SYNTHESIS AND ANTIDEPRESSANT ACTIVITIES OF SOME

1-[(N,N-DISUBSTITUTED THIOCARBAMOYLTHIO)ACETYL]

-3- (2-THIENYL)-5-ARYL-2-PYRAZOLINES

Ahmet zdemir a*, Glhan Turan-Zitouni a, Zafer Asm Kaplanckl a

a
Anadolu University, Faculty of Pharmacy, Deparment of Pharmaceutical
Chemistry, 26470, Eskisehir, Turkey.

*Correspondence:
Anadolu University, Faculty of Pharmacy,
Deparment of Pharmaceutical Chemistry,
26470, Eskisehir, Turkey.

Phone: 90 222 335 05 80 / 3774

Fax: 90 222 335 07 50
e-mail: ahmeto@anadolu.edu.tr
ABSTRACT

Fourteen new 1-[(N,N-disubstitutedthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-aryl-2-

pyrazoline derivatives were synthesized by reacting 1-(chloroacetyl)-3-(2-thienyl)-5-
aryl-2-pyrazolines and appropriate sodium salts of N,N-disubstituted dithiocarbamoic
acids in acetone. The structures of the synthesized compounds were confirmed by UV,
1
IR, H-NMR and FAB+-MS spectral data. The antidepressant activities of the
synthesized compounds are screening.

Keywords: 2-Pyrazolines / Sodium salts of N,N-disubstituted dithiocarbamoic acids /

Antidepressant activity / Forced-swimming test

INTRODUCTION
Mood disorders are among the most prevalent, recurrent, and disabling of mental
illness. Major depressive disorder (MDD) is a serious disorder that affects
approximately 17% of the population at some point in life, resulting in major social and
economic consequences. According to the Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV), MDD is a heterogeneous disorder that manifests with symptoms
at the psychological, behavioral, and physiological levels. There is still very little
known about the neurobiological alterations that underlie the pathophysiology or
treatment of MDD. Several lines of evidence suggest that depression in most people is
caused by interactions between a genetic predisposition and some environmental factors
(Hashimoto, et al., 2004).
Current therapies include the use of electroconvulsive (shock) therapy, psychiatric
intervention, and antidepressant drugs such as tricyclic antidepressants, monoamine
oxidase inhibitors, and seratonin-selective reuptake inhibitors. However, all of these
drugs have been associated with particular adverse effects, which can range from being
a mild nuisance or moderate discomfort to those causing intolerable distress and even
life-threatening conditions (Holsboer, 2001; Henry, 1992).
Therefore, a major challenge of the pharmaceutical industry is to develop drugs that
have antidepressant activities but lack the toxic side effects.
 Considerable interest has been focused on the pyrazole structure, which has been
known to possess a broad spectrum of biological activities such as tranquillising, muscle
relaxant, psychoanaleptic, anticonvulsant, antihypotensive and antidepressant activities
(Polevoi, 1964; Batulin, 1968; Parmar, et al., 1974; Soni, et al., 1987; Turan-Zitouni, et
al., 2000; Palaska, et al., 2001, Prasad, et al., 2005). The discovery of this class of drugs
provides an outstanding case history of modern drug development and also points out
the unpredictability of biological activity from structural modification of a prototype
drug molecule. Prodrug-based monoamine oxidase (MAO) inhibitors have hydrazide.
Hydrazine and amine moiety such as isocarboxazid (Shader and Greenblatt, 1999),
phenelzine (Urichuk, et al., 2000) and moclobemide (Ferigolo, M., et al., 1998) show
prominent antidepressant activity in laboratory animals and man. Additionally,
tranylcypromine-like MAO inhibitors are mechanism-based inactivators and they are
metabolised by MAO with one electron of the nitrogen pair and to generate an imine the
other residing on a methylene carbon (R-C=NH2+). MAO inhibitory properties of 1,3,5-
triphenyl-2-pyrazolines, which bear a cyclic hydrazine moiety, have also been shown in
earlier studies by Parmar (Parmar, et al., 1974) and Soni (Soni, et al., 1987). At the
same time it is noteworthy that the structures of 3-thienyl-5-aryl-2-pyrazoline
derivatives are very similar to those of isocarboxazid (Figure 1).

O N
O
S
N R1 N N H
N
H H
R H H

3-Thienyl-5-aryl-2-pyrazoline derivatives Isocarboxazid

Figure 1. Structures of 3-thienyl-5-aryl-2-pyrazoline derivatives and isocarboxazid

 A popular strategy used in medicinal chemistry is to modify compounds containing
an aromatic or heteroaromatic ring by replacing the original ring with a range of other
heteroaromatic rings of different ring sizes and heteroaromatic positions in medicinal
chemistry. In the light of this knowledge, we aimed to synthesize new pyrazoline
derivatives containing a thienyl ring and tested their antidepressant activities using
Behavioural Despair Test.

MATERIALS AND METHODS

Chermistry
All reagents were used as purchased from commercial suppliers without further
purification. Melting points were determined by using an Electrothermal 9100 digital
melting point apparatus and were uncorrected. The compounds were checked for purity
by TLC on silica gel 60 F254. Spectroscopic data were recorded on the following
instruments: UV, Shimadzu Model 160A UV spectrophotometer; IR, Shimadzu 435 IR
spectrophotometer; 1H-NMR, Bruker 250 MHz NMR spectrometer in DMSO-d6 using
TMS as internal standard; Elemental analyses were performed on a Perkin Elmer EAL
240 elemental analyser; MS-FAB, VG Quattro mass spectrometer.

1-(2-Thienyl)-3-aryl-2-propen-1-ones (3)
A mixture of 2-acetylthiophene (0.04 mol) (1), aromatic aldehyde (0.04 mol) (2) and
10% aqueous sodium hydroxide (10 mL) in ethanol (30 mL) was stirred at room
temperature for about 3 h. The resulting solid was washed, dried and crystallised from
ethanol (Kabli, et al., 1991).

5-Aryl-3-(2-thienyl)-2-pyrazolines (4)
A solution of the appropriate thienyl chalcone (0.01 mol) (3) and hydrazine hydrate
(80%) (0.02 mol) in ethanol (30 mL) was refluxed for 3 h. The reaction mixture was
cooled and kept at 0oC overnight. The resulting solid was crystallised from ethanol
(Kabli, et al., 1991).
1-(Chloroacetyl)-3-(2-thienyl)-5-aryl-2-pyrazolines (5)
The 5-Aryl-3-(2-thienyl)-2-pyrazolines (4) (0,01 mol) and triethylamine (0,01 mol)
were dissolved in dry toluene (30 ml) with constant stirring. Later, the mixture was
cooled in an ice bath, and chloroacetylchloride (0,01 mol) was added dropwise with
stirring. The reaction mixture thus obtained was further agitated for 1 h at room
temperature. The precipitate was filtrated, the solvent was evaporated to dryness under
reduced pressure and the products were recrystallized from ethanol (Khalaf, et al.,
1993).

Sodium salts of N, N-disubstitued dithiocarbamic acids (6)

Sodium hydroxide (0.01mol) was dissolved in ethanol (80 mL) with constant stirring.
After addition of the secondary amine (0.01 mol) the mixture was cooled in an ice bath
and carbon disulphide (0.10 mol) was added dropwise with stirring. Further agitation of
the reaction mixture thus obtained for 1h at room temparature, evaporation of the
solvent under reduced pressure, and subsequent addition of dry ether until precipitation
reached completion, filtration afforded products which were recrystallized from ethanol
(Karali, et al., 1999).

1-[(N,N-Disubstitutedthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-aryl-2-pyrazolines
(7a-n)
A mixture of 1-(chloroacetyl)-3-(2-thienyl)-5-aryl-2-pyrazolines (5) (0,01 mol) and
sodium salts of the appropriate N,N-disubstituted dithiocarbamoic acid (6) (0,01 mol)
was treated in acetone at room temperature for 1 h. The solvent was evaporated, washed
with water and recrystallized from ethanol.

Some characteristics of the synthesized compounds are shown in Table 1. Analytical and
spectral data (UV, IR, 1H-NMR, FAB+-MS) confirmed the structures of the new
compounds.
1-[(4-Morpholinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-phenyl-2-pyrazoline (7a): UV [ max EtOH
nm), log ]: 208.2 (4.90), 316.4 (4.72). - IR [n, cm-1, KBr]: 1666 (C=O), 1517-1407 (C=N, C=C), 1232
(C=S). - 1H-NMR (250 MHz, ppm, DMSO-d6,): 3.18 (1H, dd JAM= 18.00 Hz, JAX= 4.60 Hz, C4-HA of
pyrazoline ring), 3.70 (4H, m, morpholine CH2-O-CH2), 3.85-4.30, 3.92 (5H, m, morpholine CH2-N-CH2
and dd JMA= 18.00 Hz, JMX= 11.70 Hz, C4-HM of pyrazoline ring), 4.60 (1H, d J= 16.20 Hz, COCH
geminal proton), 4.65 (1H, d J= 16.18 Hz, COCH geminal proton), 5.57 (1H, dd JMX= 11.57 Hz, JAX=
4.45 Hz, C5-HX of pyrazoline ring), 7.20 (6H, m, phenyl protons and thiophene C 4-H), 7.50 (1H, s,
thiophene C3-H), 7.80 (1H, s, thiophene C5-H). MS-FAB+: m/z: 432 [M+1].

1-[(4-Thiomorpholinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-phenyl-2-pyrazoline (7b): UV [ max

EtOH -1
nm), log ]: 208.6 (4.94), 317.8 (4.76). - IR [n, cm , KBr]: 1664 (C=O), 1446-1406 (C=N, C=C), 1218
(C=S). - 1H-NMR (250 MHz, ppm, DMSO-d6,): 2.60-2.80 (4H, m, thiomorpholine CH2-S-CH2), 3.18
(1H, dd JAM= 18.00 Hz, JAX= 4.60 Hz, C4-HA of pyrazoline ring), 3.92 (1H, dd JMA= 17.80 Hz, JMX= 11.60
Hz, C4-HM of pyrazoline ring), 4.10-4.60 (4H, two m, thiomorpholine CH2-N-CH2), 4.65 (1H, d J= 16.15
Hz, COCH geminal proton), 4.70 (1H, d J= 16.13 Hz, COCH geminal proton), 5.57 (1H, dd JMX= 11.70
Hz, JAX= 4.60 Hz, C5-HX of pyrazoline ring), 7.10-7.40 (6H, m, phenyl protons and thiophene C 4-H), 7.45
(1H, s thiophene C3-H), 7.75 (1H, s, thiophene C5-H). MS-FAB+: m/z: 447 [M], 448 [M+1].

1-[(4-Morpholinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-methylphenyl)-2-pyrazoline (7c): UV [
EtOH
max nm), log ]: 208.8 (5.05), 320.1 (4.61). - IR [n, cm-1, KBr]: 1658 (C=O), 1588-1410 (C=N,
C=C), 1229 (C=S). - 1H-NMR (250 MHz, ppm, DMSO-d6,): 2.25 (3H, s, Ar-CH3), 3.20 (1H, dd JAM=
17.88 Hz, JAX= 4.43 Hz, C4-HA of pyrazoline ring), 3.70 (4H, m, morpholine CH2-O-CH2), 3.90 (1H, dd
JMA= 17.97 Hz, JMX= 11.76 Hz, C4-HM of pyrazoline ring), 3.95 (4H, m, morpholine CH 2-N-CH2), 4.70
(1H, d J= 16.53 Hz, COCH geminal proton), 4.75 (1H, d J= 16.55 Hz, COCH geminal proton), 5.55 (1H,
dd JMX= 11.57 Hz, JAX= 4.45 Hz, C5-HX of pyrazoline ring), 7.20 (5H, m, phenyl protons and thiophene
C4-H), 7.50 (1H, d J= 2.66 Hz, thiophene C3-H), 7.80 (1H, d J= 4.10 Hz, thiophene C5-H). MS-FAB+:
m/z: 445 [M], 446 [M+1].

1-[(4-Thiomorpholinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-methylphenyl)-2-pyrazoline (7d):
UV [ max EtOH nm), log ]: 208.6 (4.94), 318.2 (4.67). - IR [n, cm-1, KBr]: 1662 (C=O), 1514-1409
(C=N, C=C), 1215 (C=S). - 1H-NMR (250 MHz, ppm, DMSO-d6,): 2.20 (3H, s, Ar-CH3), 2.70 (4H, m,
thiomorpholine CH2-S-CH2), 3.15 (1H, dd JAM= 18.10 Hz, JAX= 4.50 Hz, C4-HA of pyrazoline ring), 3.90
(1H, dd JMA= 17.92 Hz, JMX= 11.59 Hz, C4-HM of pyrazoline ring), 4.20 (4H, m, thiomorpholine CH 2-N-
CH2), 4.70 (1H, d J= 16.13 Hz, COCH geminal proton), 4.75 (1H, d J= 16.10 Hz, COCH geminal
proton), 5.50 (1H, dd JMX= 11.63 Hz, JAX= 4.46 Hz, C5-HX of pyrazoline ring), 7.15 (5H, m, phenyl
protons and thiophene C4-H), 7.45 (1H, d J= 2.81 Hz, thiophene C3-H), 7.75 (1H, d J= 4.32 Hz, thiophene
C5-H). MS-FAB+: m/z: 461 [M], 462 [M+1].
1-[(4-Morpholinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-dimethylamino-phenyl)-2-pyrazoline
(7e):UV [ max EtOH nm), log ]: 207.6 (5.15), 317.8 (4.78). - IR [n, cm-1, KBr]: 1660 (C=O), 1614-1410
(C=N, C=C), 1230 (C=S).
1-[(4-Thiomorpholinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-dimethylaminophenyl)-2-
pyrazoline (7f): UV [ max EtOH nm), log ]: 207.4 (4.87), 316.6 (4.59). - IR [n, cm-1, KBr]: 1660 (C=O),
1614-1402 (C=N, C=C), 1215 (C=S). - 1H-NMR (250 MHz, ppm, DMSO-d6,): 2.75 (4H, m,
thiomorpholine CH2-S-CH2), 2.90 (6H, s, N(CH3)2), 3.20 (1H, dd JAM= 17.87 Hz, JAX= 4.31 Hz, C4-HA of
pyrazoline ring), 3.90 (1H, dd JMA= 17.93 Hz, JMX= 11.51 Hz, C4-HM of pyrazoline ring), 4.30 (4H, m,
thiomorpholine CH2-N-CH2), 4.70 (1H, d J= 16.06 Hz, COCH geminal proton), 4.75 (1H, d J= 16.05 Hz,
COCH geminal proton), 5.50 (1H, dd JMX= 11.42 Hz, JAX= 4.14 Hz, C5-HX of pyrazoline ring), 6.65 (2H,
d J= 8.72 Hz, phenyl C2,6-H), 7.10 ( 2H, d J= 8.70 Hz, phenyl C3,5-H), 7.20 (1H, t J= 4.35, thiophene C4-
H), 7.55 (1H, d J= 2.81 Hz, thiophene C3-H), 7.80 (1H, d J= 4.98 Hz, thiophene C5-H). MS-FAB+: m/z:
490 [M], 491 [M+1].

1-[(4-Morpholinylthiocarbamoylthio)acetyl]-3-(2-thienyl)- 5-(4-hydroxyphenyl)-2-pyrazoline (7g): UV

[ max EtOH nm), log ]: 208.6 (5.50), 318.8 (5.36). - IR [n, cm-1, KBr]: 3232 (O-H), 1660 (C=O), 1614-
1417 (C=N, C=C), 1269 (C=S).

1-[(4-Thiomorpholinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-hydroxyphenyl)-2-pyrazoline (7h):
UV [ max EtOH nm), log ]: 207.6 (5.03), 318.2 (4.98). - IR [n, cm-1, KBr]: 3222 (O-H), 1643 (C=O),
1614-1419 (C=N, C=C), 1278 (C=S). - 1H-NMR (250 MHz, ppm, DMSO-d6,): 2.70 (4H, m,
thiomorpholine CH2-S-CH2), 3.10 (1H, dd JAM= 18.09 Hz, JAX= 4.28 Hz, C4-HA of pyrazoline ring), 3.80
(1H, dd JMA= 17.83 Hz, JMX= 11.62 Hz, C4-HM of pyrazoline ring), 4.40 (4H, m, thiomorpholine CH 2-N-
CH2), 4.60 (1H, d J= 16.15 Hz, COCH geminal proton), 4.65 (1H, d J= 16.17 Hz, COCH geminal
proton), 5.45 (1H, dd JMX= 11.56 Hz, JAX= 4.28 Hz, C5-HX of pyrazoline ring), 6.60 (2H, d J= 8.46 Hz,
phenyl C2,6-H), 7.00 ( 2H, d J= 8.48 Hz, phenyl C3,5-H), 7.10 (1H, t J= 3.82, thiophene C4-H), 7.45 (1H, d
J= 3.11 Hz, thiophene C3-H), 7.75 (1H, d J= 4.96 Hz, thiophene C5-H), 9.35 (1H, s, Ar-OH). MS-FAB+:
m/z: 464 [M+1].

1-[(4-Morpholinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-methoxyphenyl)-2-pyrazoline (7i): UV
[ max EtOH nm), log ]: 207.8 (4.89), 319.6 (4.49). - IR [n, cm-1, KBr]: 1662 (C=O), 1610-1408 (C=N,
C=C), 1267 (C=S). - 1H-NMR (250 MHz, ppm, DMSO-d6,): 3.15 (1H, dd JAM= 18.00 Hz, JAX= 4.43 Hz,
C4-HA of pyrazoline ring), 3.60 (4H, m, morpholine CH2-O-CH2), 3.70 (3H, s, Ar-OCH3), 3.85 (1H, dd
JMA= 17.91 Hz, JMX= 11.63 Hz, C4-HM of pyrazoline ring), 3.90 (4H, m, morpholine CH 2-N-CH2), 4.65
(1H, d J= 16.11 Hz, COCH geminal proton), 4.70 (1H, d J= 16.10 Hz, COCH geminal proton), 5.50 (1H,
dd JMX= 11.56 Hz, JAX= 4.46 Hz, C5-HX of pyrazoline ring), 6.85 (2H, d J= 8.66 Hz, phenyl C2,6-H), 7.15
(2H, d J= 8.69 Hz, phenyl C3,5-H and 1H, d J= 4.22, thiophene C4-H), 7.45 (1H, d J= 3.49 Hz, thiophene
C3-H), 7.75 (1H, d J= 5.04 Hz, thiophene C5-H). MS-FAB+: m/z: 461 [M], 462 [M+1].
1-[(4-Thiomorpholinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-methoxyphenyl)-2-pyrazoline (7j):
UV [ max EtOH nm), log ]: 208.4 (4.96), 319.5 (4.67). - IR [n, cm-1, KBr]: 1659 (C=O), 1611-1410
(C=N, C=C), 1226 (C=S). - 1H-NMR (250 MHz, ppm, DMSO-d6,): 2.70 (4H, m, thiomorpholine CH2-
S-CH2), 3.15 (1H, dd JAM= 17.84 Hz, JAX= 4.45 Hz, C4-HA of pyrazoline ring), 3.30 (3H, s, Ar-OCH 3),
3.90 (1H, dd JMA= 17.90 Hz, JMX= 11.66 Hz, C4-HM of pyrazoline ring), 4.25 (4H, m, thiomorpholine
CH2-N-CH2), 4.70 (1H, d J= 16.13 Hz, COCH geminal proton), 4.75 (1H, d J= 16.14 Hz, COCH geminal
proton), 5.50 (1H, dd JMX= 11.59 Hz, JAX= 4.37 Hz, C5-HX of pyrazoline ring), 6.85 (2H, d J= 8.69 Hz,
phenyl C2,6-H), 7.15 (2H, d J= 8.61 Hz, phenyl C3,5-H and 1H, d J= 4.38 Hz, thiophene C4-H), 7.45 (1H, d
J= 2.68 Hz, thiophene C3-H), 7.75 (1H, d J= 4.21 Hz, thiophene C5-H). MS-FAB+: m/z: 477 [M], 478
[M+1].

1-[(4-Morpholinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-fluorophenyl)-2-pyrazoline (7k): UV [
EtOH
max nm), log ]: 208.8 (4.80), 318.5 (4.57). - IR [n, cm-1, KBr]: 1664 (C=O), 1602-1409 (C=N,
C=C), 1228 (C=S).

1-[(4-Thiomorpholinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-fluorophenyl)-2-pyrazoline (7l):
EtOH -1
UV [ max nm), log ]: 208.4 (5.08), 318.6 (4.84). - IR [n, cm , KBr]: 1662 (C=O), 1602-1413
(C=N, C=C), 1228 (C=S). - 1H-NMR (250 MHz, ppm, DMSO-d6,): 2.70 (4H, m, thiomorpholine CH2-
S-CH2), 3.20 (1H, dd JAM= 17.99 Hz, JAX= 4.68 Hz, C4-HA of pyrazoline ring), 3.95 (1H, dd JMA= 17.98
Hz, JMX= 11.69 Hz, C4-HM of pyrazoline ring), 4.25 (4H, m, thiomorpholine CH 2-N-CH2), 4.65 (1H, d J=
16.21 Hz, COCH geminal proton), 4.70 (1H, d J= 16.20 Hz, COCH geminal proton), 5.60 (1H, dd JMX=
11.56 Hz, JAX= 4.48 Hz, C5-HX of pyrazoline ring), 7.10-7.25 (5H, m, phenyl protons and thiophene C 4-
H), 7.45 (1H, d J= 2.75 Hz, thiophene C3-H), 7.75 (1H, d J= 4.99 Hz, thiophene C5-H). MS-FAB+: m/z:
466 [M+1].

1-[(4-Morpholinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-chlorophenyl)-2-pyrazoline (7m): UV
[ max EtOH nm), log ]: 208.6 (4.94), 320.1 (4.68). - IR [n, cm-1, KBr]: 1662 (C=O), 1593-1408 (C=N,
C=C), 1230 (C=S). MS-FAB+: m/z: 466 [M], 467 [M+1], 468 [M+2].

1-[(4-Thiomorpholinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-chlorophenyl)-2-pyrazoline (7n):
EtOH -1
UV [ max nm), log ]: 212.8 (4.87), 318.5 (4.62). - IR [n, cm , KBr]: 1662 (C=O), 1593-1411
(C=N, C=C), 1228 (C=S). - 1H-NMR (250 MHz, ppm, DMSO-d6,): 2.80 (4H, m, thiomorpholine CH2-
S-CH2), 3.30 (1H, dd JAM= 17.97 Hz, JAX= 4.70 Hz, C4-HA of pyrazoline ring), 4.00 (1H, dd JMA= 17.97
Hz, JMX= 11.83 Hz, C4-HM of pyrazoline ring), 4.30 (4H, m, thiomorpholine CH 2-N-CH2), 4.65 (1H, d J=
16.20 Hz, COCH geminal proton), 4.70 (1H, d J= 16.21 Hz, COCH geminal proton), 5.65 (1H, dd JMX=
11.73 Hz, JAX= 4.63 Hz, C5-HX of pyrazoline ring), 7.20 (1H, t J=4.33 Hz, thiophene C 4-H), 7.30 (2H, d
J= 8.49 Hz, phenyl C2,6-H), 7.40 (2H, d J= 8.48 Hz, phenyl C3,5-H), 7.55 (1H, d J= 2.71 Hz, thiophene C3-
H), 7.80 (1H, d J= 4.24 Hz, thiophene C5-H). MS-FAB+: m/z: 482 [M], 483 [M+1], 484 [M+2].
 Table I. Experimental data for compounds 7a-n.

Compd. R1 R2 Molecular MW Mp Yield

Fo (oC) (%)
rm
ula
7a H Morpholine C20H21N3O2S3 431.6 144 48
7b H Thiomorpholine C20H21N3OS4 447.6 161 50
7c CH3 Morpholine C21H23N3O2S3 445.6 116-118 49
7d CH3 Thiomorpholine C21H23N3OS4 461.6 91-93 51
7e N(CH3)2 Morpholine C22H26N4O2S3 474.6 86 69
7f N(CH3)2 Thiomorpholine C22H26N4OS4 490.7 87 71
7g OH Morpholine C20H21N3O3S3 447.6 203 56
7h OH Thiomorpholine C20H21N3O2S4 463.6 208 58
7i OCH3 Morpholine C21H23N3O3S3 461.6 84 57
7j OCH3 Thiomorpholine C21H23N3O2S4 477.6 168 59
7k F Morpholine C20H20FN3O2S3 449.5 119 53
7l F Thiomorpholine C20H20FN3OS4 465.6 171-172 56
7m Cl Morpholine C20H20ClN3O2S3 466.0 90-92 66
7n Cl Thiomorpholine C20H20ClN3OS4 482.1 166 67

Pharmacology
Adult male albino SwissWebster mice (222 g) were used as subjects in the study.
They were housed in a quiet and temperature and humidity-controlled room (223 C
and 605%, respectively) in which a 12 h. light/dark cycle was maintained (08:00
20:00 h. light). Food and water intake of the subjects was not restricted during the study.
Clomipramine and tranylcypromine were supplied by Sigma Chemical Co.

Test Procedure
The mice were housed in Plexiglass cages with six animals for each cage. Porsolt
Forced Swimming Test, a behavioural despair test, was used for evaluating if the
compounds have antidepressant activity. On the testing day, mice were assigned into
different groups (n=6 for each group). The synthesized compounds, clomipramine and
tranylcypromine were suspended in aqueous Tween 80 (0.2% w/v, 0.9% NaCl). All the
synthesised compounds (100 mg/kg), clomipramine and tranylcypromine (10 and 20
mg/kg) were injected intraperitoneally to mice at a volume of 0.5 ml. per 100 g. body
weight. One hour later, the mice were dropped one at a time into a Plexiglass cylinder
(25 cm. height, 30 cm. diameter, containing 20 cm. height of water at 21-23 C) and left
for 6 min. At the end of the first 2 min. the animals showing initial vigorous struggling
were immobile. Then, the immobility times of each Mouse was measured in the period
of 4 min.

RESULT AND DISCUSSION

Chemistry
In this study, 14 new compounds were synthesized. The structures of the obtained
compounds were elucidated by spectral data. The IR data were very informative and
provided evidence for the formation of the expected structures. C=O, C=N, C=C and
C=S functions absorbed strongly in the expected regions: O-H at 3222-3232 cm-1, C=O at
1666-1643 cm-1, C=N and C=C at 1614-1402 cm-1 and C=S at 1215-1278 cm-1,
respectively. The 1H-NMR spectral data were also consistent with the assigned structures.
In the 250 MHz 1H-NMR spectrum of compounds, the CH2 protons of the pyrazoline ring
resonated as a pair of doublets of doublets at 3.10-3.30 ppm, 3.85-4.00 ppm. The CH
proton appeared as doublet of doublets at 5.45-5.65 ppm due to vicinal coupling with
the two magnetically non-equivalent protons of the methylene group at position 4 of the
pyrazoline ring (JAM= 17.80-18.10 Hz, J AX = 4.14-4.70 Hz, J MX = 11.42-11.83 Hz). The
CH2 protons of acetyl which are on 1 position of pyrazoline (7a-n) are observed at 4.60-
4.75 ppm as double doublets (J=16.06-16.53 Hz, J=16.05-16.55) this geminal coupling is
result from steric structure of compound. These geminal protons are observed as double
doublet because of possible two different conformation since rigid protons were
occurred. All the other aromatic and aliphatic protons were observed at expected regions.
Mass spectra (MS (FAB)) of the compounds showed M+1 peaks, which were in
agreement with their molecular formula.
The antidepressant activities of the synthesized compounds are screening.
 Scheme 1. Synthetic route of the title compounds.

O O
NaOH H2N NH2
S C O+H R1
C C CH CH R1
S
CH3
1 2 3

S (C2H5)3N S
N R1 + ClCOCH2Cl N R1
N N
O
H
Cl
4 5
S
- +
R2H + CS2 + NaOH R C S Na
2
-H2O
6

S
N R1
Acetone N
5 + 6
-NaCl O
S
S
R2
7 a-n

R1= -H, -CH3, -N(CH3)2, -OH, -OCH3, -F, -Cl

R2= N O , N S

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