Synthesis of novel pyrazole derivatives and evaluation of their antidepressant and anticonvulsant activities

Article abstract of DOI:10.1016/j.ejmech.2009.01.032

Substituted carboxylic acid hydrazides 1a-d reacted with ethenetetracarbonitril 2 in dimethyl formamide with the formation of diacylhydrazines 4a-d and 5-amino-1-substiuted pyrazole-3,3,4-tricarbonitriles 5a-d. On the other hand, 1a-d reacted with diethyl

Full text of DOI:10.1016/j.ejmech.2009.01.032

European Journal of Medicinal Chemistry 44 (2009) 3480–3487
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of novel pyrazole derivatives and evaluation of their antidepressant
and anticonvulsant activities
,
a
b
Mohamed Abdel-Aziz a , Gamal El-Din A. Abuo-Rahma , Alaa A. Hassan
*
a Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia, Egypt
b Department of Chemistry, Faculty of Science, Minia University, Minia, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Substituted carboxylic acid hydrazides 1a–d reacted with ethenetetracarbonitril 2 in dimethyl form-
amide with the formation of diacylhydrazines 4a–d and 5-amino-1-substiuted pyrazole-3,3,4-tri-
carbonitriles 5a–d. On the other hand, 1a–d reacted with diethyl (E)-2,3-dicyanobutenedioate 3 to give
oxadiazole derivatives 10a–d and pyrazolone derivatives 11a–d, respectively. The prepared compounds
4a–d, 5a–d and 11a–d were evaluated each for antidepressant activity using tail suspension behavioral
despair test and anticonvulsant activity against PTZ induced seizures in mice. Compounds 4a and 4b
induced markedly antidepressant activity compared to imipramine, and their activities as antidepres-
sant nearly equal twice the activity of imipramine at 10 mg kgꢀ1 dose level. On the other hand,
compounds 11b, 11a and 11d exhibited remarkable protective effect against clonic seizures induced by
ip injection of PTZ at a dose level of 20 mg kgꢀ1. The results of anticonvulsant activity are nearly close to
phenobarbital sodium at a dose level of 30 mg kgꢀ1and more potent than phenytoin sodium at a dose
Received 21 October 2008
Received in revised form
4 December 2008
Accepted 29 January 2009
Available online 5 February 2009
Keywords:
Carboxylic acid hydrazides
Pyrazole
Oxadiazole derivatives
Antidepressant
Anticonvulsant
level of 30 mg kgꢀ1
.
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
[19,20] and pyrazolotriazoloquinoline derivatives [21]. 1,2,4-
Triazines were formed via the condensation of 1,2-diketones with
acylhydrazides and ammonium acetate under traditional thermal
and dry media microwave assisted reaction conditions [22,23].
Ethenetetracarbonitrile (tetracyanoethylene) as well as its
derivatives containing the dicyanovinylidene moiety are electron
deficient substances, and it is well known that their monoelectronic
reduction usually results in the formation of fairly long-lived radical
anions [24,25], this also applies to other species containing cyano
groups bound to a double bond [26–29]. Tetracyanoethylene shows
a great affinity for electrons, and is thus a fairly good dehydrogen-
ating agents towards dihydroaromatic and dihydrohetero aromatic
systems [30,31]. It behaves as a strong electron acceptor towards
suitable electron donors [32–34].
The reaction of methylhydrazine with tetracyanoethylene has
been studied in several laboratories [35–37]. A mixture of 1-N- and
2-N-methyl derivatives of 5-amino-3,4-dicyanopyrazole was iso-
lated [37].
As a part of our program aimed at the development of new simple
and efficient procedures for the synthesis of some important
heterocyclic systems from hydrazinecarbothioamides, we have
recently reported different successful approaches for synthesis of
thiazole, thiazine, thiadiazole, thiadiazidine, thiadiazepine, indoazole
and pyridazine derivatives [38–42]. Promoted with the above-
mentioned studies, this paper reports several heterocyclization of
Antidepressants and anticonvulsants are among the most
widely utilized drugs for the treatment of CNS disorders [1–4].
Considerable interest has been focused on the pyrazole structure,
which has been known to possess a broad spectrum of biological
activities such as tranquillizing, muscle relaxant, psychoanaleptic,
anticonvulsant, antihypotensive, and antidepressant activities
[5–10]. Moreover, hydrazides and their derivatives have been
reported to exhibit various pharmacological activities such HIV-1
integrase inhibitors [11], anti-tubercular [12], antidepressant [13],
anticonvulsant [13] and aspartic protease inhibitory activities [14].
Additionally, hydrazide compounds, such as furoic hydrazide,
thiophencarboxylic hydrazide and isonicotinic acid hydrazide
reacted with a series of 4-alkoxy-4-alkyl(aryl)-1,1,1-trifluro-3-
alken-2-ones to give 3-alkyl (aryl)-5-trifluoromethyl substiuted
pyrazoles [15]. One pot reactions between carboxylic hydrazides
and 2-isothiocyanatobenzonitrile afforded pharmacologically
relevant 1,2,4-triazolo[1,5-c]quinazoline-5-thiones [16]. Hydrazide
compounds were also converted to triazole-3-thiols [17], 1,3,4-
oxadiazole [18], 1,3,4-oxadiazine [18], pyrazolotriazolopyrimidine
* Corresponding author. Tel./fax: þ2086 2369075.
E-mail address: abulnil@hotmail.com (M. Abdel-Aziz).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.01.032

M. Abdel-Aziz et al. / European Journal of Medicinal Chemistry 44 (2009) 3480–3487
3481
1-acylhydrazines 1a–d using ethenetetracarbonitrile (tetracyano-
O
C
R1
CN
ethylene, 2) and diethyl (E)-2,3-dicyanobutenedioate (dicyanofuma-
rate, 3) either as a reaction mediator or as a building block Fig. 1. The
synthesized compounds including open chain hydrazide derivatives
4a–d and the cyclized ones including pyrazole derivatives 5a–d and
pyrazolone derivatives 11a–d were evaluated each for antidepressant
activity using tail suspension behavioral despair test [43] and anti-
convulsant activity against PTZ induced seizures in mice [44].
R
N
H
NH2
R2
NC
1a-d
2
2, R1 = R =
CN
R = R2 =
1
3,
CO2C2H5
a
c
b
1
d
2. Results and discussion
R
2.1. Chemistry
S
N
H
N
Treatment of 1a–d with two molar equivalents of 2 in DMF as
solvent at room temperature resulted in a green coloration of the
solution that quickly turned into brown. Concentration of the
mixture to dryness and the residue subjected to vacuum sublima-
tion to remove any unreacted of 2. Chromatographic separation of
the residue in each case gave two zones, containing diacylhy-
drazines 4a–d (22–27%) and 5-amino-1-substituted-1H-pyrazole-
3,3,4-(2H)-tricarbonitriles 5a–d (64–69%). On the other hand,
equimolar solutions of 2 and 1a–d in DMF under the previous
mentioned conditions, afforded 5a–d as major products (38–41%)
and 4a–d as minor products (11–16%), in addition to unreacted
1a–d. The reaction sequences are outlined in Scheme 2.
The formation of diacylhydrazines 4a–d, does not take place if
tetracyanoethylene 2 is not added to different solutions of 1a–d in
DMF, the presence of 2 is definitely required for the transformation
observed. Charge-transfer complexes may (but not necessarily have
to) play an intermediate role. Since, the formation of 4a–d involves
intermolecular nucleophilic attacks by hydrazide-NH2 on the
carbonyl group of the adduct 6. It is conceivable that 2 accelerates
the process, possibly through intermediate 6 (Scheme 2), activating
the respective C]O bond towards nucleophilic addition from
another molecule of 1a–d. This behavior may well be supported by
the polar nature of the solvent stabilizing zwitterionic adduct. After
nucleophilic addition; 2 is released with the elimination of one
molecule of hydrazine to give 4a–d.
Fig. 1. Different forms of substituted carboxylic acid hydrazides 1a–d, tetracyano-
ethylene 2 and dicyanofumarate 3.
Singh et al. [45] earlier reported that iodobenzene diacetate
(IBD) has been found to be an excellent reagent to the oxidation of
similar acid hydrazides [R ¼ methyl(phenyl)pyrazolyl, methyl
(4-methylquinolinyl)pyrazolyl, phenyl, 4–Cl–C6H4, 4-MeO–C6H4
and PhCH2] to N,N1-diacylhydrazines [45].
The pyrazole structure in 5a–d has been assigned on the basis of
elemental analysis and spectral data. For example the 1H NMR
spectrum of 5b clearly shows the presence of two broad signals
with the ratio of 2:1 centered at
exocyclic-NH2 and pyrazole-NH. The 13C NMR shows signals at
46.23 (C-3), 117.89, 118.96 (CN) and 169.86 (CO). Pyrazole C-4 and
C-5 resonate at 64.51 and 158.52, respectively, are in accordance
with the observed trends in the values for C-atoms in push–pull
d 6.92 and 11.52 ppm due to
d
d
d
alkenes [46,47]. Further peaks are supported with the assigned
structure given in experimental part.
The analytical data of compounds 5 would also match for other
isomers of products 7 and 8 (Scheme 1). The alternative structures
7 and 8 could be ruled out on the basis of 1H NMR, 13C NMR, IR and
the fragment ions in the mass spectrum of 5b at 243, 215, 111, 83
and 66.
Furthermore, compound 5b was also assigned on the basis of
intramolecular H-bridge detected by IR (in dilute CCl4) and 1H NMR
(see Section 4) as shown from Scheme 2, structure 5b fits best to all
the spectroscopic data.
The structures of 4a–d are further supported on the basis of
their IR, NMR and mass spectral data, and comparison with
authentic samples.
R
O
O
C
O
C
H
N
C
2
CN
O
R
C
N
H
NH2
R
N
H
N
H
R
+
N
DMF, room temp.
CN
1a-d
4a-d (22-27 %)
H2N
CN
5a-d (64-69 %)
c
b
1
a
d
R
S
N
H
N
R
H
N
CN
CN
O
H
N
N
H
CN
Scheme 1. Synthesis of diacylhydrazines 4a-d and 5-amino-1-substituted pyrazole-3,3,4-tricarbonitriles 5a-d.

3482
M. Abdel-Aziz et al. / European Journal of Medicinal Chemistry 44 (2009) 3480–3487
N
R
NH
CN
CN
1a-d + 2
[ CT- complex ]
O
CN
H2N
8
H
N
+
=
R
NH2
CN
O
R
C
O
O
R
C
N
H
NH
NH
N
CN
CN
CN
CN
CN
-
NC
..
NH2
CN
6
C
H2N
CN
HN
R
C
O
NH
CN
5a-d
=
OH
R
+
NH2
R
N
H
O
CN
CN
R
C
O
N
H
NH
NC
NH
N
NC
NC
-
NH2
CN
9
CN
1) -2
2) -NH2NH2
7
R
C
O
N
H
N
H
C
O
R
4a-d
Scheme 2. Mechanism of formation of diacylhydrazines 4a-d and 5-amino-1-substituted pyrazole-3,3,4-tricarbonitriles 5a-d.
Diethyl (E)-2,3-dicyanobutenedioate (dicyanofumarate, 3) was
The suggested mechanism for the formation of oxadiazole
derivatives 10a–d and pyrazolone derivatives 11a–d is illustrated in
Scheme 4.
chosen to compare its reactivity towards the acylhydrazines
1a–d with 2. One might expect that acylhydrazines 1a–d should
react with 3 similarly like 2, but the results were completely
different. Not only the structure of the acceptor is the reason for the
instability of the CT-complexes and subsequent chemical reaction,
but also the electron affinity of the acceptors and ease of under-
going the formation of adduct or tricyanovinylation product is an
important factor.
The oxadiazole derivative 10c exhibited three IR absorption
bands at
n 3315 (NH), 1720 (C]O of ester), 2225 (CN) and 1085
(C–O–C).[48] Upon transformation of 1a–d to 10a–d the salient
features of NMR spectra (including 13C-DEPT spectral) of 10c are
following: signals at
(C-5) and 171.36 (CO).
The 1H NMR spectra of compounds 11a–d show the presence of
NH group by broad signals for 1H between 12.43 and 12.55 ppm.
d 14.28 (CH3), 61.17 (CH2O), 79.89 (C-2), 156.24
Heating at reflux of equimolar amounts of 1a–d and 3 in ethyl
acetate for 4–18 h afforded the corresponding oxadiazole deriva-
tives 10a–d and pyrazolone derivatives 11a–d (Scheme 3).
d
Signals around 89.19 (C-4), 118.84 (CN), 155.98 (C-3), 165.34 (C-5),
ROC
N
NH
CO2Et
CN
+ 3
N
NH
1a-d
+
Ethyl acetate
R
O
O
CO2Et
10 a-d (52-55 %)
CN
11a-d (33-37 %)
c
b
1
a
d
R
S
N
H
N
Scheme 3. Synthesis of oxadiazole derivatives 10a–d and pyrazolone derivatives 11a–d.

M. Abdel-Aziz et al. / European Journal of Medicinal Chemistry 44 (2009) 3480–3487
3483
Table 1
O
C
EtO2C
NC
CN
Antidepressant activities of the tested compounds 4a–d, 5a–d and 11a–d compared
to imipramine.
R
N
H
NH2
+
Compoundsa
Antidepressant activities
CO2Et
1a-d
3
Duration of immobility (s)
Change from control (%)
(mean ꢁ S.E.M.)
4a
4b
4c
4d
5a
68.23 ꢁ 1.30
ꢀ71.96
ꢀ72.22
ꢀ32.39
ꢀ17.80
ꢀ9.37
H
N
67.58 ꢁ 3.90
CO2Et
CN
CO2Et
HN
NH
HN
164.50 ꢁ 10.50
200.00 ꢁ 10.00
220.50 ꢁ 1.50
CN
R
C
R
C
O
- HCN
CO2Et
O
H
5b
5c
5d
217.50 ꢁ 3.50
149.00 ꢁ 2.50
200.30 ꢁ 0.88
ꢀ10.60
ꢀ38.76
ꢀ17.67
CN
EtO
O
12
13
11a
11b
183.90 ꢁ 9.30
198.70 ꢁ 6.80
ꢀ24.41
ꢀ18.33
-NCCH2CO2Et
- EtOH
NH
O
11c
11d
153.30 ꢁ 4.60
169.00 ꢁ 9.60
ꢀ36.99
ꢀ30.54
R
N
NH
N
CO2Et
Imipramine
Control
132.00 ꢁ 2.60
243.30 ꢁ 14.42
ꢀ45.75
R
CN
CO2Et
–
O
O
10a-d
Values represent the mean ꢁ S.E.M. (n ¼ 6).
a
Tested compounds and imipramine were tested at 10 mg kgꢀ1 dose level, ip.
CN
11a-d
Scheme 4. Mechanism of formation of oxadiazole derivatives 10a–d and pyrazolone
derivatives 11a–d.
of the tested compounds and reference drug are given in Table 1.
Compounds 4a and 4b induced markedly antidepressant activity
compared to imipramine, their activities as antidepressant nearly
equal twice the activity of imipramine. Compounds 4a and 4b
significantly reduced the duration of immobility times to be 68.23
and 67.58 s, respectively, compared to 132.00 s reduction of the
duration of immobility for imipramine at 10 mg kgꢀ1 dose level.
Compounds 5c, 11c, 4c, 11d, 11a and 11b give good antidepressant
activity, their activities nearly equal to 88.60, 86.10, 80.20, 78.10,
71.80 and 66.40% of the activity of imipramine at 10 mg kgꢀ1 dose
level. Other tested compounds including 4d, 5d, 5b and 5a
exhibited weak antidepressant activity compared to imipramine at
10 mg kgꢀ1 dose level.
168.49 (ester-CO) and 171.36 (CO) in 13C NMR spectrum of 11d lend
further support to the structures assigned to 11a–d. The analytical
data of compounds 11 would also match for other isomers of
products 14 and 15 (Fig. 2). The alternative structures 14 and 15
could be ruled out on the basis of IR, 1H NMR, 13C NMR and the
fragment ions in the mass spectrum of 11b at m/z 263, 246, 180, 111
and 83. As shown from Fig. 2, structure 11b fits best to all the
spectroscopic data (see Section 4).
2.2. Pharmacology
2.2.2. Anticonvulsant activity
2.2.1. Antidepressant activity
The synthesized compounds 4a–d, 5a–d and 11a–d were also
evaluated for anticonvulsant activity against PTZ induced seizures
in mice [44].
The results of these experiments are listed in Fig. 3A–C and were
determined using the following formula [49].
The synthesized compounds 4a–d, 5a–d and 11a–d were
screened for antidepressant activity using tail suspension behav-
ioral despair test [43]. This test is used effectively in predicting the
activity of a wide variety of antidepressants such as MAO inhibitors
and tricyclic antidepressants. Results of the antidepressant activity
number of convulsions of control ꢀ number of convulsions of treated
%of protection ¼
ꢂ 100
number of convulsions of control
O
O
R
R
N
NH
R
NH
N
N
N
CO2Et
O
CO2Et
O
CO2Et
O
CN
CN
15
CN
11b
1) 3 CO
2) Pyrazole -NH
3) One CN
O
14
1) 3 CO
2) No -NH
3) One CN
4) Cyclic -CH
1) 2 CO
2) Oxadiazepine -NH
3) One CN
4) No cyclic -CH
4) No cyclic -CH
Fig. 2. Different alternative structures 14 and 15 for pyrazolone derivative 11b.

3484
M. Abdel-Aziz et al. / European Journal of Medicinal Chemistry 44 (2009) 3480–3487
A 100
B 100
90
90
80
70
60
50
40
30
20
10
0
80
phb
ph
5a
5b
5c
phb
ph
70
60
4a
50
4b
4c
4d
40
30
5d
20
10
0
Compounds
Compounds
C 100
90
80
70
60
50
40
30
20
10
0
phb
ph
11a
11b
11c
11d
Compounds
Fig. 3. Anticonvulsant activity of compounds 4a–d, 5a–d and 11a–d expressed as mean ꢁ S.E. compared to phenobarbital sodium (phb) and phenytoin sodium (ph) at a dose level of
(30 mg kgꢀ1). Compounds were tested at 20 mg kgꢀ1 dose level, ip. values represent the mean ꢁ S.E.M. (n ¼ 6).
Compounds 11b,11a and 11d exhibited the most protective class
of the tested compounds against clonic seizures induced by ip
injection of PTZ, they induced 78.7, 74.5 and 74% protection,
respectively, against clonic seizures induced by ip injection of PTZ
at a dose level of 20 mg kgꢀ1. Compounds 11b, 11a and 11d
exhibited a remarkable protective effect nearly close to phenobar-
bital sodium at a dose level of 30 mg kgꢀ1and better than phenytoin
uncorrected. The IR spectra were recorded with a Shimadzu 408 or
Bruker Vactor 22 FTIR instruments, using potassium bromide
pellets or CCl4. The 1H NMR (400.134 MHz) and 13C NMR
(100.6 MHz) spectra were measured in DMSO-d6 using a Bruker
AM400 with TMS as an internal standard, chemical shifts are
expressed as
q ¼ quartet, m ¼ multiplet and b ¼ broad.
d
(ppm), s ¼ singlet, d ¼ doublet, t ¼ triplet,
sodium at a dose level of 30 mg kgꢀ1
.
Assignment of carbon resonances has been supported by DEPT
experiment. Moreover, the signals caused by quaternary carbons
were identified by the comparison between 13C NMR and DEPT
spectra. Mass spectra have been obtained with a Varian MAT 312
instrument using electron impact ionization (70 eV). Elemental
analysis has been detected by the Microanalytical Center, Cairo
University, Egypt. Preparation layer chromatography (plc): Glass
plates (48 cm ꢂ 20 cm) were coated with silica gel Merck Pf254
(applied as aqueous slurry and air-dried affording a 1 mm layer).
Zones were detected by indicator fluorescence quenching upon
254 nm illuminations, removed from plates and extract with
acetone.
Compounds 4a, 5b and 11c exhibited a moderate protection
against clonic seizures induced by ip injection of PTZ at a dose level
of 20 mg kgꢀ1, they induced 65.1, 56.8 and 53.7%, respectively,
protection against clonic seizures induced by ip injection of PTZ.
Compounds 4a, 5b and 11c exhibited a moderate protection
compared to phenobarbital sodium at a dose level of 30 mg kgꢀ1
.
Compounds 4d, 4c and 5c exhibited a weak protection against
clonic seizures induced by ip injection of PTZ at a dose level of
20 mg kgꢀ1. The results are illustrated in Fig. 3A–C.
3. Conclusion
4.1.1. Substituted carboxylic hydrazide
Compounds 4a and 4b induced remarkable antidepressant
activity compared to imipramine at 10 mg kgꢀ1 dose level, other
compounds including 5c, 11c, 4c, 11d, 11a and 11b give good anti-
depressant activity. Moreover, compounds 11b, 11a and 11d
exhibited the most protective class of the tested compounds
against clonic seizures induced by ip injection of PTZ. Other
compounds 11b, 11a and 11d exhibited a remarkable protective
effect nearly close to phenobarbital sodium at a dose level of
1a–d were prepared according to published procedures [18,50–
55] as were 2-thiophene carboxylic hydrazide 1b mp135–137 ꢃC
(lit. [50] 134–136 ꢃC); 2-pyridine carboxylic hydrazide 1c mp 136–
138 ꢃC (lit. [52,53], 137 ꢃC); indole-2-carboxylic hydrazide 1d, mp
243–245 ꢃC (lit. [18,54,55], 246 ꢃC); phenyl carboxylic hydrazide 1a
and diethyl (E)-2,3-dicyanobutenedioate 3 (Aldrich) were used as
received. Ethentetracarbonitrile (2, Merck) was purified by crys-
tallization from chlorobenzene and sublimed.
30 mg kgꢀ1
. Therefore, they seem to be really promising
compounds for their antidepressant and anticonvulsant activities.
The synthesis studies should be continued concerning this group of
compounds followed with further in vivo studies.
4.1.2. General procedure for the reaction of substituted carboxylic
hydrazides 1a–d with ethentetracarbonitrile 2
To a stirred solution of (256 mg; 2.0 mmol) of 2 in 10 mL of
dimethylformamide, a solution of 1.0 mmol of 1a–d was added in
a dropwise manner, a spontaneous change of color from yellow to
dark green and finally to brown was observed. The mixture was
stirred for 4 h and left standing for 48 h at room temperature. After
concentration to dryness, the residues were sublimed at 80 ꢃC and
then subjected to plc using toluene/ethyl acetate (3:1) as eluent for
4. Experimental
4.1. Chemistry
Melting points have been determined using open glass capil-
laries on
a Gallenkamp melting point apparatus and are

M. Abdel-Aziz et al. / European Journal of Medicinal Chemistry 44 (2009) 3480–3487
3485
the reaction of 1a, 1b with 2. On the other hand, toluene/ethyl
acetate (2:1) was used as eluent for the reaction of 1c, 1d with 2.
Chromatographic separation of the residue (after sublimation) gave
numerous zones, two of which (with high intensity) were removed
and extracted. The fastest moving zone contained the pyrazole
derivatives 5a–d, while the slowest moving zone contained the
diacylhydrazines 4a–d. Extraction of the zones with acetone and
concentration gave residues, which were rechromatographed and
recrystallized to give pure crystals.
and indole-C-2), 158.45 (C-5), 170.72 (CO). MS (m/z, %): 303 (Mþ,
41), 276 (17), 248 (21), 144 (100), 116 (64), 66 (54). Anal. Calcd; For
C15H9N7O (303.28): C, 59.40; H, 2.99; N, 32.33. Found: C, 59.23; H,
3.11; N, 32.19.
4.1.3. General procedure for the reaction of substituted carboxylic
hydrazides 1a–d with diethyl (E)-2,3-dicyanobutenedioate 3
A solution of (222 mg; 1.0 mmol) of 3 in 30 mL of dry ethyl
acetate was heated with 1.0 mmol of 1a–d and stirred under reflux
for 4 h (a), 8 h (b) and 18 h (c,d), respectively. During which time
the color of the solution changed from colorless to reddish orange.
Concentration of the reaction mixture to dryness, the residues was
subjected to plc using toluene/ethyl acetate (2:1) as eluent. Chro-
matographic separation of the residue gave numerous zones, two of
which (with high intensity) were removed and extracted. The
fastest move zone contained the oxadiazole derivatives 10a–d,
while the slowest moving zone contained the pyrazolone deriva-
tives 11a–d. Extraction of the zones with acetone and recrystallized
gave the pure compounds.
4.1.2.1. N0-Benzoylbenzohydrazide 4a. Yield (65 mg, 27%), mp 239–
241 ꢃC (lit. [45,56], 237–238 ꢃC).
4.1.2.2. N0-(Thiophene-2-carbonyl)thiophen-2-carbohydrazide
4b. Yield (66 mg, 24%), mp 276–278 ꢃC (lit. [56,57], 274–277 ꢃC).
4.1.2.3. N0-Picolinoylpicolinohydrazide 4c. Yield (56 mg, 23%), mp
224–226 ꢃC (lit. [58] 224–225 ꢃC).
4.1.2.4. N0-(1H-Indole-2-carbonyl)-1H-indole-2-carbohydrazide
4d. Yield (80 mg, 25%), mp 355–357 ꢃC (lit. [58] 356.5–357.5 ꢃC).
4.1.3.1. Ethyl
2-cyano-5-phenyl-2,3-dihydro-1,3,4-oxadiazole-2-
carboxylate 10a. Orange crystals (methanol) in (135 mg, 55%), mp
4.1.2.5. 5-Amino-1-benzoyl-1H-pyrazole-3,3,4-(2H)-tricarbonitrile
5a. Pale yellow crystals (ethanol) in (182 mg, 69%), mp 210–212 ꢃC.
IR; nmax (KBr) cmꢀ1: 3380, 3300–3220 (NH2, NH), 2225, 2220 (CN),
192–194 ꢃC. IR; nmax (KBr) cmꢀ1: 3335 (NH), 2225 (CN), 1715 (CO),
1085 (C–O–C). 1H NMR (DMSO-d6):
d
1.2 (t, 3H, CH3, J ¼ 7.12 Hz),
4.21 (q, 2H, CH2O, J ¼ 7.12 Hz) 7.07–7.64 (m, 5H, Ar–H), 11.93 (br, 1H,
oxadiazole–NH). 13C NMR (DMSO-d6):
14.43 (CH3), 61.12 (CH2O),
1660 (CO), 1585 (Ar–C]C). 1H NMR (DMSO-d6):
d
¼ 6.98 (br, 2H,
NH2), 7.57–7.93 (m, 5H, Ar–H), 11.47 (pyrazole-NH). 13C NMR
(DMSO-d6):
d
80.14 (C-2), 118.36 (CN), 126.76, 128.93, 131.12 (Ar–CH), 132.77 (Ar–
C), 156.18 (C-5), 171.18 (CO). MS (m/z, %): 245 (Mþ, 39), 218 (22), 190
(16), 105 (100), 77 (86), 65 (56). Anal. Calcd; For C12H11N3O3
(245.23): C, 58.77; H, 4.52; N, 17.13. Found: C, 58.57; H, 4.69; N,
16.89.
d
¼ 48.48 (C-3), 64.14 (C-4), 117.94, 118.18, 119.26 (CN),
127.76, 128.93, 130.17 (Ar–CH), 134.36 (Ar–C), 158.64 (pyrazole-C-
5), 170.19 (CO). MS (m/z, %): 264 (Mþ, 33), 237 (18), 171 (26), 105
(100), 66 (71). Anal. Calcd; For C13H8N6O (264.08): C, 59.09; H, 3.05;
N, 31.80. Found: C, 58.87; H, 2.92; N, 32.04.
4.1.3.2. Ethyl 2-cyano-5-(thiophen-2-yl)-2,3-dihydro-1,3,4-oxadia-
zole-2-carboxylate 10b. Pale orange crystals (acetonitrile) in
(133 mg, 53%), mp 207–209 ꢃC. IR; nmax (KBr) cmꢀ1: 3320 (NH),
4.1.2.6. 5-Amino-1-(thiophene-2-carbonyl)-1H-pyrazole-3,3,4-(2H)-
tricarbonitrile 5b. Pale yellow crystals (acetonitrile) in (176 mg,
65%), mp 224–226 ꢃC. IR; nmax (KBr) cmꢀ1: 3385, 3310, 3210 (NH2,
NH), 2225, 2220 (CN), 1655 (CO), 1590 (Ar–C]C) nmax (CCl4, 10ꢀ3 M,
d ¼ 3 cm) 3370, 3195 cmꢀ1 (broad NH2 and OH assoc.), 1660 (CO).
2220 (CN), 1710 (CO), 1080 (C–O–C). 1H NMR (DMSO-d6):
d
¼ 1.22 (t,
3H, CH3, J ¼ 7.10 Hz), 4.18 (q, 2H, CH2O, J ¼ 7.10 Hz), 7.19–7.18 (m,
thiophene-H), 11.87 (br, 1H, oxadiazole-NH). 13C NMR (DMSO-d6):
1H NMR (DMSO-d6):
d
¼ 6.92 (br, 2H, NH2), 7.21–7.87 (thiophene-
¼ 46.23 (C-
d
¼ 14.39 (CH3), 61.26 (CH2O), 80.26 (C-2), 118.67 (CN), 126.84,
CH), 11.52 (br, H, pyrazole-NH). 13C NMR (DMSO-d6):
d
127.56, 127.83 (thiophene-CH), 129.35 (thiophene-C), 156.26 (C-5),
171.36 (CO). MS (m/z, %): 251 (Mþ, 53), 224 (37), 196 (63), 111 (100),
45 (86). Anal. Calcd; For C10H9N3O3S (251.26): C, 47.80; H, 3.61; N,
16.72; S, 12.76. Found: C, 48.02; H, 3.52; N, 16. 94; S, 12.54.
3), 64.51 (C-4), 117.89, 118.08, 118.96 (CN), 129.23, 130.34, 131.67
(thiophene-CH), 137.69 (thiophene-C-2), 158.52 (C-5), 169.86 (CO).
MS (m/z, %): 270 (Mþ, 27), 243 (31), 215 (23), 111 (100), 83 (69), 66
(49). Anal. Calcd; For C11H6N6OS (270.27): C, 48.88; H, 2.24; N,
31.09; S, 11.86. Found: C, 49.08; H, 2.31; N, 30.88; S, 12.05.
4.1.3.3. Ethyl 2-cyano-5-(pyridin-2-yl)-2,3-dihydro-1,3,4-oxadiazole-
2-carboxylate 10c. Pale orange crystals (methanol) in (135 mg,
55%), mp 202–204 ꢃC. IR; nmax (KBr) cmꢀ1: 3315 (NH), 1720 (CO),
4.1.2.7. 5-Amino-1-picolinoyl-1H-pyrazole-3,3,4-(2H)-tricarbonitrile
5c. Yellow crystals (ethanol) in (175 mg, 66%), mp 215–217 ꢃC. IR;
nmax (KBr) cmꢀ1: 3375, 3300, 3230 (NH2, NH), 2225, 2220 (CN),
2225 (CN), 1085 (C–O–C). 1H NMR (DMSO-d6):
d
¼ 1.18 (t, 3H, CH3,
J ¼ 7.05 Hz), 4.21 (q, 2H, CH2O, J ¼ 7.05 Hz), 7.58–8.42 (m, 4H, pyr-
1660 (CO), 1585 (Ar–C]C). 1H NMR (DMSO-d6):
d
¼ 6.95 (br, 2H,
NH2), 7.81–8.39 (pyridine-CH), 11.64 (pyrazole-NH). 13C NMR
(DMSO-d6):
idyl-H), 11.89 (br, 1H, oxadiazole-NH). 13C NMR (DMSO-d6):
d
¼ 14.28 (CH3), 61.17 (CH2O), 79.89 (C-2), 118.72 (CN), 126.18,
d
¼ 45.96 (C-3), 64.22 (C-4), 118.02, 118.28, 119.14 (CN),
127.83, 130.12, 144.11 (pyridyl-CH), 147.82 (pyridyl-C), 156.24 (C-5),
171.36 (CO). MS (m/z, %): 246 (Mþ, 51), 219 (28), 191 (11), 106 (93),
78 (100), 45 (32). Anal. Calcd; For C11H10N4O3 (246.22): C, 53.66; H,
4.09; N, 22.75. Found: C, 53.48; H, 3.96; N, 22.59.
126.56, 128.77, 131.12, 142.66 (pyridine-CH), 150.34 (pyridine-C),
158.56 (C-5), 170.12 (CO). MS (m/z, %): 265 (Mþ, 37), 238 (22), 210
(11), 106 (100), 78 (57), 66 (42). Anal. Calcd; For C12H7N7O (265.23):
C, 54.34; H, 2.66; N, 36.97. Found: C, 54.16; H, 2.59; N, 37.15.
4.1.3.4. Ethyl 2-cyano-5-(1H-indol-2-yl)-2,3-dihydro-1,3,4-oxadia-
zole-2-carboxylate 10d. Orange crystals (acetonitrile) in (151 mg,
53%), mp 259–261 ꢃC. IR; nmax (KBr) cmꢀ1: 3340–3305 (NH), 2220
4.1.2.8. 5-Amino-1-(1H-indole-2-carbonyl)-1H-pyrazole-3,3,4-(2H)-
tricarbonitrile 5d. Yellow crystals (acetonitrile) in (194 mg, 64%),
mp 276–278 ꢃC. IR; nmax (KBr) cmꢀ1: 3410, 3350–3230 (NH2, NH),
2225, 2220 (CN), 1650 (CO), 1595 (Ar–C]C). 1H NMR (DMSO-d6):
(CN), 1710 (CO), 1080 (C–O–C). 1H NMR (DMSO-d6):
d
¼ 1.21 (t, 3H,
CH3, J ¼ 6.90 Hz), 4.16 (q, 2H, CH2O, J ¼ 6.90 Hz), 6.98–7.55 (m, 5H,
d
¼ 6.87 (br, 2H, NH2), 7.11–7.67 (m, 5H, Ar–H), 11.41 (br, 1H, pyr-
Ar–H), 11.71 (br, 1H, indole-NH), 11.91 (br, 1H, oxadiazole-NH). 13C
azole-NH), 11.76 (br, 1H, indole-NH). 13C NMR (DMSO-d6):
d
¼ 46.18
NMR (DMSO-d6):
(indole-CH), 118.65 (CN), 126.26, 126.76, 128.75, 129.24 (Ar–CH),
130.61, 131.55, 132.25 (Ar–C and indole-C-2), 155.93 (C-5), 171.42
d
¼ 14.31 (CH3), 61.33 (CH2O), 80.12 (C-2), 111.23
(C-3), 64.42 (C-4), 115.18 (indole-CH), 117.93, 118.17, 119.12 (CN),
126.71, 127.16, 128.57, 129.63 (Ar–CH), 131.84, 138.66, 139.94 (Ar–C

3486
M. Abdel-Aziz et al. / European Journal of Medicinal Chemistry 44 (2009) 3480–3487
(CO). MS (m/z, %): 284 (Mþ, 26), 257 (16), 292 (28), 140 (33), 144
(100), 116 (76), 92 (67), 77 (54). Anal. Calcd; For C14H12N4O3
(284.27): C, 59.15; H, 4.25; N, 19.71. Found: C, 58.92; H, 4.37; N,
19.64.
respectively) in which a 12 h light/dark cycle was maintained
(08:00–20.00 h light). The animals were acclimated to their envi-
ronment for at least 2 days before the experiments and were
allowed free access to food and water before being tested.
4.1.3.5. Ethyl 1-benzoyl-4-cyano-5-oxo-2,5-dihydro-1H-pyrazole-3-
carboxylate 11a. Brown crystals (ethanol) in (99 mg, 35%), mp 227–
229 ꢃC. IR; nmax (KBr) cmꢀ1: 3345 (NH), 2220 (CN), 1710, 1680 and
1655 (CO), 1620 (C]N), 1590 (Ar–C]C). 1H NMR (DMSO-d6):
4.2.1. Antidepressant activity
The micewere housedin Plexiglass cages withsix animals foreach
cage. ‘‘Tail suspension test’’ a behavioral despair test, was used for
evaluating if the compounds have antidepressant activity. On the
testing day, mice were assigned into different groups (n ¼ 6 for each
group). The tested compounds and referencedrug (imipramine)were
dissolved in carboxy methyl cellulose (CMC) solution (0.5% w/v in
d
¼ 1.27 (t, 3H, CH3, J ¼ 7.10 Hz), 4.28 (q, 2H, CH2O, J ¼ 7.10 Hz), 7.36–
7.87 (m, 5H, Ar–H), 12.51 (br, 1H, pyrazole-NH). 13C NMR (DMSO-
d6):
d
¼ 14.28 (CH3), 61.49 (CH2O), 88.12 (C-4), 118.62 (CN), 128.22,
128.93 and 129.84 (Ar–CH),131.55 (Ar–C),156.11 (C-3),166.53 (C-5),
169.23 (CO-ester), 171.12 (CO). MS (m/z, %): 285 (Mþ, 51), 257 (27),
240 (29), 180 (64), 105 (82), 77 (100), 65 (66). Anal. Calcd; For
C14H11N3O4 (285.25): C, 58.95; H, 3.89; N, 14.73. Found: C, 59.19; H,
4.12; N, 14.51.
water). All the tested compounds 4a–d, 5a–d and 11a–d (10 mg kgꢀ1
)
and imipramine (10 mg kgꢀ1) were injected ip to mice at a volume of
0.5 mL per 100 g body weight. Control animals were similarly treated
with CMC solution (0.5% w/v in water). One hour later, the mice were
suspended by the tail to the edge of a shelf 80 cm above the floor. The
tail was secured to the shelf by adhesive tape placed approximately
1 cm from the tip of the tail. The duration of the immobility was
recorded for a period of 6 min. Mice was considered immobile only
when they hung passively and completely motionless.
4.1.3.6. Ethyl 1-(thiophene-2-carbonyl)-4-cyano-5-oxo-2,5-dihydro-
1H-pyrazole-3-carboxylate 11b. Brown crystals (acetonitrile) in
(107 mg, 37%), mp 237–239 ꢃC. IR; nmax (KBr) cmꢀ1: 3330 (NH),
2225 (CN), 1725, 1675 and 1660 (CO), 1625 (C]N), 1585 (Ar–C]C).
1H NMR (DMSO-d6):
d
¼ 1.24 (t, 3H, CH3, J ¼ 7.06 Hz), 4.25 (q, 2H,
CH2O, J ¼ 7.06 Hz), 7.19–7.82 (m, 3H, thiophene-H), 12.46 (br, 1H,
pyrazole-NH). 13C NMR (DMSO-d6):
4.2.2. Anticonvulsant activity
The synthesized compounds 4a–d, 5a–d and 11a–d were eval-
uated for anticonvulsant activity against PTZ induced seizures in
mice [44].
d
¼ 14.28 (CH3), 61.36 (CH2O),
88.38 (C-4), 118.76 (CN), 127.83, 128.24 and 128.55 (thiophene-CH),
130.12 (thiophene-C-2), 155.89 (C-3), 165.94 (C-5), 168.97 (ester-
CO), 170.92 (CO). MS (m/z, %): 291 (Mþ, 39), 263 (11), 246 (54), 180
(36), 111 (100), 83 (56). Anal. Calcd; For C12H9N3O4S (291.28): C,
49.48; H, 3.11; N, 14.43; S, 11.01. Found: C, 49.61; H, 3.39; N, 14.51; S,
10.87.
On the testing day mice were assigned into different groups
(n ¼ 6 for each group). The tested compounds were dissolved in
carboxymethylcellulose (CMC) solution (0.5% w/v in water) and
administered to animals at a dose of (20 mg kgꢀ1) ip at a volume of
0.5 mL per 100 g body weight. One hour after the administration of
the tested compound, mice were injected PTZ (100 mg kgꢀ1) as
a 0.5% solution ip that produces clonic seizures lasting for a period
of at least five seconds in greater than 95% of animals tested. The
animal was observed for 30 min, failure to observe even a threshold
seizure (a single episode of clonic spasms of at least 5 s duration)
was defined as protection. Animals devoid of generalized convul-
sions were considered to be protected and results were represented
as percentage protection [49]. Standard drug used was phenobar-
4.1.3.7. Ethyl 1-picolinoyl-4-cyano-5-oxo-2,5-dihydro-1H-pyrazole-
3-carboxylate 11c. Pale brown crystals (acetonitrile) in (103 mg,
36%), mp 231–233 ꢃC. IR; nmax (KBr) cmꢀ1: 3325 (NH), 2215 (CN),
1710, 1680 and 1665 (CO), 1625 (C]N), 1600 (Ar–C]C). 1H NMR
(DMSO-d6):
d
¼ 1.29 (t, 3H, CH3, J ¼ 7.05 Hz), 4.28 (q, 2H, CH2O,
J ¼ 7.05 Hz), 7.61–8.44 (pyridyl-H), 12.45 (br, 1H, pyrazole-NH). 13C
NMR (DMSO-d6):
d
¼ 14.29 (CH3), 61.41 (CH2O), 89.35 (C-4), 119.16
(CN), 126.83, 127.22, 130.14, 143.22 (pyridyl-CH), 147.12 (pyridyl-C-
2), 156.24 (C-3), 165.54 (C-5), 168.84 (ester-CO), 171.38 (CO). MS (m/
z, %): 286 (Mþ, 46), 258 (6), 180 (19), 106 (100), 78 (87). Anal. Calcd;
For C13H10N4O4 (286.24): C, 54.55; H, 3.52; N,19.57. Found: C, 54.76;
H, 3.36; N, 19.69.
bital sodium and phenytoin sodium at a dose level of 30 mg kgꢀ1
.
4.3. Statistical analysis
Results are expressed as mean ꢁ S.E.M.;
n represents the
number of animals. Data obtained from pharmacological experi-
ments were analyzed by one-way analysis of variance (ANOVA). A
p-value of less than 0.05 was considered statistically significant.
4.1.3.8. Ethyl 1-(1H-indole-2-carbonyl)-4-cyano-5-oxo-2,5-dihydro-
1H-pyrazole-3-carboxylate 11d. Brown crystals (acetonitrile) in
(113 mg, 35%), mp 287–289 ꢃC IR; nmax (KBr) cmꢀ1: 3335, 3270
(NH), 2220 (CN), 1715, 1675 and 1660 (CO), 1625 (C]N), 1595 (Ar–
Acknowledgements
C]C). 1H NMR (DMSO-d6):
d
¼ 1.23 (t, 3H, CH3, J ¼ 7.12 Hz), 4.25 (q,
2H, CH2O, J ¼ 7.12 Hz), 6.72 (indole-CH), 7.22–7.65 (m, 4H, Ar–H),
A.A. Hassan is indebted to the A.V. Humboldt-Foundation for the
donation of the Shimadzu 408 IR spectrophotometer. Authors also
introduce their great thanks to Dr. Al-Shimaa Faisel, Pharmacology
Department, Faculty of Pharmacy, Minia University for her valuable
help in measuring the antidepressant and anticonvulsant activities.
11.63 (br, 1H, indole-NH), 12.55 (br, 1H, pyrazole-NH). 13C NMR
(DMSO-d6):
d
¼ 14.22 (CH3), 61.72 (CH2O), 89.19 (C-4), 111.22
(indole-CH), 118.89 (CN), 126.74, 128.12, 128.81, 129.17 (Ar–CH),
130.55, 131.67 (Ar–C), 155.98 (C-3), 165.34 (C-5), 168.49 (ester-CO),
171.36 (CO). MS (m/z, %): 324 (Mþ, 35), 296 (24), 180 (52), 144 (86),
116 (43), 92 (91), 77 (100), 65 (86). Anal. Calcd; For C16H12N4O4
(324.29): C, 59.26; H, 3.73; N, 17.28. Found: C, 59.02; H, 3.92; N,
17.45.
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