, NH), 8.41 (d, J = 4.8 Hz, 1H, H6), 8.40 (s, 1H, =CH–),
hydrazide (12n)
It was obtained as a lemon yellow solid, yield 90 %. m.p.
227–229 °C. IR (KBr) 3520, 3459 (NH), 1677 (C=O)
1
cm-1. H NMR (DMSO-d6) d 12.85 (bs, 1H, NH), 10.55
0
8.21 (d, J = 8.0 Hz, 1H, H4), 8.11 (s, 1H, H2 ), 7.49 (d,
0
J = 8.0 Hz, 1H, H4 ), 7.37 (s, 1H, H2 ’), 7.32 (t, J = 8.0 Hz,
0
00 00
(bs, 1H, NH), 8.81 (d, J = 4.0 Hz, 2H, H3 ,5 ), 8.57 (s, 1H,
0
1H, H5 ),7.23 (d, J = 7.6 Hz, 1H, H6 ’), 7.05–6.96 (m, 3H,
0
=CH–), 8.44 (d, J = 4.5 Hz, 1H, H6), 8.32 (d, J = 8.0 Hz,
0
0
0
1H, H4), 8.09 (s, 1H, H2 ), 8.00 (d, J = 4.0 Hz, 2H, H2 ,6 ),
00 00
H6 & H5 & H5 ’), 3.84 (s, 3H, OCH3), 3.82 (s, 3H, OCH3).
13C NMR (DMSO-d6) d 164.2 (C=O), 154.5 (C2), 151.4
00
(C4 ), 151.2 (C6), 149.5 (C3 ), 149.3 (=CH–), 142.1 (C1 ),
0
7.49 (d, J = 8.0 Hz, 1H, H4 ), 7.23 (t, J = 8.0 Hz, 1H,
H5 ), 7.07–6.94 (m, 2H, H6 & H5). 13C NMR (DMSO-d6) d
00
0
0
0
0
137.9 (C4), 133.6 (C3 ), 130.7 (C5 ), 127.2 (C1 ), 122.7 (C4 ),
0
00
0
00 00
165.0 (C=O), 154.6 (C2), 151.9 (C6), 146.6 (C2 ,6 ), 144.9
00
0
0
00
121.6 (C6 ), 119.0 (C2 ), 118.3 (C6 ), 114.6 (C5), 111.9 (C2 ),
0 0 00
(=CH–), 142.0 (C1 ), 138.5 (C4), 133.5 (C3 ), 133.5 (C1 ),
00
111.7 (C3), 108.5 (C5 ), 56.0 (CH3), 55.9 (CH3).
0 00 00 0 0
130.7 (C5 ), 122.9 (C3 ,5 ), 121.8 (C4 ), 119.2 (C2 ), 118.5
0
(C6 ), 114.7 (C5), 110.9 (C3).
Anal. Calcd. for C21H19ClN4O3: C, 61.39; H, 4.66; N,
13.64. Found: C, 61.32; H, 4.41; N, 13.83.
Anal. Calcd. for C18H14ClN5O: C, 61.46; H, 4.01; N,
19.91. Found: C, 61.27; H, 4.20; N, 20.06.
(3,4,5-Trimethoxybenzylidene)-2-(3-
chloroanilino)nicotinic acid hydrazide (12l)
(Furan-2-ylmethylene)-2-(3-chloroanilino)nicotinic acid
hydrazide 12o
It was obtained as a lemon yellow solid, yield 92 %. m.p.
215–217 °C. IR (KBr) 3380, 3293 (NH), 1674 (C=O) cm-1
.
It was obtained as a greenish umber solid, yield 71 %. m.p.
104–106 °C. IR (KBr) 3298 (NH), 1687 (C=O) cm-1. H
NMR (DMSO-d6) d 11.72 (bs, 1H, NH), 10.51 (bs, 1H, NH),
8.42 (d, J = 4.5 Hz, 1H, H6), 8.31 (s, 1H, =CH–), 8.16 (d,
1H NMR (DMSO-d6) d 12.25 (bs, 1H, NH), 10.68 (bs, 1H,
NH), 8.43 (s, 1H, =CH–), 8.40 (d, J = 4.9 Hz, 1H, H6), 8.28
1
0
(d, J = 8.0 Hz, 1H, H4), 8.10 (s, 1H, H2 ), 7.49 (d,
0
J = 7.8 Hz, 1H, H4 ), 7.33 (t, J = 7.8 Hz, 1H, H5 ),
0
0 0
J = 7.5 Hz, 1H, H4), 8.09 (s, 1H, H2 ), 7.88 (s, 1H, H5 ’), 7.44
0
0 0
(d, J = 8.0 Hz, 1H, H4 ), 7.31 (t, J = 8.0 Hz, 1H, H5 ),
7.10–6.95 (m, 2H, H6 & H5), 3.85 (s, 6H, OCH3), 3.72 (s, 3H,
OCH3). 13C NMR (DMSO-d6) d 164.1 (C=O), 154.2 (C2),
7.10–6.96 (m, 3H, H6 & H5 & H3 ’), 6.62 (s, 1H, H4 ’). 13C
0
0
0
00 00
0
153.7 (C3 ,5 ), 150.3 (C6), 149.1 (=CH–), 141.7 (C1 ), 139.8
NMR (DMSO-d6) d 164.3 (C=O), 154.5 (C2), 151.4 (C6),
00
(C4 ), 138.7 (C4), 133.6 (C3 ), 130.8 (C5 ), 130.1 (C1 ), 122.2
0
0
00
00 00 0
149.7 (C2 ), 146.0 (C5 ), 142.1 (C1 ), 138.8 (C4), 137.9
0
0
0
(C4 ), 119.6 (C2 ), 118.9 (C6 ), 114.6 (C5), 112.0 (C3), 104.8
0 0 0 0
(=CH–), 133.6 (C3 ), 130.7 (C5 ), 121.7 (C4 ), 119.0 (C2 ),
00
00 00
00 00
0
00
00
(C2 ,6 ), 60.6 (OCH3-4 ), 56.4 (OCH3-3 ,5 ).
Anal. Calcd. for C22H21ClN4O4: C, 59.93; H, 4.80; N,
12.71. Found: C, 59.85; H, 4.66; N, 12.54.
118.3 (C6 ), 114.7 (C4 ), 114.6 (C5), 112.8 (C3 ), 111.5 (C3).
Anal. Calcd. for C17H13ClN4O2: C, 59.92; H, 3.85; N,
16.44. Found: C, 59.82; H, 3.99; N, 16.28.
(Pyridin-3-ylmethylene)-2-(3-chloroanilino)nicotinic acid
(Thiophen-2-ylmethylene)-2-(3-chloroanilino)nicotinic
hydrazide (12m)
acid hydrazide (12p)
It was obtained as a lemon yellow solid, yield. 95 %. m.p.
1
It was obtained as a yellowish white solid, yield 76 %. m.p.
1
229–231 °C. IR (KBr) 3187 (NH), 1660 (C=O) cm-1. H
227–229 °C. IR (KBr) 3341 (NH), 1656 (C=O) cm-1. H
123

Med Chem Res
Statistics
NMR (DMSO-d6) d 10.83 (bs, 1H, NH), 10.69 (s, 1H,
=CH–), 10.59 (bs, 1H, NH), 8.44 (dd, J = 2.0, 4.0 Hz, 1H,
H6), 8.19 (d, J = 6.8 Hz, 1H, H4), 8.11 (t, J = 2.4 Hz, 1H,
The results are expressed as the mean SEM of 6 animals
per group. The data were statistically analyzed by one way
analysis of Variance (ANOVA) followed by Tukey mul-
ticomparison test. Differences with P \ 0.05 between
experiments group were considered statistically significant.
0
H2 ), 7.93 (d, J = 4.0 Hz, 1H, H3 ’), 7.89 (d, J = 4.8 Hz,
0
0
1H, H5 ’), 7.46 (dd, J = 2.4, 8.0 Hz, 1H, H4 ), 7.31 (t,
0
0
0
J = 8.0 Hz, 1H, H5 ), 7.24 (dd, J = 4.0, 4.8 Hz, 1H, H4 ’),
7.05–6.96 (m, 2H, H6 & H5). 13C NMR (DMSO-d6) d
0
00
167.6 (C=O), 161.5 (C2 ), 154.4 (C2), 151.7 (C6), 142.0
Acknowledgments This study was supported by grants from the
Medicinal Chemistry Center of Excellence and Drug Design and
Development Research Center.
0
(C1 ), 137.6 (C4), 137.3 (C3 ), 133.6 (C3 ), 132.5 (C4 ),
00
0
00
0
00
130.8 (C5 ), 129.8 (C5 ), 128.8 (=CH–), 121.8 (C4 ), 119.0
0
0
(C2 ), 118.3 (C6 ), 114.9 (C5), 110.8 (C3).
0
Anal. Calcd. for C17H13ClN4OS: C, 57.22; H, 3.67; N,
15.70. Found: C, 57.39; H, 3.54; N, 15.66.
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