Synthesis and studies on antidepressant and anticonvulsant activities of some 3-(2-furyl)-pyrazoline derivatives

Article abstract of DOI:10.1016/j.ejmech.2006.09.006

Twelve 1-phenyl-, 1-thiocarbamoyl- and 1-N-substituted thiocarbamoyl-3-(2-furyl)-5-phenyl/(2-furyl)-2-pyrazoline derivatives were synthesized. The chemical structures of the compounds were proved by IR, ¹H NMR, Mass spectrometric data and micro

Full text of DOI:10.1016/j.ejmech.2006.09.006

European Journal of Medicinal Chemistry 42 (2007) 373e379
http://www.elsevier.com/locate/ejmech
Original article
Synthesis and studies on antidepressant and anticonvulsant activities
of some 3-(2-furyl)-pyrazoline derivatives
a
b
b
a
a,
¨
¨
*
Zuhal Ozdemir , H. Burak Kandilci , Bulent Gumuxsel , Unsal C¸ alıxs , A. Altan Bilgin
¨
¨ ¨
a Hacettepe University Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100 Ankara, Turkey
b Hacettepe University Faculty of Pharmacy, Department of Pharmacology, 06100 Ankara, Turkey
Received 27 February 2006; received in revised form 4 September 2006; accepted 7 September 2006
Available online 25 October 2006
Abstract
Twelve 1-phenyl-, 1-thiocarbamoyl- and 1-N-substituted thiocarbamoyl-3-(2-furyl)-5-phenyl/(2-furyl)-2-pyrazoline derivatives were
synthesized. The chemical structures of the compounds were proved by IR, 1H NMR, Mass spectrometric data and microanalyses. The
antidepressant activities of the compounds were investigated by Porsolt’s behavioural despair (forced swimming) test on albino mice. 1-N-Ethyl-
thiocarbamoyl-3-(2-furyl)-5-phenyl-2-pyrazoline (6) and 1-N-allylthiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (11) reduced 33.80e31.42%
duration of immobility times at 10 mg kgꢀ1 dose level. Anticonvulsant activities of the compounds were determined by maximal electroshock
seizure (MES) and subcutaneous pentylenetetrazole (metrazol) (scMet.) tests, neurotoxicities were determined by rotarod toxicity test on albino
mice. 1,5-Diphenyl-3-(2-furyl)-2-pyrazoline (2), 1-N-allylthiocarbamoyl-3-(2-furyl)-5-phenyl-2-pyrazoline (7), 1-N-allylthiocarbamoyl-3,
5-di(2-furyl)-2-pyrazoline (11) and 1-N-phenylthiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (12) were active at 100e300 mg kgꢀ1 dose levels.
1-Thiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (4), 1-N-methylthiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (9) and 1-N-ethylthiocarbamoyl-3,
5-di(2-furyl)-2-pyrazoline (10) were found protective against MES and scMet. at 30e300 mg kgꢀ1 dose levels.
Ó 2006 Elsevier Masson SAS. All rights reserved.
Keywords: Pyrazolines; Thiocarbamoyl compounds; Antidepressant activity; Anticonvulsant activity
1. Introduction
5-triphenyl- [4], 1-thiocarbamoyl-3,5-diphenyl-2-pyrazolines
[5] and their condensed analogs 8-thiocarbamoyl-7,8-diazabi-
cyclo[4.3.0]non-6-enes [6] and 1-N-substituted thiocarba
moyl-3-phenyl-5-thienyl-2-pyrazolines [7] have significant
antidepressant activities. In our recent studies, some 1-thiocar-
bamoyl-3-phenyl-5-heteroaryl-2-pyrazolines [8] and their
3-(2-napthyl) analogs [9] were also found to have significantly
high antidepressant or anticonvulsant activity against the
MES-induced seizures.
As part of our continuous efforts in this area, a series of
some new 1-phenyl-, 1-thiocarbamoyl- and 1-N-substituted
thiocarbamoyl-3-(2-furyl)-5-phenyl/(2-furyl)-2-pyrazoline de-
rivatives have been synthesized according to Scheme 1 and
evaluated for their antidepressant activities by using Porsolt’s
behavioural despair (forced swimming) test [10]. Anticonvul-
sant activities of the synthesized compounds were also
determined by maximal electroshock (MES) and subcutaneous
pentylenetetrazole (metrazol) (scMet.) tests. Seizure assays
Increasing evidence suggests that pyrazoline derivatives
possess a broad spectrum of biological activities such as
tranquillizing, muscle relaxant, antidepressant, anticonvulsant,
psychoanaleptic, and antihypotensive activities. Earlier studies
by Parmar et al. [1] and Soni et al. [2] demonstrated that 1,3,5-
triphenyl-2-pyrazolines have monoamine oxidase (MAO)
inhibitory activities. In a recent paper Chimenti et al. [3]
reported enantioselective MAO-A and MAO-B inhibiting
properties of 1-thiocarbamoyl-2-pyrazolines.
In our previous studies, we synthesized several pyrazoline
derivatives and tested them for their antidepressant and
anticonvulsant activities [4e9]. We reported that 1,3,
* Corresponding author. Tel.: þ90 312 3053018; fax: þ90 312 3114777.
E-mail address: abilgin@hacettepe.edu.tr (A.A. Bilgin).
0223-5234/$ - see front matter Ó 2006 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.09.006

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Z. Ozdemir et al. / European Journal of Medicinal Chemistry 42 (2007) 373e379
374
Table 1
Structures, yields and melting points of the synthesized compounds
O
C
O
O
CH3
Ar
H
+
C
O
OH-
Ar
N
O
N
R
O
C
CH CH Ar
Compounds Ar
R
Yield (%) m.p. (ꢁC) Crystallization
solvents
C6H5NHNH2
H2N-NH2
H2NNHCSNH2
O
1
Phenyl Phenyl
2-Furyl Phenyl
Phenyl CSNH2
2-Furyl CSNH2
64
78
63
57
125e126 Ethanol
92e93 Ethanolewater
176e177 Ethanol
O
2
3
N
Ar
N
N
Ar
4
162e163 Ethanol
N
1, 2
O
5
Phenyl CSNHCH3 58
Phenyl CSNHC2H5 61
Phenyl CSNHC3H5 47
Phenyl CSNHC6H5 77
2-Furyl CSNHCH3 36
2-Furyl CSNHC2H5 47
2-Furyl CSNHC3H5 49
2-Furyl CSNHC6H5 68
133e134 Ethanolewater
99e100 Ethanolewater
116e117 Ethanolewater
126e127 Ethanol
164e165 Ethanolewater
135e136 Methanol
H
6
7
N
S
Ar
N
C
8
R-NCS
3, 4
9
10
11
12
NH2
113 Methanol
149e150 Ethanol
O
N
S
Ar
N
C
5- 12
3. Pharmacology
Ar: C6H5-, 2-furyl-
R: CH3-, C2H5-, C3H5-, C6H5-
NH
R
3.1. Antidepressant activity
Scheme 1. Synthetic route.
The synthesized compounds were screened for their antide-
pressant activity using Porsolt’s behavioural despair (forced
swimming) test [10]. The synthesized compounds
(10 mg kgꢀ1), and tranylcypromine sulfate, as a reference
antidepressant drug (10 mg kgꢀ1) were suspended in a 1%
aqueous solution of Tween 80. The drugs were injected intra-
peritoneally (ip) in a standard volume of 0.5 ml/20 g body
weight, 1 h prior to the test. Control animals received 1%
aqueous solution of Tween 80. Then, the mice were dropped
individually into the Plexiglass cylinder and left in the water
for 6 min. After the first 2 min of the initial vigorous
struggling the animals were immobile. A mouse was judged
immobile if it floated in the water in an upright position and
made only slight movements in order to prevent sinking.
The duration of immobility was recorded during the last
4 min of the 6 min test.
and neurotoxicity were determined by rotarod toxicity test
according to the phase I tests of antiepileptic drug develop-
ment (ADD) programme which were developed by the
National Institute of Neurological and Communicative Disor-
ders and Stroke (NINCDS) [11,12].
Three of the reported compounds have been previously
synthesized e [1,5-diphenyl-3-(2-furyl)-2-pyrazoline (1) and
1-phenyl-3,5-di(2-furyl)-2-pyrazoline (2)] by Ried and
Dankert [13] and [1-N-phenylthiocarbamoyl-3,5-di(2-furyl)-
2-pyrazoline (12)] by Angeloni et al. [14] but have not been
tested for their pharmacological activities.
2. Chemistry
The synthetic work was carried out beginning from
2-acetylfuran according to Scheme 1. 2-Acetylfuran in
a ClaiseneSchmidt condensation with benzaldehyde and
2-furylaldehyde afforded 1-(2-furyl)-3-phenyl/(2-furyl)-2-
propen-1-ons which gave with phenylhydrazine (sodium
hydroxide, ethanol) 1-phenyl- (1 and 2), with thiosemicarba-
zide (sodium hydroxide, ethanol) 1-thiocarbamoyl- (3 and
4), with hydrazine hydrate (ethanol) followed by
thiocyanates (triethylamine, ether) 1-N-substituted thiocarba-
3.2. Anticonvulsant activity
The compounds were tested for their anticonvulsant activity
against MES and scMet.-induced seizures and rotarod toxicity
test was performed for neurological toxicity according to the
phase I tests of ADD (Antiepileptic Drug Development)
programme [11,12]. The synthesized compounds were
suspended in 30% aqueous solution of PEG 400 and adminis-
tered ip in a standard volume of 0.5 ml/20 g body weight at 30,
100, 300 mg kgꢀ1 doses. Control animals received 30%
aqueous PEG 400. Pentylenetetrazole (metrazol) was adminis-
tered subcutaneously (sc) from the back of the neck. Rotarod
moyl-3-(2-furyl)-5-phenyl/(2-furyl)-2-pyrazolines
respectively.
(5e12),
The structures, yields and melting points of the synthesized
compounds are given in Table 1.

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Z. Ozdemir et al. / European Journal of Medicinal Chemistry 42 (2007) 373e379
375
Table 2
Antidepressant activities of the compounds
toxicity test was performed on a 1 inch diameter knurled
wooden rod, rotating at 6 rpm.
Compounds
Antidepressant activities
4. Results and discussion
Duration of immobility
(s) (mean ꢂ S.E.M.)
Change from
control (%)
The structures, yields and melting points of the compounds
are listed in Table 1. All spectral data are in accordance with
assumed structures. In the UV spectra of the compounds
two absorption maxima were observed at 206e244 and
327e353 nm due to C]N and AreNeN]CeAr groups,
respectively. The IR spectra of the compounds afforded
pyrazoline C]N stretching (1501e1576 cmꢀ1), C4eH
deformation (1362e1464), C5eN1 stretching (1069e1189),
furan CeOeC stretching (1048e1075) and except Com-
pounds 1 and 2, thiocarbamoyl group NeH stretching
1
213 ꢂ 5.7
169 ꢂ 9.9
202 ꢂ 9.8
182 ꢂ 17.2
201 ꢂ 12.9
139 ꢂ 12
1.42
ꢀ19.52
3.81
2
3
4
ꢀ13.33
ꢀ4.28
5
6
ꢀ33.80*
ꢀ9.52
7
190 ꢂ 18
8
184 ꢂ 16.4
186 ꢂ 22
ꢀ12.38
ꢀ11.42
0.48
9
10
211 ꢂ 9.8
144 ꢂ 21.4
181 ꢂ 16.7
57 ꢂ 11.6
11
12
ꢀ31.42*
ꢀ13.81
ꢀ72.85*
(3112e3481 cmꢀ1) and C]S stretching (1315e1357 cmꢀ1
)
Tranylcypromine sulfate
(10 mg kgꢀ1, ip)
Control
bands.
1
210 ꢂ 7.3
e
In the H NMR spectra of the compounds HA, HB and HX
protons of pyrazoline ring were observed as doublet of doublet
Values represent the mean ꢂ S.E.M. (n ¼ 6).
*Significantly compared to control (Dunnet’s test; p < 0.05).
at d 2.98e3.30 (JAB: 17.44e17.69 Hz), 3.43e3.71 (JAX
:
4e10 Hz) and 5.98e6.97 ppm (JBX: 11.34e11.66 Hz), respec-
tively. NeH protons of the thiocarbamoyl group were seen at
7.23e9.10 ppm generally as broad bands. The protons of
methyl, ethyl, allyl, phenyl groups and benzene and furan
rings were observed at expected ppms.
was observed in none of the synthesized compounds in the
dose range of 30e300 mg kgꢀ1 (Table 3).
In the Mass spectra of the compounds molecular ion (Mþ)
and Mþ2 (5.5% M) pics were observed. Microanalysis results
were also in accordance with the theoretical amounts
(performed only for the new compounds).
5. Conclusion
Only two of the synthesized compounds (6 and 11) have
shown significant antidepressant activity, but generally, the
synthesized compounds having a 2-furyl substituent at the
fifth position of the pyrazoline ring (2, 4, 9e12) possess
remarkable anticonvulsant activity. Therefore, they seem to
be really promising compounds for their anticonvulsant activ-
ities. The synthesis studies should be continued concerning
this group of compounds followed with further in vivo
studies.
The forced swimming test is a behavioural test used to
predict the efficacy of antidepressant treatments [10]. It is
used effectively in predicting the activity of a wide variety
of antidepressants such as MAO inhibitors and atypical antide-
pressants [15]. It has good predictive value for antidepressant
potency in humans [16]. The obtained data on the antidepres-
sant activity of the compounds and reference drug are given in
Table 2. In our study, 1-N-ethylthiocarbamoyl-3-(2-furyl)-5-
phenyl-2-pyrazoline (6) and 1-N-allylthiocarbamoyl-3,5-di(2-
furyl)-2-pyrazoline (11) significantly reduced the duration of
immobility times at 10 mg kgꢀ1 dose level when compared
to control ( p < 0.05, Table 2).
6. Experimental protocols
6.1. Chemistry
The anticonvulsant activities of the synthesized compounds
were also investigated and results from these experiments
are shown in Table 3. 1,5-Diphenyl-3-(2-furyl)-2-pyrazoline
(2) and 1-N-allylthiocarbamoyl-3-(2-furyl)-5-phenyl-2-pyrazo-
line (7) were found protective only against MES-induced
seizures. 1-Thiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (4),
1-N-ethylthiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (10) and
1-N-phenylthiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (12) only
exhibited activity against scMet.-induced seizures, however, 1-
N-methylthiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (9) and
1-N-allylthiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (11) were
found to be protective against MES and scMet.-induced
seizures. 1-Thiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (4)
and 1-N-ethylthiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (10)
were found to be protective against scMet.-induced seizures
at 30e300 mg kgꢀ1 dose levels at half an hour. Neurotoxicity
All chemicals used in this study were supplied by E. Merck,
Aldrich Chemical Co. and Fluka AG. Melting points were
taken in a Thomas Hoover capillary melting point apparatus
and are uncorrected. UV spectra were obtained on Agilent
8453 UVevis spectrophotometer in methanol. IR spectra
were recorded in a Bruker Vector 22 IR Opus Spectroscopic
Software Version 2.0 using KBr pellets. 1H NMR spectra
were recorded on a Bruker Avance 400 MHz FT spectrometer
in CDCl3 using TMS as internal standard. Mass spectra were
recorded on Scientific Instrument Service HPP7-M direct
insertion probe spectrometer using Agilent 5973 network
mass selective electron impact detector. Microanalyses of the
compounds were performed at ATAL The Laboratory of
Instrumental AnalysesdThe Scientific and Technical
Research Council of Turkey (Instrument: Leco CHNS-932).

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Z. Ozdemir et al. / European Journal of Medicinal Chemistry 42 (2007) 373e379
376
Table 3
Phase I anticonvulsant screening of the compounds
Compounds
MES
scMet.
1/2 h
Toxicity
1/2 h
1/2 h
4 h
4 h
4 h
mg kgꢀ1
mg kgꢀ1
mg kgꢀ1
mg kgꢀ1
mg kgꢀ1
mg kgꢀ1
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
1
0/1
0/1
0/1
0/1
0/1
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
1/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
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
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
0/1
0/1
0/1
1/1
0/1
1/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
0/1
1/1
1/1
0/1
1/1
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
0/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
1/1
0/1
0/1
0/1
1/1
0/1
1/1
0/1
0/1
0/1
1/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
1/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
1/1
1/1
0/1
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
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
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
2
3
4
5
6
7
8
9
10
11
12
MES: maximal electroshock seizure test, scMet.: subcutaneous pentylenetetrazole (metrazol) seizure test, toxicity: rotarod test.
0/1: no activity at dose level, 1/1: noticeable activity at dose level (given in italics).
6.1.1. 1-(2-Furyl)-3-phenyl/(2-furyl)-2-propen-
1-ons (chalcones)
Chalcone derivatives were obtained from 2-acetylfuran
(0.01 mol) and appropriate aldehydes (0.01 mol) by known
methods [17e20].
H5). MS m/e 278 (Mþ, %100), 186 (M ꢀ C5H2N2O), 91
(M ꢀ C11H9NO2), 77 (M ꢀ C11H9N2O2).
6.1.3. 1-Thiocarbamoyl-3-(2-furyl)-5-phenyl/(2-furyl)-2-
pyrazolines
1-Thiocarbamoyl-3-(2-furyl)-5-phenyl/(2-furyl)-2-pyrazo-
lines were obtained by heating (2 h) thiosemicarbazide
(0.012 mol) with appropriate chalcone (0.01 mol) and sodium
hydroxide (0.025 mol in 5 ml water) in ethanol (50 ml). The
product was poured into ice water and the crude product which
was separated out was filtered and crystallised from proper
solvent.
6.1.2. 1-Phenyl-3-(2-furyl)-5-phenyl/(2-furyl)-2-pyrazolines
The solution of appropriate chalcone (0.01 mol) and
phenylhydrazine (0.02 mol) in ethanolic sodium hydroxide
(0.025 mol, 20 ml) was refluxed for 4 h. The product was
poured into ice water and the crude product which was
separated out was filtered and crystallised from proper
solvent.
6.1.3.1. 1-Thiocarbamoyl-3-(2-furyl)-5-phenyl-2-pyrazoline (3).
Yield 63.46%. m.p. 176e177 ꢁC (EtOH). UV lMMeaOksH 206
(log 3: 4.68), 327 nm (log 3: 4.88). IR n (KBr) 3481, 1614,
6.1.2.1. 1,5-Diphenyl-3-(2-furyl)-pyrazoline (1). Yield 63.88%.
m.p. 125e126 ꢁC (EtOH). UV lMMaekOsH 202 (log 3: 4.75), 244
(log 3: 4.44), 353 nm (log 3: 4.63). IR n (KBr) 1501, 1365,
1
1465, 1376, 1357, 1074 cmꢀ1. H NMR d (CDCl3) 3.25 (1H;
1119, 1065 cmꢀ1
.
1H NMR d (CDCl3) 3.05 (1H; dd; HA,
dd; pyrazoline HA, JAB: 17.6 Hz, JAX: 3.61 Hz), 3.80 (1H; dd;
pyrazoline HB, JAB: 17.67 Hz, JBX: 11.47 Hz), 6.05 (1H; dd;
pyrazoline HX, JAX: 3.55 Hz, JBX: 11.48 Hz), 6.10 (1H; b;
NH), 6.55 (1H; m; furan H4), 6.80 (1H; d; JAB: 3.49 Hz, furan
H3), 7.10 (1H; b; NH), 7.20e7.60 ppm (6H; m; furan H5 and
benzene). MS m/e 273 (M þ 2, %4.5 Mþ), 271 (Mþ, %100),
238 (M ꢀ SH), 211 (M ꢀ CSNH2), 177 (M ꢀ C6H6O), 103
(M ꢀ C6H6N3OS), 77 (M ꢀ C8H8N3OS). Calcd. for
C13H12N2OS % C 61.97, H 4.83, N 15.49, S 11.82; found C
61.82, H 4.26, N 15.47, S 11.50.
J
AB: 17.47 Hz, JAX: 7.19 Hz), 3.75 (1H; dd; HB, JAB
17.07 Hz, JBX: 12.38 Hz), 5.18 (1H; dd; HX, JAX: 7.18 Hz,
BX: 12.35 Hz), 6.30 (1H; m; furan H4), 6.40 (1H; d; furan
:
J
H3, JAB: 3.36 Hz), 6.60e7.60 ppm (11H; m; furan H5, ben-
zene). MS m/e 288 (Mþ, %100), 259 (M ꢀ CHO), 211
(M ꢀ C6H5), 115 (M ꢀ C10H9N2O), 91 (M ꢀ C12H9N2O), 77
(M ꢀ C13H11N2O).
6.1.2.2. 1-Phenyl-3,5-di(2-furyl)-2-pyrazoline (2). Yield 78.42%.
MeOH
Maks
m.p. 92e93 ꢁC (EtOHeH2O). UV l
244 (log 3: 4.63), 349 nm (log 3: 4.83). IR n (KBr) 1501,
201 (log 3: 4.82),
6.1.3.2. 1-Thiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (4). Yield
56.70%. m.p. 162e163 ꢁC (EtOH). UV lMMaekOsH 213 (log 3:
4.68) and 325 nm (log 3: 4.94). IR n (KBr) 3483, 1576,
.
1464, 1349, 1083, 1055 cmꢀ1 1H NMR d (CDCl3) 3.40
1362, 1103, 1070 cmꢀ1. H NMR d (CDCl3) 3.22 (1H; dd;
1
HA, JAB: 16.94 Hz, JAX: 6.59 Hz), 3.65 (1H; dd; HB, JAB
16.62 Hz, JBX: 12.10 Hz), 5.25 (1H; dd; HX, JAX: 6.60 Hz,
BX: 12.08 Hz), 6.15 (1H; d; 5-furan H3, J: 3.22 Hz), 6.20
:
J
(1H; dd; HA, JAB: 17.53 Hz, JAX: 3.21 Hz), 3.60 (1H; dd;
HB, JAB: 17.51 Hz, JBX: 11.42 Hz), 6.10 (1H; dd; HX, JAX
(1H; m; 5-furan H4), 6.40 (1H; m; 3-furan H4), 6.55 (1H; d;
3-furan H3, J: 3.36 Hz), 6.75 (1H; t; phenyl H4, J: 7.21 Hz),
7.05 (2H; d; phenyl H3,5, J: 22.48 Hz), 7.20 (2H; m; phenyl
H2,6), 7.25 (1H; m; 5-furan H5), 7.45 ppm (1H; m; 3-furan
:
3.45 Hz, JBX: 11.27 Hz), 6.15 (1H; b; NH), 6.35 (1H; m;
3-furan H4), 6.42 (1H; d; J: 3.26 Hz, 3-furan H3), 6.57
(1H; m; 5-furan H4), 6.85 (1H; d; J: 3.46 Hz, 5-furan H3),

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377
7.00 (1H; b; NH), 7.35 (1H; d; J: 1.65 Hz, 3-furan H5),
7.60 ppm (1H; d; J: 1.51 Hz, 5-furan H5). MS m/e 263
(M þ 2, %4.5 Mþ), 261 (Mþ), 244 (M ꢀ NH3), 201
(M ꢀ CH2NS), 185 (M ꢀ CH4N2S), 173 (M ꢀ CH2N3S), 115
(M ꢀ C9H6O2), 94 (M ꢀ C7H7N2OS), 81 (M ꢀ C7H6N3OS),
60 (M ꢀ C11H9N2O2, %100). Calcd. for C14H13N3O2S % C
55.16, H 4.24, N 16.08, S 12.27; found C 55.16, H 3.86,
N 16.02, S 11.93.
(2H; m; eCH2), 5.10e5.25 (2H; m; ]CH2), 5.80e6.00
(1H; m; ]CH), 6.01 (1H; dd; HX, JAX: 3.56 Hz, JBX
:
:
11.60 Hz), 6.45 (1H; m; furan H4), 6.70 (1H; d; JAB
3.44 Hz, furan H3), 7.05e7.50 (6H; m; furan H5 and benzene),
7.42 ppm (1H; s; NH). MS m/e 313 (M þ 2, %4.5 Mþ), 311
(Mþ), 296 (M ꢀ CH3), 278 (M ꢀ SH), 255 (M ꢀ C3H6N,
%100), 211 (M ꢀ C4H6NS), 196 (M ꢀ C4H7N2S), 104
(M ꢀ C9H13N3OS), 91 (M ꢀ C10H14N3OS), 77 (M ꢀ C11H12
N3OS), 56 (M ꢀ C14H11N2OS), 41 (M ꢀ C14H12N3OS). Calcd.
for C17H17N3OS % C 65.57, H 5.50, N 13.49, S 10.30; found
C 65.63, H 5.15, N 13.41, S 10.20.
6.1.4. 1-N-Substituted thiocarbamoyl-3-(2-furyl)-5-phenyl/
(2-furyl)-2-pyrazolines
Hydrazine hydrate (0.02 mol) was added to an ethanolic
solution of appropriate chalcone (0.01 mol, 10 ml ethanol)
and refluxed for 2 h. The solvent was evaporated at reduced
pressure. The residue was dissolved in dry ether. Isothiocya-
nate (0.01 mol) and 4 drops of triethylamine were added and
stirred for 4 h at room temperature. The mixture was evapo-
rated to dryness and the residue was crystallised from proper
solvent.
6.1.4.4. 1-N-Phenylthiocarbamoyl-3-(2-furyl)-5 phenyl-2-pyra-
zoline (8). Yield 76.94%. m.p. 126e127 ꢁC (EtOH). UV
MeOH
Maks
l
202 (log 3: 4.47), 335 nm (log 3: 4.50). IR n (KBr)
3212, 1547, 1483, 1445, 1337, 1189, 1071 cmꢀ1. H NMR
d (CDCl3) 3.07 (1H; dd; HA, JAB: 17.66 Hz, JAX: 3.46 Hz),
3.75 (1H; dd; HB, JAB: 17.65 Hz, JBX: 11.56 Hz), 6.45 (1H;
1
m; furan H4), 6.50 (1H; dd; HX, JAX: 3.39 Hz, JBX
:
11.52 Hz), 6.75 (1H; d; JAB: 3.38 Hz, furan H3) 7.05e7.60
(11H; m; furan H5 and benzene), 9.10 ppm (1H; s; NH). MS
m/e 349 (M þ 2, %4.5 Mþ), 347 (Mþ), 270 (M ꢀ C6H5),
255 (M ꢀ C6H6N) 212 (M ꢀ C7H5NS, %100), 183 (M ꢀ C7H6
N3S), 135 (M ꢀ C13H12N2O), 77 (M ꢀ C14H12N3OS). Calcd.
for C20H17N3OS % C 69.14, H 4.93, N 12.09, S 9.23; found
C 69.37, H 5.06, N 12.13, S 9.04.
6.1.4.1. 1-N-Methylthiocarbamoyl-3-(2-furyl)-5-phenyl-2-pyra-
zoline (5). Yield 57.89%. m.p. 133e134 ꢁC (EtOHeH2O).
MeOH
Maks
UV l
202 (log 3: 4.39), 329 nm (log 3: 4.51). IR n
1
(KBr) 3401, 1528, 1439, 1345, 1112, 1057 cmꢀ1. H NMR
d (CDCl3) 2.98 (1H; dd; HA, JAB: 17.57 Hz, JAX: 3.71 Hz),
3.10 (3H; d; JAB: 4.77 Hz, CH3), 3.72 (1H; dd; HB, JAB
17.57 Hz, JBX: 11.66 Hz), 5.98 (1H; dd; HX, JAX: 3.68 Hz,
BX: 11.63 Hz), 6.41 (1H; m; furan H4), 6.67 (1H; d; JAB
:
J
:
6.1.4.5. 1-N-Methylthiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline
3.48 Hz, furan H3), 7.10e7.55 (6H; m; furan H5 and benzene),
7.38 ppm (1H; b; NH). MS m/e 287 (M þ 2, %4.5 Mþ), 285
(Mþ) (%100), 252 (M ꢀ SH), 242 (M ꢀ CH3N2), 212
(M ꢀ C2H4NS), 177 (M ꢀ C6H6NO), 91 (M ꢀ C8H8N3OS),
74 (M ꢀ C13H11N2O). Calcd. for C15H15N3OS % C 63.13, H
5.30, N 14.73, S 11.24; found C 63.30, H 5.53, N 14.76, S
10.91.
(9). Yield 35.63%. m.p. 164e165 ꢁC (EtOHeH2O). UV
MeOH
Maks
l
4.68). IR n (KBr) 3291, 1529, 1483, 1370, 1315, 1105,
201 (log 3: 4.39), 216 (log 3: 4.45), 327 nm (log 3:
1059 cmꢀ1. H NMR d (CDCl3) 3.05 (3H; d; JAB: 4.78 Hz,
1
CH3), 3.25 (1H; dd; HA, JAB: 17.43 Hz, JAX: 3.55 Hz), 3.55
(1H; dd; HB, JAB: 17.43 Hz, JBX: 11.48 Hz), 6.08 (1H; dd;
HX, JAX: 3.47 Hz, JBX: 11.43 Hz), 6.22 (1H; m; 5-furan H4),
6.32 (1H; d; JAB: 3.19 Hz; 5-furan H3), 6.48 (1H; m; 3-furan
H4), 6.72 (1H; d; JAB: 3.47 Hz; 3-furan H3), 7.20e7.50 (2H;
m; 3- and 5-furan H5), 7.30 ppm (1H; b; NH). MS m/e 277
(M þ 2, %4.5 Mþ), 275 (Mþ, %100), 246 (M ꢀ CH3N), 201
(M ꢀ C2H4NS), 173 (M ꢀ C2H4N3S), 109 (M ꢀ C7H6N2OS),
81 (M ꢀ C8H8O). Calcd. for C13H13N3O2S % C 56.71, H
4.76, N 15.26, S 11.65; found C 56.86, H 4.47, N 15.22,
S 11.35.
6.1.4.2. 1-N-Ethylthiocarbamoyl-3-(2-furyl)-5-phenyl-2-pyra-
zoline (6). Yield 60.86%. m.p. 99e100 ꢁC (EtOHeH2O).
MeOH
Maks
UV l
202 (log 3: 4.52), 330 nm (log 3: 4.65). IR n
(KBr) 3375, 1522, 1454, 1363, 1332, 1180, 1075 cmꢀ1. H
NMR d (CDCl3) 1.17 (3H; t; JAB: 5.62 Hz, CH3), 3.00 (1H;
dd; HA, JAB: 17.55 Hz, JAX: 3.63 Hz), 3.50e3.70 (3H; m;
1
HB and CH2), 5.97 (1H; dd; HX, JAX: 3.6 Hz, JBX
11.63 Hz), 6.45 (1H; m; furan H4), 6.65 (1H; d; JAB
:
:
3.41 Hz, furan H3), 7.05e7.55 (6H; m; furan H5 and benzene),
7.30 ppm (1H; b; NH). MS m/e 301 (M þ 2, %4.5 Mþ), 299
(Mþ), 266 (M ꢀ SH), 212 (M ꢀ C3H5NS), 104 (M ꢀ C8H11
N3OS), 77 (M ꢀ C10H12N3OS), 44 (M ꢀ C14H11N2OS). Calcd.
for C16H17N3OS % C 64.19, H 5.72, N 14.04, S 10.71; found
C 64.18, H 5.34, N 14.04, S 10.35.
6.1.4.6. 1-N-Ethylthiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline
(10). Yield 47.06%. m.p. 135e136 ꢁC (MeOH). UV lMMeaOksH
200 (log 3: 4.35), 217 (log 3: 4.41), 328 nm (log 3: 4.63). IR
1
n (KBr) 3350, 1518, 1420, 1390, 1179, 1071 cmꢀ1. H NMR
d (CDCl3) 1.25 (3H; t; CH3, JAB: 7.24 Hz), 3.21 (1H; dd;
HA, JAB: 17.41 Hz, JAX: 3.46 Hz), 3.45 (1H; dd; HB, JAB
:
17.43 Hz, JBX: 11.42 Hz), 3.62 (2H; m; CH2), 6.10 (1H; dd;
HX, JAX: 3.39 Hz, JBX: 11.41 Hz), 6.22 (1H; m; 5-furan H4),
6.34 (1H; d; 5-furan H3, JAB: 3.20 Hz), 6.47 (1H; m; 3-furan
H4), 6.72 (1H; d; 3-furan H3, JAB: 3.42 Hz), 7.15e7.55 (2H;
m; 3- and 5-furan H5), 7.23 ppm (1H; b; NH). MS m/e 291
(M þ 2, %4.5 Mþ), 289 (Mþ, %100), 260 (M ꢀ C2H5), 202
(M ꢀ C3H5NS), 173 (M ꢀ C3H6N3S), 94 (M ꢀ C9H11N2OS).
6.1.4.3. 1-N-Allylthiocarbamoyl-3-(2-furyl)-5-phenyl-2-pyrazo-
line (7). Yield 46.94%. m.p. 116e117 ꢁC (EtOHeH2O). UV
MeOH
l
202 (log 3: 4.64), 330 nm (log 3: 4.75). IR n (KBr)
Maks
1
3372, 1516, 1453, 1371, 1332, 1120, 1048 cmꢀ1. H NMR
d (CDCl3) 3.06 (1H; dd; HA, JAB: 17.59 Hz, JAX: 3.61 Hz),
3.66 (1H; dd; HB, JAB: 17.58 Hz, JBX: 11.61 Hz), 4.10e4.30

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Z. Ozdemir et al. / European Journal of Medicinal Chemistry 42 (2007) 373e379
378
Calcd. for C14H15N3O2S % C 58.51, H 5.23, N 14.52, S 11.08;
found C 58.31, H 5.58, N 14.13, S 10.78.
activity. The rotarod used in the neurotoxicity test was made
by Hacettepe University Technical Department. Pentylenete-
trazole was supplied by Sigma Chemical Co. Twelve albino
male mice (20e24 g) in our laboratory according to the
NINCDS-ADD programme [11,12] were used for each
compound.
6.1.4.7. 1-N-Allylthiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline
(11). Yield 48.84%. m.p. 113 ꢁC (MeOH). UV lMMeaOksH 201
(log 3: 4.39), 217 (log 3: 4.42), 328 nm (log 3: 4.62). IR n
(KBr) 3382, 1517, 1483, 1368, 1326, 1069, 1050 cmꢀ1
.
1H NMR d (CDCl3) 3.25 (1H; dd; HA, JAB: 17.44 Hz, JAX
:
6.2.2.1. Maximal electroshock seizure (MES) test. Maximal
electroshock seizures are elicited with a 60-cycle alternating
current of 50 mA intensity (5e7 times that is 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 compo-
nent of the seizure is defined as protection.
3.43 Hz), 3.55 (1H; dd; HB, JAB: 17.44 Hz, JBX: 11.41 Hz),
4.10e4.30 (2H; m; eCH2), 5.05e5.20 (2H; m; ]CH2),
5.80e6.00 (1H; m; eCH]), 6.23 (1H; dd; HX, JAX
:
3.40 Hz, JBX: 11.38 Hz), 6.25 (1H; m; 5-furan H4), 6.30
(1H; d; 5-furan H3, JAB: 3.21 Hz), 6.45 (1H; m; 3-furan H4),
6.73 (1H; d; 3-furan H3, JAB: 3.46 Hz), 7.20e7.50 (2H; m;
3- and 5-furan H5), 7.33 ppm (1H; s; NH). MS m/e 303
(M þ 2, %4.5 Mþ), 301 (Mþ), 286 (M ꢀ CH3), 272
(M ꢀ C2H5), 245 (M ꢀ C3H6N), 202 (M ꢀ C4H5NS), 187
6.2.2.2. Subcutaneous pentylenetetrazole (metrazol) (scMet.)
test. Pentylenetetrazole (85 mg kgꢀ1) (produces seizures in
greater than 95% of mice) is administered as a 0.5% solution
sc in the posterior midline. 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.
(M ꢀ C4H6N2S,
%100),
173
(M ꢀ C4H6N3S),
115
(M ꢀ C11H8NO2), 94 (M ꢀ C9H9N2OS), 81 (M ꢀ C10H10
N2OS), 65 (M ꢀ C11H14N3OS), 41 (C12H10N3O2S). Calcd.
for C15H15N3O2S % C 59.78, H 5.02, N 13.94, S 10.64; found
C 59.74, H 5.32, N 13.89, S 10.63.
6.1.4.8. 1-N-Phenylthiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline
(12). Yield 67.95%. m.p. 149e150 ꢁC (EtOH). UV lMMeaOksH
201 (log 3: 4.58), 333 nm (log 3: 4.70). IR n (KBr) 3450,
6.2.2.3. Neurotoxicity. The rotarod test was used to evaluate
neurotoxicity. The animal was placed on a 1 inch diameter
knurled wooden rod rotating at 6 rpm. Normal mice remain
on a rod rotating at this speed indefinitely. Neurologic toxicity
was defined as the failure of the animal to remain on the rod
for 1 min.
1541, 1448, 1389, 1320, 1075, 1050 cmꢀ1
.
1H NMR
d (CDCl3) 3.30 (1H; dd; HA, JAB: 17.52 Hz, JAX: 3.35 Hz),
3.49 (1H; dd; HB, JAB: 17.51 Hz, JBX: 11.34 Hz), 6.15 (1H;
dd; HX, JAX: 3.31 Hz, JBX: 11.32 Hz), 6.25 (1H; m; 5-furan
H4), 6.40 (1H; d; 5-furan H3, JAB: 3.13 Hz), 6.50 (1H; m; 3-
furan H4), 6.82 (1H; d; 3-furan H3, JAB: 3.40 Hz), 7.05e
7.55 (7H; m; 3- and 5-furan H5 and benzene), 9.00 ppm
(1H; s; NH). MS m/e 339 (M þ 2, %4.5 Mþ), 337 (Mþ,
%100), 308 (M ꢀ CHO), 202 (M ꢀ C7H5NS), 173
(M ꢀ C7H6N3S), 152 (M ꢀ C11H9NO2), 135 (M ꢀ C11H10
N2O2), 93 (M ꢀ C13H12N2OS), 77 (M ꢀ C12H10N3O2S).
6.2.3. Statistical analysis
Results are expressed as mean ꢂ S.E.M.; n represents the
number of animals. Data obtained from pharmacological ex-
periments were analyzed by one way analysis of variance
(ANOVA) followed by Dunnet’s post hoc test and used to eval-
uate the results, employing Pharmacologic Calculation System
Version 4.1. (Microcomputer Specialists). A p-value of less
than 0.05 was considered statistically significant.
6.2. Pharmacology
The present study was approved by the Ethics Committee
of Hacettepe University, School of Medicine (# 04/1-1).
Acknowledgment
This study was supported by Hacettepe University Scien-
tific Research Foundation (Project no: 0302 301003).
6.2.1. Antidepressant activity
Local breed, male albino mice (20e24 g) were used in the
forced swimming test under standard conditions with free
access to food and water. They were housed in groups of
six. On test day mice were dropped one at a time into a Plex-
iglass cylinder (height 25 cm, diameter 10 cm) containing
10 cm of water at 23e25 ꢁC [10]. On the testing day, mice
were assigned into different groups (n ¼ 6e9 for each group).
Tranylcypromine sulfate was supplied by Sigma Chemical Co.
References
[1] S.S. Parmar, B.R. Pandey, C. Dwivedi, R.D. Harbison, J. Pharm. Sci. 63
(1974) 1152e1155.
[2] N. Soni, K. Pande, R. Kalsi, T.K. Gupta, S.S. Parmar, J.P. Barthwal, Res.
Commun. Chem. Pathol. Pharmacol. 56 (1987) 129e132.
[3] F. Chimenti, E. Maccioni, D. Secci, A. Bolasco, P. Chimenti, A. Granese,
O. Befani, P. Turini, S. Alcaro, F. Ortuso, R. Cirilli, F. La Torre,
M.C. Cardia, S. Distinto, J. Med. Chem. 48 (2005) 7113e7122.
[4] A.A. Bilgin, E. Palaska, R. Sunal, B. Gumuxsel, Pharmazie 49 (1994)
6.2.2. Anticonvulsant activity
¨
¨
Stimulator (Grass S88, Astro-Med. Inc.), constant current
unit (Grass CCU1A, Grass Medical Instruments), and corneal
electrode were used for the evaluation of anticonvulsant
67e69.
[5] A.A. Bilgin, E. Palaska, R. Sunal, Arzneimittel-forschung/Drug Res. 43
(1993) 1041e1044.

¨
Z. Ozdemir et al. / European Journal of Medicinal Chemistry 42 (2007) 373e379
379
[6] A.A. Bilgin, A. Yexsilada, E. Palaska, R. Sunal, Arzneimittel-forschung/
Drug Res. 42 (1992) 1271e1273.
[12] R.L. Krall, J.K. Penry, B.G. White, H.J. Kupferberg, E.A. Swinyard,
Epilepsia 19 (1978) 409e428.
[7] N. Gokhan, A. Yexsilada, G. Uc¸ar, K. Erol, A.A. Bilgin, Arch. Pharm.
[13] W. Ried, G. Dankert, Chem. Ber. 90 (1957) 2707e2711.
[14] A.S. Angeloni, A. Bellotti, E. Coghi, Ann. Chim. 53 (1963)
1392e1398.
[15] R.D. Porsolt, Antidepressants: Neurochemical, Behavioural and Clinical
Perspectives, in: S.J. Enna, J.B. Malick, E. Richelson (Eds.), Raven
Press, New York, 1981, pp. 129e139.
¨
Med. Chem. 336 (2003) 362e371.
¨
¨
˘
[8] O. Ruhoglu, Z. Ozdemir, U. C¸ alıxs, B. Gumuxsel, A.A. Bilgin, Arzneimit-
¨
tel-forschung/Drug Res. 55 (2005) 431e436.
¨
_
¨
¨
˘
[9] P. Iyidogan, Z. Ozdemir, B. Kandilci, B. Gumuxsel, U. C¸ alıxs, A.A. Bilgin,
¨
¨
_
J. Fac. Pharm. Istanbul, in press.
[10] R.D. Porsolt, A. Bertin, M. Jalfre, Arch. Int. Pharmacodyn. Ther. 229
(1977) 327e336.
[16] P. Willner, P.J. Mitchell, Behav. Pharmacol. 13 (2002) 169e188.
[17] St.v. Kostanecki, L. Podrajansky, Chem. Ber. 29 (1896) 2248e2250.
[18] W.E. Kaufmann, R. Adams, J. Am. Chem. Soc. 45 (1923) 3029e3044.
[19] C. Weygand, F. Strobelt, Chem. Ber. 68B (1935) 1839e1847.
[20] W.S. Emerson, T.M. Patrick, J. Org. Chem. 14 (1949) 790e797.
[11] H. Schafer, Handbook of Experimental Pharmacology: Antiepileptic
¨
Drugs, in: H.H. Frey, D. Janz (Eds.), Springer-Verlag, Berlin, 1985, pp.
199e210.