Synthesis, anti-inflammatory activity, and QSAR study of some Schiff bases derived from 5-mercapto-3-(4′-pyridyl)-4H-1,2,4-triazol-4-yl- thiosemicarbazide

Article abstract of DOI:10.1007/s00044-013-0507-6

The purpose of this research is to synthesize better anti-inflammatory compounds derived from 5-mercapto-3-(4′-pyridyl)-4H-1,2,4-triazol-4-yl- thiosemicarbazide (5). 2-Substituted-N-[3-(pyridin-4-yl)-5-sulfanyl-4H-1,2,4- triazol-4-yl]hydrazine carbothioamide derivatives (6a-j)/(7a-e) are synthesized by the condensation of 5 with variously substituted aromatic aldehydes/1H-indole-2,3-diones, respectively, under conventional and microwave irradiation methods. The microwave method is found to be superior with higher chemical yields, tremendous reduction in time, and is environmentally benign as compared to conventional heating method. The chemical structures of the newly synthesized compounds (6/7) have been confirmed by IR, ¹H NMR, and ¹³C NMR spectra and have been evaluated for anti-inflammatory activity by carrageenan-induced acute paw edema method in rats.

Full text of DOI:10.1007/s00044-013-0507-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0507-6
ORIGINAL RESEARCH
Synthesis, anti-inflammatory activity, and QSAR study of some
Schiff bases derived from 5-mercapto-3-(40-pyridyl)-4H-1,2,4-
triazol-4-yl-thiosemicarbazide
•
Harshita Sachdeva Diksha Dwivedi
•
•
Kapil Arya Sarita Khaturia Rekha Saroj
•
Received: 7 November 2012 / Accepted: 19 January 2013
Ó Springer Science+Business Media New York 2013
Abstract The purpose of this research is to synthesize
better anti-inflammatory compounds derived from 5-mer-
capto-3-(40-pyridyl)-4H-1,2,4-triazol-4-yl-thiosemicarbazide
(5). 2-Substituted-N-[3-(pyridin-4-yl)-5-sulfanyl-4H-1,2,4-
triazol-4-yl]hydrazine carbothioamide derivatives (6a–j)/
(7a–e) are synthesized by the condensation of 5 with var-
iously substituted aromatic aldehydes/1H-indole-2,3-di-
ones, respectively, under conventional and microwave
irradiation methods. The microwave method is found to be
superior with higher chemical yields, tremendous reduction
in time, and is environmentally benign as compared to
conventional heating method. The chemical structures of
the newly synthesized compounds (6/7) have been con-
to improve the quality of life. In the family of heterocyclic
compounds, nitrogen containing heterocycles are frequently
found in privileged structures and have played an important
role in medicinal chemistry. Pyridine derivatives are
potential and proven source of pharmaceuticals and agro-
chemicals, for the treatment of Alzheimer’s disease (Davis
et al., 1996), agonists at 5-HT1A receptors (Vacher et al.,
1998), Mycobacterium tuberculosis H37Rv3 (Gezginci
et al., 2001), calcium channel agonist–antagonist modula-
tion activities (Shan et al., 2002), sodium channel inhibitors
(Shao et al., 2004), neuronal nicotinic acetylcholine
receptors (Wei et al., 2005), and so on.
The search for new antimicrobial agent is one of the
most challenging tasks to the medicinal chemist. The
synthesis of high nitrogen containing heterocyclic system
has been attracting increasing interest because of their
utility in various applications such as propellants, explo-
sives, pyrotechnics, and especially chemotherapy. The
widespread use of 1,2,4-triazoles as a scaffold in medicinal
chemistry established this moiety as a member of the
privileged structures class. Literature survey reveals that
1,2,4-triazole nucleus has been incorporated into a
wide variety of therapeutically interesting drug candidates
including antifungal (Papaqkonstantinon-Garoufalias et al.,
2002), insecticidal (Ghorab et al., 1996), antibacterial
(Patel et al., 2010), anti-inflammatory (Labanauskas et al.,
2004), antitubercular (Foroumadi et al., 2003), anticon-
vulsants (Mahendra et al., 2007), H1/H2 histamine receptor
blockers, cholinesterase active agents, CNS stimulants,
antianxiety agents, and sedatives (Schreier, 1976). The
most important use, however, is as antimycotics in
drugs such as fluconazole, itraconazole, and voriconazole
(Haber, 2001).
1
firmed by IR, H NMR, and 13C NMR spectra and have
been evaluated for anti-inflammatory activity by carra-
geenan-induced acute paw edema method in rats.
Keywords Schiff bases ꢀ Triazoles ꢀ Anti-inflammatory ꢀ
QSAR ꢀ Microwave irradiation
Introduction
Heterocycles have contributed to the development of soci-
ety from a biological and industrial point of view as well as
H. Sachdeva (&) ꢀ D. Dwivedi ꢀ S. Khaturia ꢀ R. Saroj
Department of Chemistry, Faculty of Engineering and
Technology, Mody Institute of Technology and Science,
Lakshmangarh, Sikar 332311, Rajasthan, India
e-mail: drhmsachdevaster@gmail.com;
hsachdeva.et@mitsuniversity.ac.in
K. Arya
Department of Chemistry, University of Delhi,
Delhi 110007, India
During the past few decades, interest has been rapidly
growing in gaining insight into the properties and
123

Med Chem Res
transformations of these heterocycles. As a result, variety
of new compounds is being added to this field every year.
Among the sulfur and nitrogen containing heterocyclic
compounds, semicarbazones and thiosemicarbazones have
potential pharmacological activities (Cardiaa et al., 2006;
Ku¨c¸u¨kgu¨zel et al., 2006; Plech et al., 2011). In recent
times, microwave-assisted organic reactions have become
very popular and have gained special attention due to their
ecofriendly nature, safety, less reaction time, and higher
yields (Polshettiwar and Varma, 2008; Gomha and Riyadh,
2009). Moreover, there are only few reports (Aniket et al.,
2009) available in the literature on the synthesis of mer-
capto-pyrido-triazol-thiosemicarbazide. Therefore, an
attempt has been made to synthesize some novel Schiff
bases (6 and 7) incorporating 1,2,4-triazole nucleus and to
screen them for anti-inflammatory activity.
Table 1 Comparative results of synthesis of 6a–j under conventional
heating (D) and microwave irradiation (MW) methods
Entry Ar
Time (min/h) Yield (%) M.P (oC)
MW/D
MW/D
6a
6b
6c
6d
6e
6f
C6H5
43/25
30/20
38/28
40/24
38/22
32/40
90/52
88/55
85/52
84/49
84/42
82/53
80/50
82/41
85/42
82/42
260
235
280
272
292
232
247
255
288
240
4-NO2C6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-OCH3C6H4
6g
6h
6i
3,4,5-trimethoxyphenyl 42/30
3-OHC6H5
40/33
34/25
30/22
3-OH, 4-OCH3C6H3
4-F-C6H4
6j
Hence, in continuation of our interest on synthesis of
nitrogen containing heterocyclic compounds (Dandia et al.,
2001a; 2001b; 2006; Sachdeva et al., 2011; Sachdeva and
Dwivedi, 2012), we report herein the synthesis of novel
2-substituted-N-[3-(pyridin-4-yl)-5-sulfanyl-4H-1,2,4-tria-
zol-4-yl]hydrazine carbothioamide derivatives (6a–j/7a–e)
(Scheme 1) (Tables 1, 2) by condensation of newly syn-
thesized 5-mercapto-3-(40-pyridyl)-4H-1,2,4-triazol-4-yl-
thiosemicarbazide (5) with substituted aromatic aldehydes/
1H-indole-2,3-diones, respectively, under conventional heating
and microwave irradiation. The structures of the synthesized
Table 2 Comparative results of synthesis of 7a–e under conventional
heating (D) and microwave irradiation (MW) methods
Entry
R
Time (min/h)
MW/D
Yield (%)
MW/D
M.P (oC)
7a
7b
7c
7d
7e
H
20/30
25/19
30/18
32/20
22/20
82/45
74/52
77/38
80/40
82/52
160
183
148
220
192
5-Cl
5-Br
5-CH3
5-NO2
SK
SH
CH2CH3
O
N
N
HN
NH
S
NH2
NH
O
N
O
NH2
O
NH2NH2.H2O
NH2NH2.H2O
CS2,Alc.KOH
NaOH,CS2,DMF
NH2NH2.H2O
N
(1)
N
(2)
N
N
(3)
(4)
SH
6a = Ar = C6H5
7a = R = H
N
N
N
SH
6b = Ar = 4-NO2C6H4
6c = Ar = 2-ClC6H4
6d = Ar = 3-ClC6H4
6e = Ar = 4-ClC6H4
7b = R = 5-Cl
7c = R = 5-Br
NH
N
N
NH
NH2
S
N
NH
NH
7d = R = 5-CH3
7e = R = 5-NO2
ArCHO
S
N
A/B/C
N
CHAr
(5)
6f = Ar = 4-OCH3C6H4
N
O
6g = Ar = 3,4,5-trimethoxyphenyl
6h = Ar = 3-OHC6H4
(6 a-j)
R
O
6i = Ar = 3-OH,4-OCH3C6H3
6j = Ar = 4-FC6H4
N
H
SH
N
N
A= K10 Clay, MW
B= EtOH Containing catalytic amount of AcOH, Reflux
C= EtOH Containing catalytic amount of AcOH, MW
N
NH
NH
N
S
N
H
N
O
(7 a-e)
Scheme 1 Synthesis of 2-Substituted-N-[3-(pyridin-4-yl)-5-sulfanyl-4H-1,2,4-triazol-4-yl]hydrazine carbothioamide derivatives (6a–j)/(7a–e)
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Med Chem Res
compounds are determined on the basis of their FTIR,
1HNMR, and 13C NMR spectra. Compounds have also been
screened for their anti-inflammatory activity and are found to
be biologically active (Figs. 1, 2).
Results and discussion
Reaction of ethyl isonicotinate and hydrazine hydrate in
absolute ethanol resulted in the formation of pyridine-4-
carbohydrazide (2) which on treatment with CS2 and KOH
produced potassium salt of pyridine-4-carbohydrazide (3)
in 12–18 h. Compound 3 was dissolved in water and 99 %
hydrazine hydrate was added and refluxed until evolution
of H2S ceases which was checked by decolorization of the
filter paper (black) when dipped in lead acetate solution
and then diluted with cold water, acidified with concen-
trated HCl to give white solid of 5-mercapto-4-amino-3-
(40-pyridyl)-1,2,4-triazole (4). Compound 5 was synthe-
sized by the reaction of 4 with NaOH and CS2 followed by
reaction with hydrazine hydrate. The reaction of 5 with
substituted aromatic aldehyde/1H-indole-2,3-diones was
carried out under conventional heating and microwave
irradiation to give novel 2-substituted-N-[3-(pyridin-4-yl)-
5-sulfanyl-4H-1,2,4-triazol-4-yl]hydrazine carbothioamide
derivatives (6/7), respectively (Scheme 1) (Tables 1, 2).
When the reaction of 5 was carried out with benzalde-
hyde/1H-indole-2,3-dione in the presence of glacial acetic
acid under conventional heating, 52/45 % yield of the
product 6a/7a was obtained with longer reaction time of
25/30 h, respectively. On the other hand, when compound
5 and benzaldehyde/1H-indole-2,3-dione were adsorbed on
montmorillonite K10 clay with the help of suitable solvent
and irradiated inside microwave oven, reaction was com-
pleted in 43/20 min giving 90/82 % yields of the products
6a/7a, respectively (Tables 1, 2). The products were
extracted and recrystallized from ethanol. Encouraged by
these results, we extended this reaction to variously
substituted aromatic aldehydes/1H-indole-2,3-diones under
similar conditions to furnish the respective Schiff bases (6
and 7) in good to excellent yields (74–90 %) without the
formation of any side products (Tables 1, 2, 3).
The in vivo anti-inflammatory activity of the synthe-
sized compounds 6b, 6c, 6e, 6g, and 6i was evaluated by
carrageenan-induced acute paw edema in rats and indo-
methacin as standard. Data of anti-inflammatory activity
were expressed as mean SD and Dunnett’s test was
applied to determine the significance of the difference
between the control group and rats treated with the test
compounds. The anti-inflammatory activity of compounds
was compared with the standard showing 84.00 % inhibi-
tion of rat paw edema whereas the tested compounds
showed inhibition ranging from 41.53 to 76.92 % after 5 h
(Table 4). QSAR studies were undertaken using the mul-
tiple linear regression (MLR) method to determine the role
of structural features that influence the observed activity of
the newly synthesized compounds.
100
80
1 h
2 h
5 h
60
40
20
0
6b
6c
6e
6g
6i
Std.
Fig. 1 Comparison of % edema inhibition shown by the test and
standard compounds at 1, 2, and 5 h
The structural assignments of the newly synthesized
compounds are based on spectroscopic data. IR spectrum
of compound 2 shows peaks at 3,325 cm-1 for N–H and
1,662 cm-1 for carbonyl (C=O) stretching. Appearance of
broad band at 3,425 cm-1 regarded as combination of
bands due to multiple (N–H) stretching and (OH) bands
(Keto-enol tautomers) shows the formation of compound 3.
The IR spectrum also shows absorptions at 1,660, 1,290,
and 1,050 cm-1 corresponding to C=O, NH–NH, and C=S
stretching vibrations, respectively. The disappearance of
absorption band at 1,050 (C=S) and 1,290 (NH–NH) in 3
and appearance of band at 1,648 (C=N) in 4 due to cycli-
zation and two peaks at 3,248 and 3,220 cm-1 due to
asymmetric and symmetric stretching of primary amino
group confirms the transformation of compound 3 into 4.
Formation of compound 5 is confirmed by the appearance
of absorption band at 1,342 (C=S) cm-1. Appearance of
Fig. 2 Plot of predicted activity against experimental activity for
compounds (R2 = 0.736)
123

Med Chem Res
Table 3 Infrared spectral data of the synthesized compounds (6a–j and 7a–e)
Compound
no.
Ar C–H stretching
(in cm-1
S–H stretching
(in cm-1
C=N stretching imine
(in cm-1
(–N=CH)
(in cm-1
(C=S)
(in cm-1
(C–N–C)
(in cm-1
)
)
)
)
)
)
6a
6b
6c
6d
6e
6f
3,152–3,066
3,132–3,026
3,150–3,046
3,124–3,016
3,162–3,023
3,151–3,060
3,152–3,066
3,142–3,046
3,152–3,066
3,132–3,040
3,142–3,054
3,152–3,083
3,152–3,073
3,122–3,043
3,122–3,045
2,360
2,340
2,346
2,344
2,360
2,330
2,360
2,350
2,360
2,343
2,370
2,332
2,332
2,332
2,346
1,670
1,660
1,674
1,658
1,672
1,650
1,670
1,663
1,670
1,664
1,652
1,662
1,661
1,652
1,673
1,570
1,522
1,529
1,512
1,518
1,532
1,542
1,523
1,518
1,618
1,615
1,620
1,620
1,617
1,634
1,363
1,343
1,351
1,360
1,353
1,363
1,363
1,361
1,363
1,350
1,373
1,362
1,363
1,361
1,373
1,216, 1,110, 1,064
1,226, 1,117, 1,054
1,215, 1,113, 1,045
1,217, 1,110, 1,054
1,216, 1,110, 1,070
1,256, 1,115, 1,064
1,216, 1,110, 1,064
1,226, 1,112, 1,044
1,216, 1,110, 1,064
1,210, 1,112, 1,044
1,213, 1,132, 1,044
1,216, 1,110, 1,064
1,216, 1,110, 1,064
1,216, 1,130, 1,051
1,216, 1,110, 1,064
6g
6h
6i
6j
7a
7b
7c
7d
7e
C=N stretching vibrations at 1,570 and 1,615 cm-1 shows
The anti-inflammatory activity was performed by car-
rageenan-induced acute paw edema method (Turner, 1965)
in rats. Albino rats of either sex, weighing between 200 and
250 g. were used in the experiment. Indomethacin 10 mg/
kg was administered as standard drug. The test compounds
were administered to the animals orally and after 1 h of the
treatment, 0.1 ml of 1 % carrageenan suspension was
injected subcutaneously in the subplantar tissue of the right
hind paw and 0.1 ml of saline was injected in the subpl-
antar tissue of the left hind paw (Winter et al., 1962).
Volumes of hind paws were measured using standard
mercury displacement technique. Percentage change in
paw volume at 0, 1, 2, and 5 h after drug administration
was calculated and compared between different treatments.
The percentage protection of the compounds was calcu-
lated and presented in Table 4.
the formation of compound 6 and 7, respectively.
Anti-inflammatory activity
The synthesized compounds 6b, 6c, 6e, 6g, and 6i were
evaluated for anti-inflammatory activity by carrageenan-
induced acute paw edema method (Turner, 1965) in rats.
Acute oral toxicity tests were performed for all the syn-
thesized compounds as per Organization of Economic Co-
operation and Development (OECD) guidelines. Statistical
analysis (ANOVA followed by using Dunnett’s test) was
performed for anti-inflammatory activity to ascertain the
significance of the exhibited activity.
The incorporation of Cl and OCH3 groups into phenyl
ring enhanced the anti-inflammatory activity of compounds
considerably. Among these triazole derivatives, 6e, 6c, and
6g showed significant reduction in paw edema. It was
observed that the substitution at para position is more
potent than at ortho and meta positions. The data obtained
(Table 4) revealed that paw edema was inhibited by oral
administration of the most tested compounds at a dose level
of 20 mg/kg. The most active test compounds were in the
decreasing order 6e > 6c > 6g > 6i > 6b with inhibition
effects ranging from 76.92 to 41.53 % compared to Indo-
methacin (84 %) at a dose of 10 mg/kg as standard drug.
Among the five compounds tested for anti-inflammatory
activity, compounds 6e, 6c, and 6g have shown significant
reduction in paw edema. The compound 6e showed the
highest protection of 76.92 %, followed by compounds 6c
and 6g showing 67.27 and 61.40 %, respectively.
QSAR study
In an attempt to determine the role of structural features
that appear to influence the observed activity of the
reported compounds, QSAR studies were undertaken using
the multiple linear regressions (MLR) method. Several
physicochemical descriptors such as hydrophobicity, topo-
logical indices, electronic parameters, and steric factors are
usually used in QSAR studies in order to find the effects of
different structural properties on the biological activity of
compound of interest.
All variables are examined on the best model which
depends on their of statistical parameters viz., Standard
error of estimate (s), and sequential Fischer value (F), and
123

Med Chem Res
Table 4 Anti-inflammatory activity of the synthesized compounds
Entry
0 h
1 h
2 h
5 h
Control
0.38 0.015
0.64 0.010
0.78 0.025
0.92 0.015
0.41 0.015
0.41 0.015
0.42 0.017
0.40 0.017
0.56 0.015*
14.27 %
0.58 0.025*
34.48 %
0.65 0.015*
41.53 %
6b
SH
N
N
N
NO 2
NH
NH
N
S
N
20mg/kg
0.46 0.015*
39.13 %
0.48 0.023**
62.50 %
0.55 0.010**
67.27 %
6c
6e
6g
SH
N
N
N
NH
NH
N
S
Cl
N
20mg/kg
0.44 0.025*
45.45 %
0.46 0.021**
69.56 %
0.52 0.015***
76.92 %
SH
N
N
N
Cl
NH
NH
N
S
N
20mg/kg
0.47 0.015*
36.17 %
0.51 0.015**
52.94 %
0.57 0.015**
61.40 %
SH
N
N
H3CO
N
OCH 3
OCH 3
NH
NH
N
S
N
20mg/kg
123

Med Chem Res
Table 4 continued
Entry
0 h
1 h
2 h
5 h
0.39 0.015
0.50 0.015*
28.00 %
0.54 0.015*
44.40 %
0.62 0.015*
48.38 %
6i
SH
N
N
N
OCH 3
OH
NH
NH
N
S
N
20mg/kg
Std.-indomethacin
0.40 0.017
0.42 0.015**
52.00 %
0.45 0.021***
73.00 %
0.50 0.015***
84.00 %
All values mean SD values using 5 animals in each group
Significant differences with respect to control group were evaluated by ANOVA, Dunnett’s ‘t’ test
* P \ 0.05, ** P \ 0.01, *** P \ 0.001
correlation coefficient (R), were used to evaluate the
obtained QASR. Acceptability of the regression model was
judged by examining the correlation coefficient (R), Fischer
value (F), and standard error of estimate (s), and performing
multiple liner regression analysis results in statistically sig-
nificant QASR models against anti-inflammatory activity.
The model when depends on only one parameter [C=N
STR] or [N–CHARGE] gave (R = 0.7,359, R = 0.7361),
respectively (Roy et al., 2009). The percentage of corre-
lation coefficient (R) increases when using two parameters
as shown in Eq. 1
software. The calculated descriptors were used as inde-
pendent variables in the regression analysis. The dependent
Table 5 Correlation matrix of used molecular descriptors with two
parameters Eq. 1 = a ? b 9 x1 ? c 9 x2
Descriptors
R
S
F
X1
X2
C=N length
*HOMO
Delt gap
C=N STR
C=N STR
C=N STR
C=N STR
C=N STR
C=N STR
LUMO
0.8124
0.7359
0.8703
0.8542
0.8689
0.8406
0.8325
0.8706
0.7361
1.3552
0.5462
1.1239
1.2014
1.1095
1.1898
1.1857
1.0953
0.3213
6.5502
61.2143
10.7059
7.2065
LUMO
T.E
Model-1 ¼ a þ b ꢁ x1 þ c ꢁ x2
ð1Þ
Delt gap
8.9038
Charge on C-atom
Heat formation
C=N length
*C=N length
7.5894
Model-1 shows very good correlation coefficient with
(R = 0.7359 and R = 0.7361), respectively, a significant
F value, and a low standard deviation, when the model
depends on two parameters, as Eq. 1 model A & B;
Tables 5 and 6 show the best correlation coefficient.
Since the calculated values of some electronic descrip-
tors depend on the three-dimensional molecular geometry,
the optimum 3-D geometry of the molecules were obtained
by Hyperchem software (Hypercube Inc, USA), using
AM1 semi-empirical method. Due to the presence of a
large number of atoms in the studied molecules (at least 20
carbon and heteroatoms) semi-empirical methods were pre-
ferred over the ab initio method to save calculated time.
The resulting structures were used to calculate constitutional,
functional, and topological descriptors by Dragon software.
Meanwhile some electronic descriptors such as frontier
molecular orbital (HOMO, LUMO), dipole moment, and
partial charges were calculated by the Hyperchem
7.0233
10.5943
133.5543
HOMO
* Excited state of highly occupied molecular orbital
Table 6 Calculated and experimental data for the synthesized
compounds
Compounds Mp MPC Activity vector (log 1/ki)
Experimental Predicted by cross
validation
6b
6c
6e
6g
6i
0.73 0.38 -1.6
0.72 0.28 -1.9
0.72 0.25 -1.3
0.73 0.29 -2.3
0.68 0.32 -2.5
-1.35
-1.98
-1.52
-2.01
-1.69
Mp molecular polarizability, MPC maximum positive charge
123

Med Chem Res
variable is the activity of compounds expressed as the
logarithm of reciprocal inhibition percentage [log (1/ki)]
(Todeschini, 2001).
the compounds were characterized by spectral data. The
study successfully reports synthesis of 2-substituted-N-
[3-(pyridin-4-yl)-5-sulfanyl-4H-1,2,4-triazol-4-yl]hydrazin
ecarbothioamide derivatives with moderate to good
yields. The microwave method is found to be superior
with higher yields, tremendous reduction in time, and is
environmentally benign. Among the compounds tested
for anti-inflammatory activity, compounds 6e, 6c, and
6g have shown significant reduction in paw edema. The
compound 6e showed the highest protection of 76.92 %,
followed by compounds 6c and 6g which showed 67.27
and 61.40 %, respectively. With further molecular
modification and manipulation of these compounds,
several other promising bioactive molecules can be
developed in the future.
The presence of co-linear descriptors may cause diffi-
culties in certain aspects of forming a QSAR model, and
hence the predictivity and generalization of a model will
generally fail in the presence of highly co-linear descrip-
tors. In order to overcome this problem, the correlation of
the calculated descriptors with each other was examined
and collinear descriptors (r [ 0.9) were determined.
Among these, one of them, which had the highest corre-
lation with the dependent variable, was retained and others
were removed from the data matrix.
The resulted matrix of non co-linear descriptors were
used to find a multilinear equation of the form log(1/
ki) = b0 ? b1DES1 ? b2DES2 ? ꢀꢀꢀ between activity and
structural parameters. The stepwise selection and elimina-
tion of variables by SPSS software was used to find the best
set of descriptors (Sharma et al., 2004; Khalafi-Nezhad
et al., 2005; Kuramochi et al., 2005).
QSAR studies clearly showed that the compounds con-
taining nitro group are more potent than their correspond-
ing chloro series which could be due to lower molecular
polarizability values. Addition of MPC with a negative
coefficient to second equation increased the correlation of
the resulting equation. Since polarization can be related to
two main contributors of electronic and atomic polariza-
tion, it seems that polarization, rather than electrostatic
field are affecting the positive and negative charge of these
two descriptors. From the results of QSAR study, it is
concluded that electronic distribution is one of the most
important factors in determination of activity for this group
of compounds.
To improve the regression coefficients and attain a more
predictive equation, 6b and 6e were considered as outliers
and excluded from the model. Significant correlations were
found in model using constitutional and electronic
descriptors (Eqs. 2 and 3, respectively):
Log(1=kiÞ ¼ ꢂ23:6ðꢃ4:19Þ þ 30:11ðꢃ5:27Þ Mp
ð2Þ
N ¼ 10; R2 ¼ 0:77; Se ¼ 0:15; F ¼ 27:45
Log(1=kiÞ ¼ 24:88ðꢃ3:718Þ þ 32:464ðꢃ5:168Þ Mp
ꢂ 1:49ðꢃ :0796Þ MPC
N ¼ 10; R2 ¼ 0:85; Se ¼ 0:13; Rc2v ¼ 0:74; F ¼ 19:77
ð3Þ
Experimental
General
QSAR results of the biological assay showed that all three
active compounds (6b, 6g, 6i) belonging to nitro and
methoxy group were the most active analogs. Maximum
positive charge represents the maximum positive charge of
atoms in a molecule (Qmax = max (q?) and the charge
polarization is the mean absolute atomic charge in
molecules defined as
Reagents and solvents were obtained from commercial
sources and used without further purification. Melting points
were determined on a Toshniwal apparatus. The spectral
analyses of synthesized compounds have been carried out at
SAIF, IIT Madras. Purity of all compounds was checked by
TLC using ‘‘G’’ coated glass plates and n-hexane:ethyl
acetate:methanol (6:3.5:0.5) and hexane:ethyl acetate (6:4)
as eluent. IR spectra were recorded in KBr on a Perkin Elmer
Infrared RXI FTIR spectrophotometer, and 1H NMR spectra
were recorded on Bruker Avance II 500 NMR Spectrometer
using CDCl3 as solvent and tetramethylsilane (TMS) as
internal reference standard. The obtained products were
identified from their spectral (1H NMR, 13CNMR, and IR)
data. The microwave-assisted reactions were carried out in a
‘‘Catalysts Systems’’ Scientific Multimode MW oven
attached with a magnetic stirrer and reflux condenser,
operating at 700 W generating 2,450 MHz frequency.
P ¼ R ðjqj=AÞ ¼ Q=A:
The presence of molecule polarizability in EQ and its
direct relationship with activity vector was in accord with
results obtained from structure activity relationship (SAR).
Conclusions
A novel series of Schiff bases were synthesized by
conventional and microwave irradiation methods and all
123

Med Chem Res
Compounds were synthesized following the literature
reaction is checked by TLC using n-hexane:ethyl acetate as
eluent. (6:4). Yield 45 % m.p. 208–210 °C, IR (KBr, cm-1
method (Aniket et al., 2009)
)
2,360 (S–H str), 1,646 (C=N str imine), 1,532 (C–N), 1,342
(C=S), 1,210, 1,110, 1,054 (C–N–C).
Synthesis of pyridine-4-carbohydrazide (2)
A mixture of ethyl isonicotinate (80 gm; 0.53 mol) and
hydrazinehydrate(30 gm;29.12 ml;0.614 mol)wasrefluxed
in absolute ethanol (136 ml) for 6–7 h. After the completion
of reaction (as monitored by TLC using hexane:ethyl acetate
(6:4) as eluent), excess ethanol was distilled off. The reaction
mixture was cooled to room temperature and white crystals of
nicotinic acid hydrazide precipitated were filtered. Yield (%)
76 %, m.p. 168–170 °C, IR (KBr, cm-1): 3,325 (NH), 3,265
(CH of pyridyl), 1,662 (CONH), 1,587 (C=N).
General microwave procedure for synthesis of Schiff
bases of 5-mercapto-3-(40-pyridyl)-4H-1,2,4-triazol-
4-yl-thiosemicarbazide 6a–6j/7a–7e
5-Mercapto-3-(40-pyridyl)-4H-1,2,4-triazole-4-yl-thiose-
micarbazide 5 (1 mmol) and various aromatic aldehydes
(1.5 mol)/1H indole-2,3-dione (1 mmol) were adsorbed
on montmorillonite K10 clay with the help of suitable
solvent and irradiated inside microwave oven at power 6
(420 watt, 60 %) for 20–45 min resulting in the formation
of 6 and 7, respectively. The progress of reaction was
monitored by TLC. Final product was extracted and re-
crystallized from ethanol.
Synthesis of potassium salt of pyridine-
4-carbohydrazide (3)
To a solution of pyridine-4-carbohydrazide (2) in absolute
ethanol (290 ml), the carbon disulfide and potassium
hydroxide were added. This mixture was agitated for
12–18 h. It was then diluted with 207 ml of dry ether and
the product was filtered and vacuum dried at 65–70 °C.
The salts prepared as described above were obtained in
nearly quantitative yields and were used without further
purification.
Spectroscopic characterization data of the synthesized
compounds are given below:
2-Benzylidene-N-[3-(pyridin-4-yl)-5-sulfanyl-4H-1,2,4-tria-
zol-4-yl]hydrazine carbothioamide (6a) 1H NMR
(400 MHz, DMSO): 14.53 (s, 1H, SH), 10.4 (s, 1H, NH);
8.1 (s, 1H, CH), 7.67–8.45 (m, 4H, pyridyl), 7.52–7.66 (m,
5H, Ar–H), 2.73 (s, 1H, NH) ppm. 13C-NMR (400 MHz,
DMSO): 185, 164, 160, 148, 137, 126, 123, 120, 119 ppm.
Anal. Calcd. for C15H13N7S2: C, 50.69, H, 3.69, N, 27.58.
Found: C, 50.48, H, 3.67, N, 27.61.
Synthesis of 5-mercapto-4-amino-3-(40-pyridyl)-1,2,4-
triazole (4)
Compound 3 (0.1 mol) was dissolved in water. To it, 99 %
of 10 gm hydrazine hydrate (28.1 ml, 0.2 mol) was added.
The reaction mixture was refluxed on a water bath until the
evolution of H2S gas ceased. It was then diluted with cold
water (20–30 ml) and carefully acidified with concentrated
hydrochloric acid. The white solid thus separated was fil-
tered, washed with cold water, and dried and recrystallized
from ethanol. TLC using hexane:ethyl acetate:methanol
(6:3.5:.5) as eluent. Yield 78 %, m.p. 222–224 °C, IR (KBr,
cm-1) 3,220–3,248 (NH2), 3,128 (C–N), 3,042 (–CH),
1,530 (C–N), 1,648 (C=N), 1,228, 1,110, 1,046 (C–N–C).
2-(4-Nitrobenzylidene)-N-[3-(pyridin-4-yl)-5-sulfanyl-4H-1,
2,4-triazol-4yl]hydrazine carbothioamide (6b) 1H-NMR
(400 MHz, DMSO): 14.34 (S, 1H, SH), 10.16 (S, 1H, NH);
8.41 (S, 1H, CH), 7.55–8.36 (m, 4H, pyridyl), 7.17–7.43
(m, 4H, Ar–H), 2.44 (S, 1H, NH) ppm. 13C-NMR
(400 MHz, DMSO): 182, 165, 158, 146, 135, 128, 123,
120, 117 ppm. Anal. Calcd. for C15H12N8O2S2: C, 44.99,
H, 3.02, N, 27.98. Found: C, 45.17, H, 3.00, N, 27.58.
2-(2-Chlorobenzylidene)-N-[3-(pyridin-4-yl)-5-sulfanyl-
4H-1,2,4-triazol-4-yl]hydrazine carbothioamide (6c) 1H-
NMR (400 MHz, DMSO): 14.12 (s, 1H, SH), 10.34 (s, 1H,
NH); 8.11 (s, 1H, CH), 7.35–8.25 (m, 4H, pyridyl),
7.18–7.61 (m, 4H, Ar–H), 2.5 (s, 1H, NH) ppm. 13C-NMR
(400 MHz, DMSO): 182, 169, 160, 142, 135, 126, 123,
121, 115 ppm. Anal. Calcd. for C15H12ClN7S2: C, 46.21,
H, 3.10, N, 25.15. Found: C, 46.03, H, 3.11, N, 25.12.
General procedure for synthesis of 5-mercapto-3-(40-
pyridyl)-4H-1,2,4-triazol-4-yl-thiosemicarbazide (5)
To a solution of 4 (0.01 mol, 2 gm) in DMF (10 ml) sodium
hydroxide (0.015 mol, 0.62 gm) and carbon disulfide
(0.015 mol, 1.12 ml) were added and the reaction mixture
was stirred at 15–20 °C for 1 h. To the stirred mixture
hydrazine hydrate (0.015 mol) was added and stirring was
continued at 60 °C for 1 h, more on adding water, a pale
white solid separated out which on recrystallization from
DMF-ethanol afforded pale white crystals. Completion of
2-(3-Chlorobenzylidene)-N-[3-(pyridin-4-yl)-5-sulfanyl-
4H-1,2,4-triazol-4-yl]hydrazine carbothioamide (6d) 1H-
NMR (400 MHz, DMSO): 14.24 (s, 1H, SH), 10.32 (s, 1H,
NH); 8.13 (s, 1H, CH), 7.62–8.65 (m, 4H, pyridyl),
7.14–7.50 (m, 4H, Ar–H), 2.38 (s, 1H, NH) ppm. 13C-NMR
123

Med Chem Res
2-(4-Fluorobenzylidene)-N-[3-(pyridin-4-yl)-5-sulfanyl-4H-1,
2,4-triazol-4-yl]hydrazine carbothioamide (6j) 1H-NMR
(400 MHz, DMSO): 13.62 (s, 1H, SH), 9.2 (s, 1H, NH);
8.14 (s, 1H, CH), 7.62–8.55 (m, 4H, pyridyl), 7.10–7.45
(m, 4H, Ar–H), 2.40 (s, 1H, NH) ppm. 13C-NMR
(400 MHz, DMSO): 182, 167, 160, 150, 148, 131, 127,
116 ppm. Anal. Calcd. for C15H12FN7S2: C, 48.24, H, 3.24,
N, 26.26. Found: C, 48.05, H, 3.26, N, 26.28.
(400 MHz, DMSO): 186, 166, 161, 143, 140, 131, 124, 122,
117 ppm. Anal. Calcd. for C15H12ClN7S2: C, 46.21, H, 3.10,
N, 25.15. Found: C, 46.07, H, 3.08, N, 25.18.
2-(4-Chlorobenzylidene)-N-[3-(pyridin-4-yl)-5-sulfanyl-
4H-1,2,4-triazol-4-yl]hydrazine carbothioamide (6e) 1H-
NMR (400 MHz, DMSO): 14.33 (s, 1H, SH), 10.4 (s, 1H,
NH); 8.41 (s, 1H, CH), 7.45–8.65 (m, 4H, pyridyl),
7.10–7.50 (m, 4H, Ar–H), 2.44 (s, 1H, NH) ppm. 13C-NMR
(400 MHz, DMSO): 184, 164, 160, 146, 140, 131, 124, 122,
113 ppm. Anal. Calcd. for C15H12ClN7S2: C, 46.21, H, 3.10,
N, 25.15. Found: C, 46.59, H, 3.09, N, 25.13.
2-(2-Oxo-1,2-dihydro-3H-indol-3-ylidene)-N-[3-(pyridin-
4-yl)-5-sulfanyl-4H-1,2,4-triazol-4-yl]hydrazinecarbothioa-
mide (7a) 1H-NMR (400 MHz, DMSO): 14.06 (s, 1H,
SH), 10.98 (s, 1H, NH, indole), 8.71 (s, 1H, NH); 8.09 (s,
1H, CH), 7.51–7.96 (m, 4H, pyridyl), 6.90–7.06 (m, 4H,
Ar–H), 2.80 (s, 1H, NH) ppm. 13C-NMR (400 MHz,
DMSO): 184, 167, 161, 150, 146, 138, 133, 124, 121,
117 ppm. Anal. Calcd. for C16H12N8OS2: C, 48.47, H,
3.05, N, 28.26. Found: C, 48.69, H, 3.03, N, 28.23.
2-(4-Methoxybenzylidene)-N-[3-(pyridin-4-yl)-5-sulfanyl-
4H-1,2,4-triazol-4-yl] hydrazine carbothioamide (6f) 1H-
NMR (400 MHz, DMSO): 13.80 (s, 1H, SH), 10.05 (s, 1H,
NH), 8.74 (s, 1H, CH), 7.62–7.99 (m, 4H, pyridyl),
6.90–7.35 (m, 4H, Ar–H), 3.81 (s, 3H, OCH3), 2.61 (s, 1H,
NH) ppm. 13C-NMR (400 MHz, DMSO): 189, 164, 160,
150, 131, 122, 114, 56 ppm. Anal. Calcd. for C16H15N7OS2:
C, 49.85, H, 3.92, N, 25.44. Found: C, 49.33, H, 3.90, N,
25.47.
2-(5-Chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-N-
[3-(pyridin-4-yl)-5-sulfanyl-4H-1,2,4-triazol-4-yl]hydra-
zinecarbothioamide (7b) 1H-NMR (400 MHz, DMSO):
13.44 (s, 1H, SH), 10.82 (s, 1H, NH, indole), 8.93 (s, 1H,
NH); 8.11 (s, 1H, CH), 7.55–8.65 (m, 4H, pyridyl), 6.96-
7.63 (m, 3H, Ar–H), 2.01 (s, 1H, NH) ppm. 13C-NMR (400
MHz, DMSO): 188, 165, 160, 151, 146, 136, 126, 120,
114 ppm. Anal. Calcd. for C16H11ClN8OS2: C, 44.60, H,
2.57, N, 26.00. Found: C, 44.38, H, 2.59, N, 26.03.
N-[3-(pyridin-4-yl)-5-sulfanyl-4H-1,2,4-triazol-4-yl]-2-
(3,4,5-trimethoxybenzylidene) hydrazine carbothioamide
(6g) 1H-NMR (400 MHz, DMSO): 13.80 (s, 1H, SH),
10.04 (s, 1H, NH), 8.80 (s, 1H, CH), 7.65–7.91 (m, 4H,
pyridyl), 6.89–7.14 (m, 2H, Ar–H), 3.84–4.39 (s, 9H,
OCH3), 2.91(s, 1H, NH) ppm. 13C-NMR (400 MHz,
DMSO): 184, 167, 162, 150, 148, 142, 130, 124, 114, 58,
56 ppm. Anal. Calcd. for C18H19N7O3S2: C, 48.53, H, 4.30,
N, 22.01. Found: C, 48.39, H, 4.32, N, 22.03.
2-(5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-N-
[3-(pyridin-4-yl)-5-sulfanyl-4H-1,2,4-triazol-4-yl]hydra-
zinecarbothioamide (7c) 1H-NMR (400 MHz, DMSO):
13.52 (s, 1H, SH), 10.12 (s, 1H, NH, indole), 8.9 (s, 1H,
NH); 8.12 (s, 1H, CH), 7.55–8.65 (m, 4H, pyridyl),
7.02–7.43 (m, 3H, Ar–H), 2.04 (s, 1H, NH) ppm. 13C-NMR
(400 MHz, DMSO): 185, 164, 158, 148, 138, 132, 126, 121,
119 ppm. Anal. Calcd. for C16H11BrN8OS2: C, 40.43, H,
2.33, N, 23.57. Found: C, 40.20, H, 2.35, N, 23.55.
2-(3-Hydroxybenzylidene)-N-[3-(pyridin-4-yl)-5-sulfa-
nyl-4H-1,2,4-triazol-4-yl] hydrazine carbothioamide
(6h) 1H-NMR (400 MHz, DMSO): 13.92 (s, 1H, SH), 9.85
(s, 1H, NH), 9.77 (s, 1H, OH), 8.1 (s, 1H, CH) 7.65–8.11 (m,
4H, pyridyl), 7.14–7.35 (m, 4H, Ar–H), 2.42 (s, 1H, NH)
ppm. 13C-NMR (400 MHz, DMSO): 188, 162, 160, 148,142,
131, 126, 121, 114 ppm. Anal. Calcd. for C15H13N7OS2: C,
48.50, H, 3.53, N, 26.40. Found: C, 48.35, H, 3.51, N, 26.43.
2-(5-Methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-N-
[3-(pyridin-4-yl)-5-sulfanyl-4H-1,2,4-triazol-4-yl]hydra-
zinecarbothioamide (7d) 1H-NMR (400 MHz, DMSO):
13.33 (s, 1H, SH), 10.98 (s, 1H, NH, indole), 8.71 (s, 1H,
NH); 8.09 (s, 1H, CH), 7.5–8.34 (m, 4H, pyridyl), 6.90-7.96
(m, 3H, Ar–H), 2.56 (s, 3H, CH3), 2.74 (s, 1H, NH) ppm.
13C-NMR (400 MHz, DMSO): 187, 161, 150, 147, 136,
130, 127, 119, 26 ppm. Anal. Calcd. for C17H14N8OS2: C,
49.74, H, 3.44, N, 27.30. Found: C, 49.54, H, 3.46, N, 27.33.
2-(3-Hydroxy-4-methoxybenzylidene)-N-[3-(pyridin-4-yl)-
5-sulfanyl-4H-1,2,4-triazol-4-yl]hydrazine carbothioamide
(6i) 1H-NMR (400 MHz, DMSO): 13.86 (s, 1H, SH),
10.32 (s, 1H, NH); 8.1 (s, 1H, CH) 7.65-8.55 (m, 4H,
pyridyl), 7.14-7.35 (m, 3H, Ar–H), 3.78 (s, 3H, OCH3),
2.41 (s, 1H, NH) ppm. 13C-NMR (400 MHz, DMSO): 186,
165, 160, 150, 146, 132, 128, 117, 58 ppm. Anal. Calcd.
for C16H15N7O2S2: C, 47.87, H, 3.77, N, 24.42. Found: C,
48.06, H, 3.75, N, 24.39.
2-(5-Nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-N-[3-
(pyridin-4-yl)-5-sulfanyl-4H-1,2,4-triazol-4-yl]hydra-
zinecarbothioamide (7e) 1HNMR 13.42 (s, 1H, SH),
10.12 (s, 1H, NH, indole), 8.95 (s, 1H, NH); 8.11 (s, 1H,
123

Med Chem Res
thiosemicarbazides derived from diflunisal hydrazide. Eur J
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CH), 7.65-8.49 (m, 4H, pyridyl), 6.92–7.53 (m, 3H, Ar–H),
2.08 (s, 1H, NH) ppm. 13C-NMR (400 MHz, DMSO): 187,
164, 150, 146, 136, 130, 123, 118 ppm. Anal. Calcd. for
C16H11N9O3S2: C, 43.53, H, 2.51, N, 28.56. Found: C,
43.70, H, 2.49, N, 28.52.
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Acknowledgments The authors are thankful to the Dean, FET,
MITS, for providing necessary research facilities in the department.
Financial assistance from FET, MITS is gratefully acknowledged.
They are also thankful to the Director, SAIF, Punjab University,
Chandigarh for the spectral and elemental analyses and Mr Pradeep
Goyal, Goenka College of Pharmacy, Department of Pharmacology,
Laxmangarh for helping in performing anti-inflammatory activity.
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