Novel 2-pyrazoline derivatives as potential anticonvulsant agents

Article abstract of DOI:10.1007/s00044-013-0530-7

A series of new 2-pyrazoline derivatives has been synthesized by reacting 3-(substituted-phenyl)-1-pyridin-2-yl-propenones using two routes one using thiosemicarbazide and the other by hydrazine hydrate. The chemical structures were established by IR, Mas

Full text of DOI:10.1007/s00044-013-0530-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0530-7
ORIGINAL RESEARCH
Novel 2-pyrazoline derivatives as potential anticonvulsant agents
•
Shradha Bhandari Avinash C. Tripathi
•
Shailendra K. Saraf
Received: 29 November 2012 / Accepted: 31 January 2013
ꢀ Springer Science+Business Media New York 2013
Abstract A series of new 2-pyrazoline derivatives has
been synthesized by reacting 3-(substituted-phenyl)-1-pyr-
idin-2-yl-propenones using two routes one using thiosemi-
carbazide and the other by hydrazine hydrate. The chemical
disease is 0.5–1.0 % of the population and up to 50 million
people worldwide (Lowenstein et al., 2005). The anti-sei-
zure drugs act mainly by three mechanisms: calcium channel
blocking, sodium channel blocking, and GABA mediated
potassium channel opening (Kwan et al., 2001).
1
structures were established by IR, Mass, H-NMR, 13C-
NMR spectroscopic data, and elemental analysis. The anti-
convulsant activity of the synthesized compounds was
evaluated by the ‘‘maximal electroshock seizure’’ (MES) test
and pentylenetetrazole (PTZ) test using male albino mice.
Compounds 2e, 5-(naphthalene-1-yl)-3-(pyridine-2-yl)-4,5-
dihydro-1H-pyrazole-1-carbothioic acid amide, and 3c,
N-ethyl-5-(naphthalene-1-yl)-3-(pyridine-2-yl)-4,5-dihydro-
1H-pyrazole-1-carbothioamide showed appreciable activity
in the MES as well as PTZ test at all the evaluated doses.
The interest in pyrazoles stemmed from their applications
in drugs, dyes, and as anesthetics. Pyrazolines are less stable
than the corresponding pyrazoles but can be converted
into the latter using mild oxidizing agents, such as bromine
or lead tetra-acetate (Vardanyan and Hruby, 2006).
Increasing evidence suggests that pyrazoline derivatives
possess a broad spectrum of biological activities such as
antimicrobial, anticancer, tranquilizing, muscle relaxant,
antidepressant, monoamine oxidase inhibitory (MAOI),
anticonvulsant, anti-hypertensive, anti-inflammatory, and
anti-amebic (Agrawal et al., Online First, 16 November
2011; Rahman and Siddiqui, 2010; Bhatia et al., 2010;
Stirrett et al., 2008; Revanasiddappa et al., 2010; Dawane
et al. 2010; Ghorab et al., 2010; Palaska et al., 2001;
Rajendra Prasad et al., 2005; Ozdemir et al., 2007, 2008;
Jayaprakash et al., 2008; Ruhoglu et al., 2005; Parmar et al.,
1974; Guniz Kucukguzel et al., 2000; Turan-Zitouni
et al., 2000; Amir et al., 2008; Rani et al., 2004; Budakoti
et al., 2007; Budakoti et al., 2008). Nowadays, the thera-
peutic interest of MAOIs falls into two major categories.
MAO-A inhibitors have been used mostly in the treatment of
mental disorders, in particular depression, anxiety, and
convulsion; and MAO-B inhibitors which could be used in
the treatment of Parkinson’s disease and Alzheimer’s dis-
ease (Bortolato et al., 2008; Youdim et al., 2006). The
classical period of the MAO-inhibitors started with hydra-
zine derivatives and 2-pyrazolines can be considered as
cyclic hydrazine moieties, reported to have MAO inhibitory,
anti-depressant, and anticonvulsant activity (Ozdemir et al.,
2007, 2008; Manna et al., 1998, 2002; Chimenti et al., 2004,
Keywords 2- Pyrazolines ꢀ Anticonvulsant activity ꢀ
Claisen-Schmidt condensation ꢀ MES test ꢀ PTZ test
Introduction
Epilepsy is the most frequent neurologic affection, charac-
terized by excessive temporary neuronal discharge, which
may be due to a number of different causes leading to epi-
leptic seizures (Jones, 2002). The overall prevalence of the
S. Bhandari ꢀ A. C. Tripathi ꢀ S. K. Saraf (&)
Faculty of Pharmacy, Babu Banarasi Das Northern India
Institute of Technology, BBD City, Faizabad Road,
Chinhut, Lucknow 227105, U.P., India
e-mail: dirpharmniec@gmail.com
S. Bhandari
e-mail: shradhapharma@gmail.com
A. C. Tripathi
e-mail: aviniec31@gmail.com
123

Med Chem Res
O
2010; Das et al., 2012). Therefore, in the present study a
series of pyrazoline derivatives were synthesized and
screened for their anticonvulsant potential.
Ar
N
+
CH3
O
H
Base
10 - 20 0
C
Claisen-Schmidt condensation
Materials and methods
O
N
The chemicals and reagents were procured from S.D. Fine
and Sigma-Aldrich and were used as such. Melting points
were determined using melting point apparatus and are
uncorrected. Progress of the reactions was monitored by
thin layer chromatography on silica gel G plates, using
iodine vapors and UV chamber as visualizing agents. The
synthesized compounds were subjected to physical and
spectral analysis.
C
CH CH Ar
1a-e
Route 2
(NH2.NH2.H2O)
(C2H5OH)
Route 1
(H2NNHCSNH2)
(NaoH,C2H5OH)
4 hrs, reflux
2 hrs, reflux
N
N
N
N
Ar
N
N
Ar
Synthetic procedures
2f-j
H
S
NH2
R'NCS, ROR"
General procedure for the synthesis of 3-(4-
substituted-phenyl)-1-pyridin-2-yl-propenones,
i.e., chalcones (1a–e)
2a-e
(C2H5)3 NH2
N
N
N
Ar
These were synthesized by condensing 2-acetyl pyridine
with benzaldehyde derivatives in the presence of sodium
hydroxide at temperature between 10 and 20 ꢁC by Claisen-
Schmidt condensation (Furniss et al., 2007; Horning, 1985).
C
S
NHR'
3a-e
Ar= 4-Cl C6H4, 3-Cl C6H4, 4-OCH3C6H4, 4- C13H11O, C10H7; R' =C2H5.
General procedure for the synthesis of 5-(substituted-
phenyl)-3-(pyridine-2-yl)-4,5-dihydro-1H-pyrazole-1-
carbothioic acid amides (2a–e)
Scheme 1 Synthesis of 2-pyrazoline derivatives
(s,2H); 13C NMR (CDCl3, ppm): 41.1 (CH2 pyrazoline),
51.3 (CH pyrazoline), 156.5 (C pyrazoline), 126.7 (2CH
pyridine), 137.1 (CH pyridine), 148.6 (CH pyridine),
154.1 (C pyridine), 127.9 (4CH benzene), 132.2 (C
benzene), 138.8 (C benzene), 183.9 (C thioamide); Anal.
Calcd for C15H13ClN4S: C, 55.35; H, 3.98; N, 18.44; S,
10.55. Found: C, 55.32; H, 3.96; N, 18.42; S, 10.51.
To the solutions of appropriate (1a–e) derivatives in etha-
nol, thiosemicarbazide was added and the reaction mixture
was refluxed for 2–3 h. The crude product was poured on
crushed ice, filtered through a Buchner funnel, and
re-crystallized from methanol.
General procedure for the synthesis of N-ethyl-5-
(substituted-phenyl)-3-(pyridine-2-yl)-4,5-dihydro-1H-
pyrazole-1-carbothioamide (3a–e)
Compound 2b IR (KBr, v cm-1): C–H Str (Ar) (3,151.3,
3,019.2), C=N (1,678.1), N–C=S (1,216.8, 1,101.0); MS: m/
z: 316.81 (M??1 = 317.2); 1H NMR (CDCl3 d): 7.1–7.6 (q,
6H), 6.0–6.05(dd, 1H), 7.4–7.6 (m, 2H), 8.0–8.6 (t, 1H),
3.8–3.9 (t, 1H), 3.3–3.8 (d, 1H); 13C NMR (CDCl3, ppm):
41.5 (CH2 pyrazoline), 51.8 (CH pyrazoline), 155.6 (C
pyrazoline), 125.7 (2CH pyridine), 136.3 (CH pyridine),
149.2 (CH pyridine), 155.8 (C pyridine), 128.9 (2CH ben-
zene), 125.9 (CH benzene)133.9 (C benzene), 142.6 (C
benzene), 184.4 (C thioamide); Anal. Calcd for
C15H13ClN4S: C, 56.87; H, 4.14; N, 17.68; S, 10.12. Found:
C, 56.86; H, 4.16; N, 17.71; S, 10.08.
To the solution of appropriate (1a–e) derivatives in ethanol,
hydrazine hydrate was added and the reaction mixture was
refluxed for 2–3 h. The crude product was stirred at room
temperature for another 4 h, with a few drops each of trieth-
ylamine, diethyl ether, and potassium thiocynate (Scheme 1).
Spectral data of synthesized compounds
Compound 2a IR (KBr, v cm-1): C–H Str (Ar) (3,049.25),
C=N (1,642.74), N–C=S (1,157.21); MS: m/z: 316.81
(M??1 = 317.1); 1H NMR (CDCl3, d): 7.89 (s, 1H),
7.51 (s, 1H), 6.89–7.35 (m, 8H), 4.89 (s, 1H), 3.38
Compound 2c IR (KBr, v cm-1): C–H Str (Ar)
(3,151.47), C=N (1,685.67),N–C=S (1,244, 1,170.71); MS:
m/z: 388.14 (M??Na? 411.2); 1H NMR (CDCl3, d):
123

Med Chem Res
6.6–8.7 (m, 16H), 3.39–4.20 (m, 2H); 13C NMR (CDCl3,
ppm): 40.5 (CH2 pyrazoline), 51.9 (CH pyrazoline), 155.7
(C pyrazoline), 125.1 (2CH pyridine), 136.2 (CH pyridine),
150.4 (CH pyridine), 154.3 (C pyridine), 114.2 (2CH
benzene), 128.7 (2CH benzene), 135.1 (C benzene), 161.3
(C benzene), 77.3 (CH2 aliphatic), 127.6 (3CH benzene),
129.2 (2CH benzene), 141.7 (C benzene), 182.9 (C thio-
amide); Anal. Calcd for C22H20N4OS: C, 67.18; H, 5.10; N,
14.92; S, 8.54. Found: C, 67.20; H, 5.07; N, 14.94; S, 8.54.
135.1 (CH pyridine), 149.9 (CH pyridine), 153.5 (C pyridine),
113.6 (2CH benzene), 128.4 (2CH benzene), 134.9 (C ben-
zene), 160.6 (C benzene), 55.3 (CH3 aliphatic), 182.5 (C thi-
oamide), 43.7 (CH2 aliphatic), 15.2 (CH3 aliphatic); Anal.
Calcd for C18H20N4OS: C, 66.76; H, 5.94; N, 16.51; S, 5.40.
Found: C, 66.79; H, 5.90; N, 16.52; S, 5.44.
Compound 3c IR (KBr, v cm-1): C–H Str (Ar) (3,011.9),
C=N (1,608.8), N–C=S (1,219.1, 1,175.7); MS: m/z: 360.14
(M??1 = 360.18); 1H NMR (CDCl3, d): 8.54–8.57 (s, 1H),
7.7–8.5 (d, 1H), 7.6–7.7 (m, 2H) 7.42–7.45 (m, 2H),
7.39–7.45 (m, 6H), 7.34–7.36 (m, 2H), 7.1–7.2 (t, 4H), 4.9 –
5.08 (m, 3H); 13C NMR (CDCl3, ppm): 39.8 (CH2 pyrazo-
line), 50.3 (CH pyrazoline), 154.8 (C pyrazoline), 126.5
(2CH pyridine), 134.3 (CH pyridine), 148.9 (CH pyridine),
155.7 (C pyridine), 123.2 (CH naphthalene), 125.8 (2CH
naphthalene), 127.7 (3CH naphthalene), 128.2 (CH
naphthalene), 133.4 (2C naphthalene), 134.5 (C naphtha-
lene), 184.7 (C thioamide), 42.7 (CH2 aliphatic), 16.2
(CH3 aliphatic); Anal. Calcd for C21H20N4S: C, 69.97; H,
5.59; N, 18.44; S, 8.90. Found: C, 69.99; H, 5.60; N,
18.45; S, 8.93.
Compound 2d IR (KBr, v cm-1): C–H Str (Ar) (3,153.40),
C=N (1,691.46), N–C=S (1,249.79, 1,176.50); MS: m/z:
312.39 (M??1 = 313.3); 1H NMR (CDCl3, d): 6.8–8.6 (m,
9H), 3.6–3.8 (m, 4H); 13C NMR (CDCl3, ppm): 39.8 (CH2
pyrazoline), 52.1 (CH pyrazoline), 154.8 (C pyrazoline),
125.1 (2CH pyridine), 135.5 (CH pyridine), 150.2 (CH
pyridine), 153.1 (C pyridine), 113.3 (2CH benzene), 127.7
(2CH benzene), 134.5 (C benzene), 160.2 (C benzene), 55.8
(CH3 aliphatic), 182.5 (C thioamide); Anal. Calcd for
C16H16N4OS: C, 61.52; H, 5.16; N, 17.93; S, 10.26. Found:
C, 61.50; H, 5.16; N, 17.90; S, 10.29.
Compound 2e IR (KBr, v cm-1): C–H Str (Ar) (3,145.68),
C=N (1,696.95), N–C=S (1,114.78); MS: m/z: 332.11
(M??1 = 333.0); 1H NMR (CDCl3, d): 6.66–8.27 (m,
13H), 4.6–4.9 (m, 3H); 13C NMR (CDCl3, ppm): 39.3 (CH2
pyrazoline), 50.9 (CH pyrazoline), 153.9 (C pyrazoline),
126.2 (2CH pyridine), 134.8 (CH pyridine), 149.1 (CH
pyridine), 156.6 (C pyridine), 122.8 (CH naphthalene), 125.4
(2CH naphthalene), 127.1 (3CH naphthalene), 129.2 (CH
naphthalene), 133.1 (2C naphthalene), 134.1 (C naphtha-
lene), 185.1 (C thioamide); Anal. Calcd for C19H16N4OS: C,
67.69; H, 4.73; N, 17.54; S, 10.04. Found: C, 67.73; H, 4.75;
N, 17.53; S, 10.01.
Compound 3d IR (KBr, v cm-1): C–H Str (Ar) (3,049.0),
C=N (1,548.9), N–C=S (1,221.8, 1,087.5); MS: m/z: 478.17
(M??1 = 479.3); 1H NMR (CDCl3, d): 7.1–8.6 (m, 13H),
3.47 (s, 8H); 13C NMR (CDCl3, ppm): 41.1 (CH2 pyrazo-
line), 52.2 (CH pyrazoline), 154.7 (C pyrazoline), 125.5
(2CH pyridine), 135.8 (CH pyridine), 150.1 (CH pyridine),
155.3 (C pyridine), 114.7 (2CH benzene), 128.2 (2CH ben-
zene), 135.6 (C benzene), 160.3 (C benzene), 78.1 (CH2
aliphatic), 127.4 (3CH benzene), 129.1 (2CH benzene),
140.7 (C benzene), 183.9 (C thioamide), 41.8 (CH2 ali-
phatic), 16.8 (CH3 aliphatic); Anal. Calcd for C24H24N4OS:
C, 69.20; H, 5.81; N, 13.45; S, 7.70. Found: C, 69.18; H, 5.85;
N, 13.46; S, 7.74.
Compound 3a IR (KBr, v cm-1): C–H Str (Ar) (3,138.26),
C=N (1,600.81), N–C=S (1,174.57, 1,058.85); MS: m/z:
1
344.09 (M?? 1 = 344.12); H NMR (CDCl3, d): 7.7–7.8
Compound 3e IR (KBr, v cm-1): C–H Str (Ar) (3,019.2),
C=N (1,578.1),N–C=S (1,216.8); MS: m/z: 344.09
(d, 1H), 7.72–7.77 (s, 1H), 7.72–7.76 (q, d, 2H, 1H), 7.2–7.3
(m, 3H), 3.04–3.06 (d, 3H); 13C NMR (CDCl3, ppm): 41.5
(CH2 pyrazoline), 51.8 (CH pyrazoline), 155.6 (C pyrazo-
line), 125.7 (2CH pyridine), 136.3 (CH pyridine), 149.2 (CH
pyridine), 155.8 (C pyridine), 128.9 (2CH benzene), 125.4
(CH benzene)133.9 (C benzene), 142.6 (C benzene), 184.4
(C thioamide), 43.5 (CH2 aliphatic), 16.4 (CH3 aliphatic);
Anal. Calcd for C17H17 ClN4S: C, 59.21; H, 4.97; N, 16.25;
S, 9.30. Found: C, 59.25; H, 4.98; N, 16.22; S, 9.27.
1
(M??1 = 344.12); H NMR (CDCl3, d): 7.9–8.5 (s, 1H),
7.6–7.9 (q, 1H), 7.0–7.6 (m, 9H), 6.91–6.98 (q, s, 4H, 2H),
3.02–4.96 (m, 3H); 13C NMR (CDCl3, ppm): 41.4 (CH2
pyrazoline), 51.3 (CH pyrazoline), 156.5 (C pyrazoline),
126.7 (2CH pyridine), 137.1 (CH pyridine), 148.6 (CH
pyridine), 154.1 (C pyridine), 127.9 (4CH benzene), 132.2
(C benzene), 138.8 (C benzene), 183.9 (C thioamide), 42.5
(CH2 aliphatic), 15.9 (CH3 aliphatic); Anal. Calcd for
C17H17 ClN4S: C, 59.21; H, 4.97; N, 16.25; S, 9.30. Found:
C, 59.19; H, 5.01; N, 16.26; S, 9.29.
Compound 3b IR (KBr, v cm-1): C–H Str (Ar) (3,042.1),
C=N (1,613.4),N–C=S (1,247.8, 1,178.3); MS: m/z: 340.14
1
(M??1 = 340.17); H NMR (CDCl3, d): 7.6–7.8 (s, 1H),
Anticonvulsant activity
7.62–7.65 (d, 1H), 7.1–7.2 (m, 2H) 7.15–7.20 (m, 2H),6.7–6.9
(t, 2H) 4.8–4.9 (t, 1H), 3.48–3.52 (t, 2H) 3.04–3.16 (d, 7H);
13C NMR (CDCl3, ppm): 40.1 (CH2 pyrazoline), 52.5 (CH
pyrazoline), 154.7 (C pyrazoline), 125.8 (2CH pyridine),
The anticonvulsant activity studies were performed using
maximal electroshock seizure (MES) and pentylenetetrazole
123

Med Chem Res
(PTZ) method. The MES test is associated with the electrical
induction of the seizure, whereas PTZ test involves a
chemical induction to generate the convulsion. MES seizures
were elicited using the apparatus with corneal electrodes
[Medicraft Electro-Convulsiometer]. Pentylenetetrazole
was supplied by Sigma Chemical Co. The rota-rod used in
the neurotoxicity test was made by Medicraft. The synthe-
sized compounds were administrated to animals(male albino
mice, weighing 30–45 g) intraperitoneally (i.p.) at three
doses (30, 100, and 300 mg/kg, suspended in 10 percent
aqueous PEG-400). Phenobarbital (30 mg/kg, subcutane-
ous.) was taken as standard drug and all the assays were
performed at 0.5 and 4 h. Five animals for each dose level
were used for the study. Animals were procured from the
Animal House, Faculty of Pharmacy, BBDNIIT, Lucknow,
U.P., India and housed in polypropylene cages with steel net,
in temperature controlled room under standard living con-
ditions of 25 5 ꢁC and relative humidity of 55 5 with
regular 12 h light and 12 h dark cycles and allowed free
access to standard laboratory food and water. All the animals
were treated humanely in accordance with the guidelines laid
down by the Institutional Animal Ethics Committee (IAEC).
The anticonvulsant activity was approved by the IAEC with
protocol no. BBDGEI/IAEC/09/2010.
required to elicit minimal electroshock seizures) delivered
for 0.2 s via corneal electrodes. A drop of 0.9 % saline is
instilled in the eye prior to application of the electrodes in
order to prevent the death of the animal. Abolition of the
hind limb tonic extension component of the seizure is
defined as protection (Ozdemir et al., 2007).
Pentylenetetrazole (metrazol) (PTZ) test
Pentylenetetrazole (85 mg/kg) (produces seizures in greater
than 95 % of mice) is administered as a 0.5 % solution
subcutaneous in the posterior midline. The animals were
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 (Ozdemir et al., 2007).
Neurotoxicity
The rota-rod test was used to evaluate neurotoxicity. The
cardinal feature of the test is to ascertain the impairment of
motor performance, ataxia, loss of skeletal muscular
strength, and acute neurotoxicity produced by drugs in pre-
clinical studies. The animals were placed on a 1 in. diameter
knurled wooden rod rotating at 6 rpm. Normal mice remain
on a rod rotating at this speed indefinitely. Neurologic tox-
icity was defined as the failure of the animal to remain on the
rod for 1 min (Ozdemir et al., 2007).
Maximal electroshock seizure (MES) test
Maximal electroshock seizures are elicited with a 50 Hz
alternating current of 50 mA intensity (5–7 times that is
Table 1 Structure and chemical data of synthesized 2-pyrazoline derivatives (2a–e & 3a–e)
N
N
R
R
N
N
N
C
N
C
S
NHC2H5
S
NH2
(3a-e)
(2a-2e)
Compounds
R
Formula
State
Melting point (ꢁC)
Purification
Partition coefficient (log P)
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4-Chloro
C15H13ClN4S
Solid
58–60
70–72
78–80
76–78
86–88
98–100
–
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
4.21
4.15
1.17
2.82
4.51
3.20
2.92
4.70
1.46
3.64
3-Chloro
C
C
C
C
C
C
C
C
C
15H13ClN4S
22H20N4OS
16H16N4OS
19H16N4S
Solid
4-Benzyloxy
4-Methoxy
1-Naphthyl
3-Chloro
Solid
Solid
Solid
17H17ClN4S
18H20N4OS
21H20N4S
Solid
4-Methoxy
1-Naphthyl
4-Benzyloxy
4-Chloro
Semi-solid
Semi-solid
Semi-solid
Semi-solid
–
24H24N4OS
17H17ClN4S
–
–
123

Med Chem Res
Results and discussion
expressed in cm-1. Mass spectra were recorded on a JEOL-
Accu TOF, JMS-T100LC spectrometer. Proton Nuclear
Magnetic resonance spectra were recorded on Bruker
DRX-300 (at 300 MHz) spectrometer and 13C-NMR data
were recorded on Advance-400 MHz, Bruker (Switzer-
land) spectrometer. Chemical shift values were reported in
parts per million (delta value), taking TMS as an internal
standard. Elemental analysis was performed on a Elemental
Vario EL III analyzer. All the spectral studies were
A series of 2-pyrazoline derivatives was synthesized via
Claisen-Schmidt condensation and all the synthesized
pyrazoline derivatives (2a–e and 3a–e) were characterized
by chemical, spectral, and elemental data (Melting Point,
IR, Mass, NMR, and Elemental Analysis) (Table 1).
Infrared spectra were recorded on Shimadzu 8400S and
Perkin-Elmer AX-1 spectrometers and the values are
Table 2 Anticonvulsant activity of the synthesized compounds
Comp.
Dose (mg/kg)
Activity MES time (h)
Activity PTZ time (h)
aToxicity time (h)
0.5
0.5
4.0
0.5
4.0
4.0
2a
30
100
300
30
0/1
1/1
1/1
1/1
1/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
1/1
1/1
0/1
1/1
1/1
0/1
0/1
0/1
0/1
1/1
1/1
0/1
1/1
1/1
0/1
1/1
1/1
0/1
1/1
0/1
0/1
1/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
1/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
1/1
1/1
0/1
1/1
1/1
0/1
0/1
1/1
1/1
1/1
1/1
0/1
1/1
1/1
0/1
0/1
1/1
0/1
0/1
1/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
0/4
0/4
1/4
0/4
0/4
1/4
1/4
4/4
4/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
1/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
1/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
2/4
3/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
2b
2c
2d
2e
3a
3b
3c
3d
3e
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
–
Control
Standard
Control = PEG-400 (10 % suspension), Standard = Phenobarbital (30 mg/kg), 0/1 = No activity at dose level, 1/1 = Noticeable activity at
dose level, n = 5 (Number of animals tested at each dose level)
MES Maximal electroshock seizure, PTZ Pentylentetrazol (Metrazol)
a
Evaluated in rota-rod test (number of animal exhibiting toxicity/number of animal tested)
123

Med Chem Res
•
•
N-ethyl substitution at 1st position increases log P value
but no marked effect was observed on the activity.
Noticeable toxicity was observed for the compound 2c
at the evaluated doses.
performed at Central Drugs Research Institute, Lucknow,
India and the observed values were found in agreement
with calculated values.
The results presented in Table 2 showed that compounds
2e, 3c, 3b, 2a, 2b, and 3a exhibited appreciable anticon-
vulsant activity. Naphthyl group containing compounds 2e
and 3c were found to be the most active compounds in the
series showing good protection against both MES and PTZ
induced seizures. Chloro-substituted derivatives 2a, 2b, and
3a were found to possess good anticonvulsant activity but
more active against maximal electroshock induced seizures.
It was also pointed out that some of the compounds (2d and
3b) having 4-methoxy substitution in phenyl ring showed a
positive response in the PTZ test but they did not show pro-
tection in MES-induced convulsions at the same doses and
times evaluated. The 4-benzyloxy benzaldehyde derivative of
2-pyrazoline 2c was not found to possess anticonvulsant
activity as compared to other compounds synthesized in
Route 1, but the same synthesized in Route 2 having ethyl
substitution3d showed average activity. LogP is indicative of
lipophilicity of a compound. Thus, log P value of the com-
pounds was calculated using method of Hansch (Harrold and
Yee, 2005)anditwasobservedthattheanticonvulsantactivity
of the synthesized compounds increased with increment in
log P values. Noticeable neurotoxicity was observed for the
compound 2c at the evaluated doses. It is worth saying that the
compounds having 2-pyridyl substitution at 3rd position of
2-pyrazoline are important for the activity, as almost all the
derivatives bearing this substitution were found to be phar-
macologically active. Therefore, such compounds would
represent a fruitful matrix for the development of a new class
anticonvulsant agent and would deserve further investigation
and derivatization as a promising scaffold.
Acknowledgments We express our sincere gratitude to Central
Drugs Research Institute, Lucknow, India for providing the library
facilities and sophisticated analytical instrument facilities.
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