Synthesis and anticonvulsant activity of some new series of pyrrole derivatives

Article abstract of DOI:10.1007/s00044-011-9919-3

A new series of compounds 3a-f were synthesized from condensation method. Newly synthesized compounds were established by IR, 1H NMR, 13C NMR, mass spectral and elemental analysis. Synthesized compounds 3a-f were screened for anticonvulsant activity. The

Full text of DOI:10.1007/s00044-011-9919-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:3699–3708
DOI 10.1007/s00044-011-9919-3
ORIGINAL RESEARCH
Synthesis and anticonvulsant activity of some new series of pyrrole
derivatives
•
A. Idhayadhulla R. Surendra Kumar
•
•
A. Jamal Abdul Nasser S. Kavimani
•
S. Indumathy
Received: 24 June 2011 / Accepted: 17 November 2011 / Published online: 2 December 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A new series of compounds 3a–f were synthe-
sized from condensation method. Newly synthesized com-
derivative has received considerable attention of synthetic
importance (Toja et al., 1987) and importance of anticon-
vulsant activity (Sorokina et al., 1989; Carson et al., 1997)
and other pharmacological activity, such as antiviral
(Almerico et al., 2000), cytotoxicity (Dannhardt et al., 2000)
and treatment of hyperlipidemias (Justin et al., 2004).
1
pounds were established by IR, H NMR, 13C NMR, mass
spectral and elemental analysis. Synthesized compounds
3a–f were screened for anticonvulsant activity. The com-
2,20-({3-methyl-5-[2-phenylethenyl]-1H-pyrrole-
pound
2,4-diyl}dicarbonyl)dihydrazinecarbothioamide 3a showed
significant activity compared with other compounds 3b–f
against pentamethylene tetrazole-induced seizures.
Our previous investigations have shown that the 1,4-
dihydropyridine connecting with thiosemicarbazide and their
anticonvulsant activity (Surendra Kumar et al., 2010) and
more example for other pervious finding thiosemicarbazone
derivatives and their anticonvulsant activity (Chapleo et al.,
1988; Pandeya and Dimmock 1993; Ragab et al., 2010; Aly
et al., 2010; Kshirsagar et al., 2009; Karki et al., 2009;
Yogeeswari et al., 2002, 2005; Mohsen et al., 2010; Taroual
et al., 1996; Dimmock et al., 1990, 1995), and other activity
of thiosemicarbazone derivatives, such as antimicrobial
(Surendra Kumar et al., 2010), anticoagulant (Surendra
Kumar et al., 2011a, b, c), anticancer activities (Surendra
Kumar et al., 2011a, b, c), anti-inflammatory (Bindu et al.,
1999), and antifertility properties (Srivastava et al., 2002).
Structure–activity relationships (SARs) have been very use-
ful in the search of patterns that correlate the anticonvulsant
activity of a molecule with its structural properties and
reactivity features (Tripathi et al., 2011). These references
will serve as the main rationales for the synthesis of new
pyrrole connecting thiosemicarbazione derivatives 3a–f
(Scheme 1) and evaluate them for anticonvulsion activity.
Keywords Pyrrole and thiosemicarbazone derivatives ꢀ
Spectral analysis ꢀ Anticonvulsion activity ꢀ
Structure–activity relationships
Introduction
In recent years, anticonvulsants drug development has been
one of the most prominent research areas. Although several
new anticonvulsants are already in clinical use, some types of
seizures are still not adequately treated with current therapy
and have limitations, intolerable side effects. In response to
these limitations, the development of new drugs to optimally
manage seizures has been strongly advocated. Thus, the
search for new anticonvulsant drugs continues to be an active
area of investigation in medicinal chemistry. Pyrrole
A. Idhayadhulla ꢀ R. Surendra Kumar ꢀ
A. Jamal Abdul Nasser (&)
Results and discussion
P.G & Research Department of Chemistry, Jamal Mohamed
College, Tiruchirappalli 620020, Tamil Nadu, India
e-mail: jamal_abdulchem@ymail.com
Chemistry
S. Kavimani ꢀ S. Indumathy
The route used for synthesis of the new pyrrole derivatives
assessed in this study is shown in Scheme 1. Ethyl-3-oxo-5-
Department of Pharmacology, Mother Theresa Post Graduate &
Research Institute of Health Science, Puducherry 605006, India
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Med Chem Res (2012) 21:3699–3708
CHO
O
O
O
EtOH
EtO
O
+
OEt
CH3
R
R
1a-f
O
O
O
O
O
O
O
NaNo2
Zn, HOAc
H2O, Δ
H3C
OEt
H3C
OEt
HOAc, H2O
H3C
OEt
NOH
NH2
O
H3C
OEt
H3C
O
OEt
O
EtO
+
HOAc
N
H
NH2
O
EtO
O
R
R
2a-f
1a-f
H
N
NH2
O
O
H3C
N
H
H3C
OEt
S
H2N NH
S
DMSO
O
+
NH2
O
N
H
N
H
NH
HN
EtO
H2N
R
R
S
3a-f
2a-f
Scheme 1 Synthetic route of compounds 1a–f, 2a–f and 3a–f
phenylpent-4-enoate (1a) was synthesized directly by re-
fluxing ethyl acetoacetate, benzaldehyde in ethanol medium.
Diethyl 3-methyl-5-[2-phenylethenyl]-1H-pyrrole-2,4-
dicarboxylate (2a) was prepared from Fischer and Noller
condensation method by ethyl acetoacetate and glacial
acetic acid, and was cooled to an efficient freezing mixture
to 5°C. Sodium nitrite was added dropwise with vigorous
stirring at such a rate that the temperature remained
between 5 and 7°C and added dropwise to compound 1a,
and the mixture was stirred at room temperature. Zinc dust
was added to the reaction mixture and the mixture was
heated and refluxed for 1 h and poured into the water. After
standing overnight, the crude product was obtained then
filtered by suction, and washed with water (Fischer and
Noller 1935).
DMSO and ethanol medium by hydrazinolysis method
(Refaat et al., 2004; Ojha et al., 2007). The physicochemical
characteristics of compounds are presented in (Table 1).
The structure of the synthesized compounds is estab-
1
lished on the basis of IR, H NMR and 13C NMR and
elemental analyses. The IR spectra of the compound 1a
show an absorption band at 1,755 cm-1 corresponding to
C=O stretching in ester group, with another absorption
band at 3,050 cm-1 corresponding to phenyl ring CHstr.
Compound 1b, shows an absorption band at 832 cm-1
corresponding to Cl–C group, compound 1c shows an
absorption band at 1465 cm-1 corresponding to OH–C
group and compound 1d shows an absorption bands
observed at 1534 cm-1 corresponding to NO2–C group.
The 1H NMR spectrum of compound 1a shows a singlet
at d 7.64 attributable to HC=CH protons closest to the
phenyl ring and d 6.92 attributable to HC=CH proton
closest to carbonyl group.
2,20-({3-Methyl-5-[2-phenylethenyl]-1H-pyrrole-2,4-diyl}
dicarbonyl)dihydrazinecarbo thioamide (3a) was synthe-
sized from compound (2a) reacted with thiosemicarbazide
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Med Chem Res (2012) 21:3699–3708
3701
A singlet was observed at d 6.12 corresponding to NH
protons in pyrrole ring. Another important peak observed at
d 4.20, 1.30 corresponding to OCH2CH3 and OCH2CH3
protons in pyrrole ring.
Table 1 Physicochemical data of synthesized compounds
Compd. no.
R
M.P.
Yield %
M.W.
1a
1b
1c
1d
1e
1f
H
127
135
141
158
147
156
115
127
132
141
154
160
95
56
61
67
66
57
51
57
65
54
57
58
51
67
57
59
62
54
65
188.22
222.66
204.22
233.22
218.24
231.29
327.37
361.81
343.37
372.37
357.40
370.44
417.50
451.95
433.50
462.50
447.53
460.57
4-Cl
The IR spectrum of the compound 3a shows an
absorption bands at 3354, 3249, 1267, 1717, 1096 and
812 cm-1 corresponding to NH, NH2, C=S, C=O, N–C–N
and Ar-Hstr group, respectively. The 1H NMR spectrum of
compound 3a shows a singlet at d 9.66 corresponding to
NH2 protons and NH, 2,4-CONH protons resonated as a
singlet at d 6.15, 10.71, respectively. The 13C NMR
spectrum of the compound 3a shows peaks at d 123.6,
143.5, 118.5 and 144.7 corresponding to 2C, 3C, 4C and
5C carbons present in pyrrole ring. The peaks obtained at d
164.8 and 162.5 corresponding to the 2-position of CONH
and the 4-position of CONH groups, respectively. Mass
spectrum of compound 3a shows the molecular ion peak
(m/z 418.50) in Fig. 1, which is confirmed by the molecular
mass of the compound 3a. Mass spectral fragmentation is
representing in Fig. 2.
4-OH
4-NO2
4-CH3O
4-(CH3)2N
H
2a
2b
2c
2d
2e
2f
4-Cl
4-OH
4-NO2
4-CH3O
4-(CH3)2N
H
3a
3b
3c
3d
3e
3f
4-Cl
112
118
121
101
91
4-OH
4-NO2
4-CH3O
4-(CH3)2N
Anticonvulsant activity
The compounds 3a–f were evaluated for anticonvulsant
activity. Figure 3 shows the effect of compounds 3a–f on
the duration of convulsions induced by pentamethylene
tetrazole. Anticonvulsant activity values of the compounds
3a–f are summarized in Table 2.
The IR spectrum of compound 2a shows an absorption
band at 3,342 cm-1 corresponding to NHstr group, and
another absorption band at 1,747 cm-1 corresponding to
C=Ostr in the ester group. The 1H NMR spectrum of
compound 2a shows a singlet at d 7.01 attributable to
HC=CH proton closest to the phenyl ring protons and d
6.92 attributable to HC=CH protons closest to carbonyl
group.
Compounds 2a–f is inactive at the doses tested, while
compounds 3a–f causes a slight decrease at 10 mg/kg,
which is not of a high statistical significance.
Fig. 1 Mass spectrum of compound 3a
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Med Chem Res (2012) 21:3699–3708
Fig. 2 Mass spectral
fragmentation of compound 3a
O
NH2
.+
H3C
NH2
NH
O
NH
NH
H3C
-2CSNH2
O
S
O
N
H
N
H
NH
H2N
NH
NH
S
H2N
m/z 418.50
m/z 298.32
.+
.+
O
H3C
H3C
O
-2CO
N
H
-NH2NH2
N
H
m/z 183.24
.+
m/z 239.26
.+
-CH3
-Ph
N
H
N
H
CH2
m/z 93.12
m/z 169.22
.+
-H2C=C
N
H
m/z 67.12
70
60
50
40
30
20
10
0
3c–e was inactive in this test, since this compound does not
alter the threshold of neuronal excitability towards chem-
ically induced convulsions. Instead, all compounds studied,
and especially 3a, cause a significant decrease in the
number of animals affected by convulsions.
5 mg/kg
10 mg/kg
Compounds 3b and 3f show that low activity compared
with compound 3a, it can be conciliated that the compound 3a
displaysgoodanticonvulsantproperties, whilethecompounds
3c–e arenoactivityatbothdoses tested(5and 10 mg/kg). The
doses can be concluded as being far from lethal, since doses of
10 mg/kg caused no signs of toxicity during the 24 h fol-
lowing its administration to a group of animals.
It can be concluded that the compound 3a seems to act by
raising the threshold of neuronal excitability without
affecting the propagation of impulses, since they cause a
decrease in the percentage of animals affected by convul-
sions but do not significantly alter the duration of the sei-
zures. Such behaviour resembles that of barbiturates rather
than that displayed by classical anticonvulsant pyrrole
derivatives like phenytoin. Further pharmacological and
Compounds
Fig. 3 Compounds 3a–f against duration of convulsion(s), Phenytoin
is used as a standard
The effect of compounds 3a–f on neuronal excitability
as measured by their influence on the percentage of animals
affected by convulsion is shown in Table 3. The compound
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Med Chem Res (2012) 21:3699–3708
3703
2.05 ppm
Table 2 Effect of compounds 3a–f on the duration of pentamethyl-
ene tetrazole-induced convulsions, P, statistical significance accord-
ing to Student’s t test
NH2
9.66 ppm
O
H
N
2.45 ppm
H3C
N
H
S
Compound
Dose
(mg/kg)
Duration of
convulsion (s)
mean SEM
P
Percentage
of activity
10.71 ppm
O
7.05 ppm
H
N
H
6.15 ppm
2.05 ppm
HN
Placebo
–
63.6 0.92
42.2 1.23
21.8 1.82
51.2 1.07
32.8 1.34
0a
–
–
NH
10.71 ppm
3a
5
[0.001
33
66
19
48
0
H
6.90 ppm
10
5
[0.001
H2N
9.66 ppm
3b
[0.001
S
10
5
[0.001
Fig. 4 1H NMR signals in compound 3a
3c
0
10
5
0a
0a
0
0
3d
0
0
10
5
0a
0a
0a
0
0
based on characteristic signal positions of functional
groups, spin multiplicity. Aromatic proton peaks of 3a
appear in the region of 7.39–7.62 ppm as multiples. The
methyl protons attached to the pyrrole ring is resonating in
the region of 2.45 ppm as singlet with three proton inte-
grals. Pyrrole ring carbon 2,4 attached CONH appears at
10.75 ppm as a doublet and NH–NH at 2.05 ppm as a
doublet. The doublet splitting with coupling constant value
of 3.00 Hz at 10.71 ppm and the doublet splitting with
coupling constant value of 3.50 Hz at 2.05 ppm are due to
two proton of carbon 2,4 attached –CO–NH–NH, respec-
tively. Another interesting point here is that since the
CH=CH in pyrrole 5 position singlet 7.05 ppm and
CH=CH singlet appeared at 6.90 ppm of geometrical E
isomer is expected as 1H NMR provide set of signals
(Fig. 4).
The 13C NMR spectrum of compound 3a, aromatic
carbon in the region of 137.50–128.50 ppm and methyl
group at 3-position in pyrrole ring, thus the peak appearing
in the downfield of the two signals 12.1 ppm. The carbons
2 and 3 resonated at 123.6 and 143.5 ppm and CH=CH in
pyrrole 5 position singlet 123.7 ppm and CH=CH singlet
appeared at 131.2 ppm of geometrical E isomer is con-
formed by 13C NMR signals.
3e
0
0
10
5
0
0
3f
50.1 1.56
34.5 1.48
1.2 0.61
[0.001
[0.001
[0.001
21
46
98
10
10
Phenytoin
Values are mean SEM, and P [ 0.001 statistically significant from
control group (n = 5). Each compound screened for five animals per
dose 5 and 10 (mg/kg)
a
No response for screening
Table 3 Effects of compounds 3a–f on the % of convulsed animals
after administration of pentamethylene tetrazole
Treatment (dose)
Convulsed
animals (%)
Placebo
100
60
30
70
60
0
3a (5 mg/kg)
3a (10 mg/kg)
3b (5 mg/kg)
3b (10 mg/kg)
3c (5 mg/kg)
3c (10 mg/kg)
3d (5 mg/kg)
3d (10 mg/kg)
3e (5 mg/kg)
3e (10 mg/kg)
3f (5 mg/kg)
3f (10 mg/kg)
Phenytoin
0
0
0
Another important carbonyl group CONH and CSNH
resonated at 164.1 and 182.5 ppm, respectively (Fig. 5).
0
0
60
50
100
Structural activity relationship
In the present study various pyrrole-containing thiosemi-
carzone derivatives were synthesized and investigate the
pharmacophoric subsistent. The 4-substituted phenyl ring
acts as a lipophilic domain, C=S presenting in thiosemi-
carbazone act as corresponding to electron donor and NH
presenting in thiosemicarbazone act as hydrogen bonding
domain. Therefore, the above group containing pyrrole ring
may be stated that essential pharmacophoric requirements
for anticonvulsant activity.
preclinical investigations are currently underway in com-
pound 3a.
Stereochemistry
1
The H NMR spectra of 3a are used as examples for ste-
reochemistries assignment. The assignment has been made
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Med Chem Res (2012) 21:3699–3708
NH 2
182.5
1
O
H
N
12.1
H3C
N
H
164.1
NH2
O
S
143.5
NH
NH
118.5
H3C
O
S
123.6
162.5
O
144.7
123.7 ppm
N
H
N
H
NH
NH
S
NH
CH3
N
HN
182.5
H2N
2
131.2 ppm
H2N
1
S
CH3
Fig. 5 13C NMR signals in compound 3a
3
Compound 3f
Experimental
Activity variation in following compounds
(i) Compound 3a pyrrole derivative exhibited high anti-
convulsant activity compared to other compound but
low activity than standard at concentration 10 mg/kg.
Higher activity due to presence of CSNH (1), NH in
pyrrole ring (2) groups in compound 3a.
General
Melting points were recorded in open capillary tubes and
were uncorrected. The IR spectra (KBr) were recorded on a
Shimadzu 8201pc (4,000–400 cm-1). The H NMR and
1
13C NMR was recorded on a Bruker DRX-400 MHz. Mass
spectra (EI) were recorded on a Jeol JMS D-300 spec-
trometer operating at 70 eV. The elemental analysis (C, H,
N and S) was recorded using an Elementer analyzer model
(Varian EL III). The purity of the compounds was checked
by thin layer chromatography (TLC) with silica gel plates.
1
NH2
O
NH
H3C
NH
S
O
N
H
NH
NH
S
H2N
2
Chemistry
1
Synthesis of ethyl-3-oxo-5-phenylpent-4-enoate (1a)
Compound 3a
A mixture of ethyl acetoacetate (0.01 mol), benzaldehyde
(0.01 mol) in ethanol; the reaction mixture was refluxed for
2 h. The reaction mixture was poured into ice water. The
precipitate was collected by filtration and recrystallized by
absolute ethanol. The above procedure was followed by all
remaining compounds 1b–f.
(ii) Compound 3b shows that profound anticonvulsant
activity reduced compared with compound 3a at
concentration 10 mg/kg. Lower activity due to 4-Cl
substituted phenyl ring in compound 3b.
1
IR (KBr, cm-1): 3,050 (CHstr of phenyl ring), 1,755
(C=O in ester); 1,692 (C=O); 1H NMR (CDCl3, 400 MHz):
7.64 (s, 1H, HC=CH), 7.35–7.60 (m, 5H, Ph-ring), 6.92 (s,
1H, HC=CH), 4.20 (q, 2H, J = 1.6 Hz, –OCH2CH3), 3.92
(s, 2H, CH2), 1.30 (t, 3H, J = 1.8 Hz –OCH2CH3).
NH2
O
NH
H3C
NH
S
O
N
H
NH
NH
S
H2N
Cl
2
Ethyl-5-(4-chlorophenyl)-3-oxopent-4-enoate (1b)
3
1
IR(KBr, cm-1): 3,042 (CHstr of phenyl ring), 1,759 (C=O
in ester), 1,684 (C=O), 832 (C–Cl); 1H NMR (CDCl3,
400 MHz): 7.69 (s, 1H, HC=CH), 7.64–7.42 (dd, 4H, Ph-
ring), 6.96 (s, 1H, HC=CH), 4.14 (q, 2H, J = 1.5 Hz,
–OCH2CH3), 3.92 (s, 2H,CH2), 1.33 (t, 3H, J = 1.4 Hz,
–OCH2CH3).
Compound 3b
(iii) Compound 3f was found to be lose activity com-
pared to other compounds 3a and 3b due to the
presence of dimethylamine in 4-position of phenyl
ring.
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Med Chem Res (2012) 21:3699–3708
3705
Ethyl-5-(4-hydroxyphenyl)-3-oxopent-4-enoate (1c)
IR (KBr, cm-1): 3,064 (CHstr of phenyl ring), 1,747 (C=O
7.30–7.62 (5H, Ph-ring), 7.01 (s, 1H, HC=CH), 6.92 (s, 1H,
HC=CH), 6.12 (s, 1H, NH of pyridine ring), 4.20 (q, 2H,
J = 1.7 Hz, –2OCH2CH3 and –4OCH2CH3), 2.31(s, 3H,
CH3), 1.30 (t, 3H, J = 1.9 Hz, –2OCH2CH3 and
–4OCH2CH3). Elemental analysis: Calculated for C19H21
NO4: C, 69.71; H, 6.47; N, 4.28; Found: C, 69.75; H, 6.51;
N, 4.22%
1
in ester), 1,689 (C=O), 1,465 (C–OH); H NMR (CDCl3,
400 MHz): 9.38 (s, 1H, OH), 7.61 (s, 1H, HC=CH), 7.55–
6.68 (dd, 4H, Ph-ring), 6.95 (s, 1H, HC=CH), 4.25 (q, 2H,
J = 1.7 Hz, –OCH2CH3), 3.98 (s, 2H, CH2), 1.37 (t, 3H,
J = 1.8 Hz, –OCH2CH3).
Diethyl 5-[2-(4-chlorophenyl)ethenyl]-3-methyl-1H-
pyrrole-2,4-dicarboxylate (2b)
Ethyl-5-(4-nitrophenyl)-3-oxopent-4-enoate (1d)
IR (KBr, cm-1): 3,052 (CHstr of phenyl ring), 1,769 (C=O,
IR (KBr, cm-1): 3,347 (NHstr), 3,045 (CHstr of phenyl
ring), 1,744 (C=O in ester); 831 (C–Cl); 1H NMR (CDCl3,
400 MHz): 7.42–7.61(m, 5H, Ph-ring), 7.05 (s, 1H,
HC=CH), 6.94 (s, 1H, HC=CH), 6.20 (s, 1H, NH in pyri-
dine ring), 4.26 (q, 2H, J = 1.8 Hz, –2OCH2CH3 and
–4OCH2CH3), 2.32 (s, 3H, CH3), 1.37 (t, 3H, J = 1.7 Hz,
–2OCH2CH3 and –4OCH2CH3). Elemental analysis: Cal-
culated for C19H20ClNO4: C, 63.07; H, 5.57; N, 3.87;
Found: C, 63.12; H, 5.51; N, 3.82%.
1
ester), 1,681 (C=O), 1,534 (C–NO2); H NMR (CDCl3,
400 MHz): 8.11–8.01 (dd, 4H, Ph-ring), 7.59 (s, 1H,
HC=CH), 7.24 (s, 1H, HC=CH), 4.19 (q, 2H, J = 1.6 Hz,
–OCH2CH3), 3.99 (s, 2H, CH2), 1.41 (t, 3H, J = 1.7 Hz,
–OCH2CH3).
Ethyl-5-(4-methoxyphenyl)-3-oxopent-4-enoate (1e)
IR (KBr, cm-1): 3,041 (CHstr of phenyl ring), 1,762 (C=O,
1
ester), 1,674 (C=O); H NMR (CDCl3, 400 MHz): 7.66 (s,
Diethyl 5-[2-(4-hydroxyphenyl)ethenyl]-3-methyl-1H-
pyrrole-2,4-dicarboxylate (2c)
1H, HC=CH), 7.64–6.90 (dd, 4H, Ph-ring), 6.98 (s, 1H,
HC=CH), 4.32 (q, 2H, J = 1.5 Hz, –OCH2CH3), 3.96
(s, 2H, CH2), 3.87 (s, 3H, –OCH3), 1.44 (t, 3H, J = 1.4 Hz,
–OCH2CH3),
IR (KBr, cm-1): 3,342 (NHstr), 3,043 (CH str of phenyl
ring), 1,747 (C=O in ester), 1,465 (C–OH); 1H NMR
(CDCl3, 400 MHz): 9.38 (s, 1H, OH), 7.12 (s, 1H,
HC=CH), 6.96 (s, 1H, HC=CH), 6.64–7.30 (dd, 4H, Ph-
ring), 6.11 (s, 1H, NH in pyridine ring), 4.33 (q, 2H,
J = 1.7 Hz, –2OCH2CH3 and –4OCH2CH3), 2.42(s, 3H,
CH3),1.34 (t, 3H, J = 1.8 Hz, 2,4-OCH2CH3). Elemental
analysis: Calculated for C19H21NO5: C, 66.46; H, 6.16; N,
4.08; Found: C, 66.41; H, 6.18; N, 4.13%.
Ethyl-5-[4-(dimethylamino)phenyl]-3-oxopent-4-enoate
(1f)
IR (KBr, cm-1): 3,047 (CHstr of phenyl ring), 1,771 (C=O,
1
ester), 1,688 (C=O); H NMR (CDCl3, 400 MHz):7.71 (s,
1H, HC=CH), 6.90 (s, 1H, HC=CH), 6.71–7.76 (dd, 4H,
Ph-ring), 4.41 (q, 2H, J = 1.5 Hz, Hz –OCH2CH3), 3.86 (s,
2H, CH2), 3.08 (s, 1H, –N(CH3)2), 1.18 (t, 3H, J = 1.6 Hz,
–OCH2CH3),
Diethyl 5-[2-(4-methoxyphenyl)ethenyl]-3-methyl-1H-
pyrrole-2,4-dicarboxylate (2d)
IR (KBr, cm-1): 3,339 (NH str), 3,036 (C–H str in phenyl
1
ring), 1,740 (C=O in ester); H NMR (CDCl3, 400 MHz):
Synthesis of diethyl 3-methyl-5-[2-phenylethenyl]-1H-
pyrrole-2,4-dicarboxylate (2a)
7.11 (s, 1H, HC=CH), 6.90–7.60 (dd, 4H, Ph-ring), 6.88 (s,
1H, HC=CH), 6.21 (s, 1H, NH in pyridine ring), 4.41 (q,
4H, J = 1.8 Hz, –2OCH2CH3 and –4OCH2CH3), 2.41 (s,
3H, CH3), 3.88 (s, 3H, –OCH3), 1.15 (t, 6H, J = 1.9 Hz,
2,4-OCH2CH3). Elemental analysis: Calculated for
C20H23NO5: C, 67.21; H, 6.49; N, 3.92; Found: C, 67.25;
H, 6.52; N, 3.95%.
A mixture was prepared of ethyl acetoacetate and glacial
acetic acid, and was cooled to an efficient freezing mixture
to 5°C. Sodium nitrite was added dropwise with vigorous
stirring at such a rate that the temperature remained between
5 and 7°C and added dropwise to compound 1a, and the
mixture was stirred at room temperature. Zinc dust was
added to the reaction mixture and the mixture was heated
and refluxed for 1 h and poured into water. After standing
overnight, the crude product was obtained then filtered by
suction and washed with water. The above procedure was
followed for all remaining compounds 2b–f.
Diethyl 3-methyl-5-[2-(4-nitrophenyl)ethenyl]-1H-pyrrole-
2,4-dicarboxylate (2e)
IR (KBr, cm-1): 3,332 (NH str), 3,039 (C–H str in phenyl
ring), 1,755 (C=O in ester), 1,531 (C–NO2); 1H NMR
(CDCl3, 400 MHz): 8.22–8.04 (dd, 4H, Ph-ring), 7.12 (s,
IR (KBr, cm-1): 3,342 (NHstr), 3,043 (CHstr of phenyl
ring), 1,747 (C=O, ester);1H NMR (CDCl3, 400 MHz):
123

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Med Chem Res (2012) 21:3699–3708
1
1H, HC=CH), 7.01 (s, 1H, HC=CH), 6.24 (s, 1H, NH in
pyridine ring), 4.32 (q, 2H, J = 1.7 Hz, –2OCH2CH3 and
–4OCH2CH3), 2.26 (s, 3H, CH3), 1.37 (t, 6H, J = 1.8 Hz,
2,4-OCH2CH3). Elemental analysis: Calculated for
C19H20N2O6: C, 61.28; H, 5.41; N, 7.52; Found: C, 61.31;
H, 5.52; N, 7.56%.
(Ar–H); H NMR (DMSO-d6, 400 MHz): d 10.43 (d, 1H,
J = 3.10 Hz, –2CONH and –4CONH), 9.68 (s, 2H, NH2),
7.44–7.62 (m, 4H, Ph-ring), 7.00 (s, 1H, HC=CH), 6.91 (s,
1H, HC=CH), 6.32 (s, 1H, NH of pyridine ring), 2.35 (s, 2H,
CH3), 2.13(d, 1H, J = 3.56 Hz, –NHCS); 13C NMR
(DMSO-d6, 400 MHz): d 181.7 (C=S), 163.8 (C=O), 160.5
(C=0), 145.0 (C-5 in pyrrole ring), 143.8 (C-3 in pyrrole
ring), 122.7 (C-2 in pyrrole ring), 119.8 (C-4 in pyrrole ring),
123.5 (HC=CH), 131.2 (HC=CH), 142.1, 188.5, 128.7, 128.2
(Ph–Cl), 12.8 (C3–CH3); MS (m/z, (relative abundance, %)):
52.90 (M??1, 12.01), 392.86 (M?, 36.21), 332.77(M?-1,
27.08), 273.71 (M?, 100.00), 163.21(M?, 63.01), 150.16
(M?-1, 38.17), 67.08(M?, 20.01). Elemental analysis:
Calculated for C17H18ClN7O2S2: C, 45.18; H, 4.01; N, 21.69;
S, 14.19; Found: C, 45.14; H, 4.06; N, 21.66; S, 14.15%.
Diethyl 5-(4-(dimethylamino)styryl)-3-methyl-1H-pyrrole-
2,4-dicarboxylate (2f)
IR(KBr, cm-1): 3,329 (NH str), 3,041 (C–H str in phenyl
1
ring), 1,738 (C=O in ester); H NMR (CDCl3, 400 MHz):
7.21 (s, 1H, HC=CH), 6.69–7.74 (dd, 4H, Ph-ring), 6.90
(s,1H, HC=CH), 6.27 (s, 1H, NH in pyridine ring), 4.22 (q,
4H, J = 2.3 Hz, –2OCH2CH3 and –4OCH2CH3), 2.29 (s,
3H, CH3), 3.08 (s, 6H, –N(CH3)2), 1.22 (t, 3H, J = 2.2 Hz,
2,4-OCH2CH3). Elemental analysis: Calculated for
C21H26N2O4: C, 68.09; H, 7.07; N, 7.56; Found: C, 68.14;
H, 7.10; N, 7.51%.
2,20-({5-[2-(4-Hydroxyphenyl)ethenyl]-3-methyl-1H-
pyrrole-2,4-diyl}dicarbonyl) dihydrazinecarbothioamide
(3c)
Synthesis of 2,20-({3-methyl-5-[2-phenylethenyl]-1H-
pyrrole-2,4-diyl}dicarbonyl)dihydrazinecarbothioamide
(3a)
IR (KBr, cm-1): m 3,361 (NH), 3,241 (NH2), 3,019 (Ar–H),
1,718 (C=O), 1,460 (OH–C), 1,264 (C=S), 1,098 (N–C–N),
1
816 (Ar–H); H NMR (DMSO-d6, 400 MHz) : d 10.32 (d,
1H, J = 3.0 Hz, –2CONH and –4CONH), 9.50 (s, 2H,
NH2), 9.37 (s, 1H, OH), 7.01–7.22 (dd, 4H, Ph-ring), 6.98
(s, 1H, HC=CH), 6.90 (s, 1H, HC=CH), 6.26 (s, 1H, NH in
pyridine ring), 2.40 (s, 3H, CH3), 2.16 (d, 2H, J = 3.49 Hz,
2,4-NHCS); 13C NMR(DMSO-d6, 400 MHz): d 181.7
(C=S), 164.9 (C=O), 162.7 (C=0), 145.0 (C-5 in pyrrole
ring), 143.8 (C-3 in pyrrole ring), 123.8 (C-2 in pyrrole
ring), 118.5 (C-4 in pyrrole ring), 123.8 (HC=CH), 131.8
(HC=CH), 142.5, 135.7, 128.5,127.9 (Ph–OH), 12.6 (C3–
CH3); MS (m/z, (relative abundance, %)): 434.22 (M??1,
55.22), 373.41 (M?, 41.01), 255.26 (M?, 18.21), 239.26
(M?, 36.22), 163.17 (M?, 28.01), 151.16 (M?, 100.00),
122.19 (M?-1,48.07). Elemental analysis: Calculated for
C17H19N7O3S2: C, 47.10; H, 4.42; N, 22.62; S, 14.76;
Found: C, 47.15; H, 4.46; N, 22.66; S, 14.71%.
A mixture of compound 2a (0.1 mol), thiosemicarba-
zide(0.2 mol) and few drops of DMSO in ethanol; the
reaction mixture was refluxed for 7 h. The reaction mixture
was poured into crushed ice. The precipitate was collected by
filtration and recrystallized by absolute ethanol. The above
procedure was followed by remaining compounds 3b–f.
IR (KBr, cm-1): m 3,354 (NH), 3,249 (NH2), 3,021 (Ar–H),
1,717 (CONH), 1,267 (C=S), 1,096 (N–C–N); 812 (Ar–H); 1H
NMR (DMSO-d6, 400 MHz): d 10.75 (d, 2H, J = 3.00 Hz,
–2CONH and –4CONH), 9.66 (s, 2H, NH2), 7.39–7.62 (m, 5H,
Ph-ring), 7.05 (s, 1H, HC=CH), 6.90 (s, 1H, HC=CH), 6.15 (s,
1H, NH in pyridine ring), 2.45 (s, 3H, CH3), 2.05 (d, 2H,
J = 3.50 Hz, 2,4-NHCS); 13C NMR (DMSO-d6, 400 MHz):
d 182.5 (C=S), 164.8 (C=O), 162.5 (C=O), 144.7 (C-5 in
pyrrole ring), 143.5 (C-3 in pyrrole ring), 123.6 (C-2 in pyrrole
ring), 118.5 (C-4 in pyrrole ring), 123.7 (HC=CH), 131.2
(HC=CH), 137.5, 127.9, 128.6, 128.5 (Ph), 12.1(C3–CH3); MS
(m/z, (relative abundance, %)): 418.50 (M??1, 12.01), 358.32
(M?), 298.32 (M?-1), 239.26 (M?, 100.00), 183.24 (M?),
169.22(M?), 93.12(M?-1), 67.11(M?). Elemental analysis:
Calculated for C17H19N7O2S2: C, 48.90; H, 4.59; N, 23.48; S,
15.36; Found: C, 48.95; H, 4.52; N, 23.41; S, 15.40%.
2,20-({5-[2-4-Methoxyphenyl)ethenyl]-3-methyl-1H-
pyrrole-2,4-diyl}dicarbonyl)dihydrazinecarbothioamide
(3d)
IR (KBr, cm-1): m 3,373 (NH), 3,244 (NH2), 3,047 (Ar–H),
1,721 (C=O), 1,265 (C=S), 1,080 (N–C–N), 834 (Ar–H);
1H NMR (DMSO-d6, 400 MHz): d 10.41 (d, 1H,
J = 3.1 Hz, –2CONH and –4CONH), 9.49 (s, 2H, NH2),
7.10 (s, 1H, HC=CH), 6.99–7.66 (dd, 4H, Ph-ring), 6.96 (s,
1H, HC=CH), 6.33 (s, 1H, NH of pyridine ring), 2.40 (s,
2H, CH3), 2.18(d, 1H, J = 3.5 Hz, –NHCS); 13C NMR
(DMSO-d6, 400 MHz): d 184.8 (C=S), 164.5 (C=O), 161.8
(C=0), 145.9 (C-5 in pyrrole ring), 144.2 (C-3 in pyrrole
ring), 123.6 (C-2 in pyrrole ring), 117.5 (C-4 in pyrrole
2,20-({5-[2-(4-Chlorophenyl)ethenyl]-3-methyl-1H-
pyrrole-2,4-diyl}dicarbonyl)dihydrazinecarbothioamide
(3b)
IR (KBr, cm-1):m 3,365 (NH), 3,222 (NH2), 3,041 (Ar–H),
1,715 (C=O), 1,268 (C=S), 1,096 (N–C–N), 837 (C–Cl), 812
123

Med Chem Res (2012) 21:3699–3708
3707
ring), 123.8 (HC=CH), 130.5 (HC=CH), 143.3, 136.1,
129.6, 129.8 (Ph–NO2), 12.0 (C3–CH3); MS (m/z, (relative
abundance, %)): 463.45 (M??1, 40.2), 416.41 (M?, 20.2),
344.32 (M?, 22.08), 313.28 (M?-1, 30.27), 284.26 (M?,
32.18), 238.26 (M?-1, 41.08), 164.10 (M??1, 35.71),
151.16 (M?, 100.00), 123.19(M?, 61.71), 95.14 (M?,
41.71). Elemental analysis: Calculated for C18H21N7O3S2:
C, 48.31; H, 4.73; N, 21.91; S, 14.33; Found: C, 48.33; H,
4.76; N, 21.96; S, 14.37%.
Calculated for C17H19N8O4S2: C, 44.15; H, 3.92; N, 24.23;
S,13.87; Found: C, 44.20; H, 3.97; N, 24.27; S, 13.83%.
Pharmacology
Anticonvulsant activity
The anticonvulsant evaluation was undertaken by the
Department of Pharmacology, Mother Theresa Post Grad-
uate & Research Institute of Health Science, Puducherry,
605006, India.
2,20-({3-Methyl-5-[2-(4-nitrophenyl)ethenyl]-1H-pyrrole-
2,4-diyl}dicarbonyl)dihydrazinecarbothioamide (3e)
Compounds 3a–f were screened for their anticonvulsant
activity by the method given in the literature (Krall et al.,
1978; Porter et al., 1985). Swiss albino rats weighing 150 g
were divided into eight groups each containing five animals
and subjected to the following tests for each of the com-
pounds studied:
IR (KBr, cm-1): m 3,378 (NH), 3,221 (NH2), 3,043 (Ar–H),
1,723 (C=O), 1,530 (C–NO2), 1,277 (C=S), 1,095 (N–C–
1
N), 812 (Ar–H); H NMR (DMSO-d6, 400 MHz): d 10.33
(d, 1H, J = 3.2 Hz, –2CONH and –4CONH), 9.68 (s, 2H,
NH2), 8.22–8.06 (m, 4H, Ph-ring), 7.21 (s, 1H, HC=CH)
6.99 (s, 1H, HC=CH), 6.39 (s, 1H, NH of pyridine ring),
2.38 (s, 2H, CH3), 2.14 (d, 1H, J = 3.3 Hz, –NHCS); 13C
NMR(DMSO-d6, 400 MHz): d 190.2 (–CH3O), 183.7
(C=S), 164.7 (C=O), 161.5 (C=0), 144.0 (C-5 in pyrrole
ring), 12.7 (C3-CH3); MS (m/z, (relative abundance, %)):
144.7 (C-3 in pyrrole ring), 124.1 (C-2 in pyrrole ring),
119.3 (C-4 in pyrrole ring), 123.4 (HC=CH), 133.2
(HC=CH), 141.7, 138.5, 128.7, 129.5 (Ph). Elemental
analysis: Calculated for C17H18N8O4S2: C, 44.15; H, 3.92;
N, 24.23; S,13.87; Found: C, 44.19; H, 3.91; N, 24.25; S,
13.83%; MS (m/z, (relative abundance, %)): 448.50
(M??1, 41.73), 388.44 (M?, 38.01), 329.35 (M?, 30.01),
299.32 (M?, 100), 213.27(M?-1, 100.00), 183.24 (M?,
63.01), 107.81(M?, 38.17), 95.83 (M?, 20.01).
Placebo group
Isotonic saline solution was intraperitoneally administered,
followed 15 min later by an intravenous 48.7 mg dose of
pentamethylene tetrazole dissolved in physiological saline.
Assay group
A solution of the compound being tested in physiological
saline was intraperitoneally administered. After 15 min, a
time that was considered sufficient for complete absorp-
tion, the same doses of pentamethylene tetrazole was
administered.
2,20-({3-Methyl-5-[2-(4-dimethylaminophenyl)
ethenyl]-1H-pyrrole-2,4-diyl}dicarbonyl)
dihydrazinecarbothioamide (3f)
Reference group
10 mg/kg of sodium diphenylhydantoin dissolved in
physiological saline was intraperitoneally administered.
After 15 min, the same dose of pentamethylene tetrazole
was applied. In each case, the number of animals of each
group which suffered convulsions was recorded. Results
were statistically analyzed using the student’s t test.
IR (KBr, cm-1): m 3,369 (NH), 3,224 (NH2), 3,034 (Ar–H),
1,701 (C=O), 1,271 (C=S), 1,089 (N–C–N), 811 (Ar–H);
1H NMR (DMSO-d6, 400 MHz): d 10.42 (d, 2H,
J = 3.0 Hz, –2CONH and –4CONH), 9.71 (s, 2H, NH2),
7.10 (s,1H, HC=CH), 6.91 (s, 1H, HC=CH), 6.75–7.76 (dd,
4H, Ph-ring), 6.34 (s, 1H, NH in pyridine ring), 3.10 (s, 6H,
–N(CH3)2), 2.33 (s, 3H,CH3), 2.10 (d, 1H, J = 3.4 Hz,
–NHCS); 13C NMR (DMSO-d6, 400 MHz): d 182.8 (C=S),
164.8 (C=O), 161.8 (C=0), 140.8 (C-5 in pyrrole ring),
145.2 (C-3 in pyrrole ring), 125.8 (C-2 in pyrrole ring),
118.7 (C-4 in pyrrole ring), 123.8 (HC=CH), 133.8
(HC=CH), 142.7, 138.7, 127.8, 128.5 (Ph), 12.5 (C3–CH3);
MS (m/z, (relative abundance, %)): 461.57 (M??1, 31.01),
401.48 (M?, 28.27), 342.39 (M?, 22.08), 281.33 (M?-1,
15.07), 239.26 (M?, 20.01), 163.17 (M?, 2.08), 151.16
(M?, 100.00), 122.19 (M?-1, 12.08). Elemental analysis:
Conclusion
Compound 3a is found to possess anticonvulsant activity
hence can be used as lead to develop antiepileptic drugs.
Also further substitutions on pyrrole nucleus can lead to
more potent compounds.
Acknowledgments We wish to thank one of the authors Dr. S.
Kavimani, Department of Pharmacology, Mother Theresa Post
Graduate & Research Institute of Health Science, Puducherry,
123

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Med Chem Res (2012) 21:3699–3708
605006, India, for taking anticonvulsant activity. We sincerely thank
Principal of Jamal Mohamed College for providing laboratory
facilities.
Kshirsagar A, Toraskar MP, Kulkarni VM, Dhanashire S, Kadam V
(2009) Microwave assisted synthesis of potential antiinfective
and anticonvulsant thiosemicarbazones. Int J Chem Tech Res
1:696–701
Ojha S, Ameta U, Dhakar N, Talesara GLMay (2007) Synthesis and
characterization of some alkoxyphthalimide derivatives of
benzotriazolylthiadiazoles and benzotriazolylthiazolidinones.
Ind J Chem 46B:860–865
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