Synthesis and Antihypertensive Activity of 1-(2-Thiazolyl)-3,5-disubstituted -2-Pyrazolines

Article abstract of DOI:10.1002/ardp.200300810

Several substituted 3-aryl-1-(4-aryl-2-thiazolyl)-5-(3-pyridyl)-2-pyrazolines were synthesized by reacting substituted 3-aryl-5-(3-pyridyl)-1-thiocarbamoyl-2-pyrazolines with phenacyl bromide in ethanol. The structures of all compounds were confirmed by IR, ¹H-NMR, mass spectral data and elemental analyses. The antihypertensive activity of compounds was examined by the tail-cuff method and compared with clonidine. Compounds 24-28 showed significant antihypertensive activity.

Full text of DOI:10.1002/ardp.200300810

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 25–34
Synthesis and antihypertensive activity of disubstituted pyrazolines 25
Maryam Bagheria,
Synthesis and Antihypertensive Activity of
1-(2-Thiazolyl)-3,5-disubstituted -2-Pyrazolines
Maryam Shekarchia,
Masoumeh Jorjanib,
Mohammad Hossein
Ghahremanic,
Several substituted 3-aryl-1-(4-aryl-2-thiazolyl)-5-(3-pyridyl)-2-pyrazolines were
synthesized by reacting substituted 3-aryl-5-(3-pyridyl)-1-thiocarbamoyl-2-pyrazo-
lines with phenacyl bromide in ethanol.The structures of all compounds were con-
firmed by IR, 1H-NMR, mass spectral data and elemental analyses.The antihyper-
tensive activity of compounds was examined by the tail-cuff method and compared
with clonidine. Compounds 24–28 showed significant antihypertensive activity.
Mohssen Vosooghia,
Abbas Shafieea
a
Department of Medicinal
Chemistry and
Pharmaceutical Sciences
Research Center,
Keywords: Sympatholytics; Imidazoline; Antihypertensive; Pyridyl-thiazolyl-pyr-
azoline; Azachalcones
Faculty of Pharmacy,
Tehran University of Medical
Sciences, Tehran, Iran
Received: April 28, 2003; Accepted: September 1, 2003 [FP810]
DOI 10.1002/ardp.200300810
b
Neuroscience Research
Center and Department of
Pharmacology,
Faculty of Medicine,
Shaheed Beheshti
University of Medical
Sciences, Tehran, Iran
Department of
c
Pharmacology and
Toxicology,
Faculty of Pharmacy,
Tehran University of Medical
Sciences, Tehran, Iran
mellitus, bronchospastic disease and ischemic disease.
As a result, many modifications of the original structure
of clonidine have been studied, leading to new active
Introduction
Hypertension is a consequence of many diseases.Ther-
apy using antihypertensive agents evolved rapidly.In the
meanwhile a number of drugs for the treatment and con-
trol of hypertensive disease have been discovered [1].
compounds like thiazolo imidazoline derivative 4 which
The first generation of centrally acting antihypertensive
drugs such as clonidine (1) and its analogs were once
very popular in the treatment of hypertension.
The overall mechanism of action for the centrally active
sympatholytics, clonidine, guanabenz (2) and guanafa-
cine (3) appears to be stimulation of α2-adrenoceptors
and nonadrenergic imidazoline (I1) receptors in CNS
causing inhibition of sympathetic output [2, 3].This effect
results in reduced peripheral and renovascular resist-
ance and leads to decrease in systolic and diastolic
blood pressure. The central α2-adrenergic agonists are
equally effective in all age and race subgroups and can
be used for patients with renal insufficiency, diabetes
Correspondence: Abbas Shafiee, Department of Medicinal
Chemistry and Pharmaceutical Sciences Research Center,
Faculty of Pharmacy, Tehran University of Medical Sciences,
Tehran, Iran. Phone: +98 216406757, Fax: +98 216461178,
e-mail: ashafiee@ams.ac.ir
Figure 1. The structural formula of compounds having
antihypertensive activity.
© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

26 Bagheri et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 25–34
in antihypertensive test was as potent as clonidine itself
[4].This result encouraged us to synthesize several pyri-
dyl-thiazolyl-pyrazoline derivatives 5, which are structur-
ally similar to 4, and to evaluate their antihypertensive
activities (Figure 1).
The structures of compounds 9–35 were confirmed by
IR, H-NMR, mass spectra and elemental analyses. IR
1
spectra of compounds 9–35 showed C=N and C=C
stretching bands at 1640 and 1550 cm–1 respectively. In
the 1H-NMR spectra, HA, HB, HX protons of the pyrazoline
ring appeared as 3 doublets of doublets (dd) at
3.31–3.37, 3.93–4 and 5.65–5.7 ppm (JAB = 16 Hz,
JAX = 8 Hz, JBX = 12 Hz) respectively. Protons belonging
to the aromatic ring and phenyl substituents were ob-
served at expected chemical shift and integral values.
The H5-proton of thiazole was observed as a singlet be-
tween 6.9 to 7.1 ppm.The mass spectrum fragmentation
pattern of compound 9 was also in agreement with the
suggested structure.The molecular ion appeared at m/z
382. The fragment ions appeared at 304 (M+- pyridyl),
278 (M+- C6H5-CH=CH2), 266 (M+- C8H6N), 248 (M+-
C8H6S), 220 (M+- C5H4N-C+=N-N=C=S), 174 (M+-
C5H4N-CN + C6H5-CH=CH2), 134 (C8H6S), 104 (C5H4N-
CN or C6H5-CH=CH2). Compounds 10–35 gave similar
mass spectra. The physical constants of compounds
10–35 are summarized in Table 1.
Results and discussion
Chemistry
Substituted 3-aryl-1-(4-aryl-2-thiazolyl)-5-(3-pyridyl)-2-
pyrazolines were synthesized for their possible antihy-
pertensive activity.In order to prepare different 1-thiocar-
bamoyl-2-pyrazolines 7 a–d thiosemicarbazide was al-
lowed to react with various azachalcons 6 a–d in accord-
ance with the method described in the literature [5].
Compounds 9–35 were obtained by reacting com-
pounds 7 a–d with phenacyl bromide or its derivatives in
ethanol [6] (Scheme 1). The substitution on the para or
meta site of phenacyl bromide played an important role
in thiazole formation step.Namely, the phenacyl bromide
derivatives with a strong electron-withdrawing group like
NO2 in para or meta position of the benzene ring, gave
higher yield compared to the H or Br groups (see
Table 1).
Biological activity
Adult male sparague-Dawley rats weighing 200–220 g
were used in this study. Rats were housed in animals
Scheme 1. Synthesis of 1-(2-thiazolyl)-3,5-disubstituted-2-pyrazolines.
© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 25–34
Synthesis and antihypertensive activity of disubstituted pyrazolines 27
© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

28 Bagheri et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 25–34
© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 25–34
Synthesis and antihypertensive activity of disubstituted pyrazolines 29
© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

30 Bagheri et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 25–34
© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 25–34
Synthesis and antihypertensive activity of disubstituted pyrazolines 31
© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

32 Bagheri et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 25–34
rooms that were maintained at 23 3 °C and exposed to
a 12-h light-dark cycle. Animals were given a standard
laboratory chow and water ad libitum.Six rats were used
for each compound.The control group received 1 mL/kg
DMSO intraperitoneally (i.p.) only.
Results were expressed as the mean SE and reduction
of arterial blood pressure (Tables 2 and 3). As shown in
Table 3 most of the compounds reduced blood pressure
significantly 30 min after administration with p < 0.05.
Same results were obtained 60 min after administration
of compounds.Additionally the tested samples caused a
significant reduction of blood pressure in comparison to
control with p < 0.001. In addition comparing of com-
pounds 24–28 with their similar analogues which have
identical structure without the -OCH3 moiety at R2 posi-
tion, namely, 13, 15, 16, 20–23, 33–35 ( see Table 2), re-
veals that the presence of the methoxy group at the R2
position increased the antihypertensive activity.Finally, it
should be pointed out that compounds 24–28 have sig-
nificant antihypertensive activity.
To reduce spontaneous variations in blood pressure, an-
imals were adjusted to the experimental cage 3–4 times
before the start of the experiment for a period of
30–60 min. Changes of blood pressure were measured
by using an indirect tail-cuff method [7–9]. Automatic
measurement of systolic blood pressure was provided
by a pressure transducer (International Biomedical Inc.,
USA) of an 8-channel polygraph apparatus (Narcotrace
80, Narco Bio-System, USA). All compounds were dis-
solved in DMSO (Sigma) and administrated i.p. at a 10-
mg/kg dose in 0.1 mL volume.Clonidine (0.5 mg/kg) was
used as a reference drug. Mean values in systolic blood
pressure before and 15, 30, 60 min after drug adminis-
tration were determined.Note:There were no significant
differences between the mean blood pressures before
and after DMSO administration.
Experimental
Most chemicals were purchased from Merck Chemical Compa-
ny, Darmstadt, Germany. Azachalcons 6 a–d were prepared
according to the reported method [10]. Phenacyl bromides
8 a–h were prepared according to the literature [11]. All chemi-
cals were crystallized or redistilled before use. Flash chroma-
tography was performed on silica gel HT-254 (Merck). Melting
points were taken on a Kofler hot stage apparatus and are un-
corrected. 1H-NMR spectra were obtained using a Varian unity
plus 400 MHz instrument.Tetramethylsilane was used as an in-
Statistics
The statistical significance of differences was estimated
by analysis of variance (ANOVA) followed by Tukey test.
Table 2. Mean systolic blood pressure before and after administration of the test compounds.
Compound
No.
Dose
(mg/kg)
Mean blood pressure (mm Hg)
0 min
15 min
30 min
60 min
9
13
15
16
17
20
21
22
23
24
25
26
27
28
29
31
33
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
106.8 3.7
103.0 1.7
99.7 3.7
103.6 1.9
104.0 2.7
102.3 2.5
99.9 2.2
99.3 2.2
107.3 3.7
95.5 2.1
101.7 1.6
103.1 2.1
100.5 2.9
101.3 2.8
99.5 1.1
91.5 3.7
97.5 3.1
103.1 2.1
98.2 3.0
104.4 4.2
102.0 0.5
98.8 4.4
91.8 3.2
90.0 3.7
94.0 2.0
96.0 4.5
88.0 2.9
89.4 2.1
89.1 2.0
98.0 3.6
76.3 1.9
85.1 2.7
82.3 4.6
83.4 4.7
83.7 2.7
90.0 5.1
78.5 3.9
82.5 3.4
90.2 1.7
87.2 3.2
87.6 3.4
100.0 6.6
97.5 5.1
90.7 4.0
89.0 3.6
94.0 1.9
94.9 4.6
87.5 2.8
87.5 1.2
87.5 1.2
97.0 3.4
73.5 1.9
80.0 3.8
80.8 3.9
77.4 4.8
80.3 2.3
89.0 4.8
77.1 3.6
82.5 3.3
90.0 2.0
86.1 4.0
87.2 2.4
98.0 4.5
97.0 5.3
90.8 4.2
88.7 3.6
93.1 1.9
93.0 4.7
87.3 2.8
87.6 4.9
87.3 4.9
96.3 3.1
73.4 1.9
79.8 3.8
79.9 3.1
75.7 4.2
79.2 1.6
89.0 4.4
76.0 4.5
81.5 3.1
89.2 2.0
86.6 4.5
87.2 2.4
98.0 4.5
34
35
10
10
Clonidine
DMSO
0.5
1 (ml/kg)
© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 25–34
Synthesis and antihypertensive activity of disubstituted pyrazolines 33
1462, 1355 cm–1. 1H-NMR (CDCl3): δ = 2.39 (s, 3 H, CH3), 3.22
Table 3. Reduction of arterial blood pressure at 30 min
after administration of the tested compounds in compari-
son to clonidine in rat.
(dd, 1 H, JAX = 3.6 Hz, JAB = 16 Hz, HA), 3.87 (dd, 1 H, JAB
=
16 Hz, JBX = 12 Hz, HB), 6.07 (dd, 1 H, JAX = 3.6 Hz, JBX =12 Hz,
HX). 6.2 (bs, 1 H, NH), 7.19 (bs, 1 H, NH), 7.29 (m, 4 H, phenyl
and pyridine-H), 7.53 (m, 3 H, phenyl and pyridine-H), 8.54 (m,
2 H, pyridine-H). MS m/z (%): 296 (M+, 40), 263 (25), 236 (30),
208 (18), 179 (42), 158 (45), 145 (100), 103 (28).
Compound
Reduction of arterial
blood pressure at 30 min
(mm Hg) (X SEM)
N
P value
3-(4Ј-Methoxyphenyl)-5-(3-pyridyl)-1-thiocarbamoyl-2-pyrazo-
line (7 c)
This compound was prepared similar to 7 a in 38 % yield, mp
9
13
15
16
17
20
21
22
23
24
25
26
27
28
29
31
33
10.23 1.02
10.16 1.16
10.83 0.3
9.50 0.61
9.83 0.79
14.83 1.10
12.32 2.7
10.83 1.07
10.33 0.88
22.30 0.36
22.27 0.30
22.32 0.28
22.87 0.30
22.30 0.33
10.50 0.56
12.60 1.28
15.00 1.12
13.33 0.21
11.75 1.10
17.20 0.73
2.31 0.21
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
P < 0.001
P < 0.001
P < 0.001
P < 0.001
P < 0.001
P > 0.05
P > 0.05
P < 0.001
P < 0.001
P < 0.05
P < 0.05
P < 0.05
P < 0.01
P < 0.01
P < 0.001
P > 0.05
P > 0.05
P > 0.05
P < 0.001
–
163–165 °C (methanol-ether), IR: νmax = 3421, 3288, 1582,
1
1460, 1352 cm–1. H-NMR (CDCl3): δ = 3.18 (dd, 1 H, JAB
=
16 Hz, JAX = 3.6 Hz, HA), 3.81 (dd, 1 H, JAB = 16 Hz, JBX = 12 Hz,
HB), 3.92 (s, 3 H, CH3), 6.05 (dd, 1 H, JAX = 3.6 Hz, JBX = 12 Hz,
HX), 6.94 (d, 2 H, J = 8 Hz, aromatic-H), 7.22 (m, 1 H, pyridine-
H), 7.54 (m, 1 H, pyridine-H), 7.67 (d, 2 H, J = 8 Hz, aromatic-
H), 8.54 (m, 2 H, pyridine-H). MS m/z (%): 312 (M+, 58), 279
(35), 252 (40), 238 (15), 177 (60), 145 (100), 133 (26), 103 (42).
3-(4Ј-Bromophenyl)-5-(3-pyridinyl)-1-thicarbamoyl-2-pyrazoline
(7 d)
This compound was prepared similar to 7 a in 42 % yield, mp
199–201 °C (methanol-ether), IR: νmax = 3416, 3293, 1588,
1465, 1362 cm–1. 1H-NMR (CDCl3): δ = 3.2 (dd, 1 H, JAB
=
16 Hz, JAX = 3.6 Hz, HA), 3.80 (dd, 1 H, JAB = 16 Hz, JBX = 12 Hz,
HB), 6.07 (dd, 1 H, JAX = 3.6 Hz, JBX = 12 Hz, HX), 7.21 (m, 2 H,
pyridine-H), 7.49 (d, 2 H, J = 8 Hz, aromatic-H), 7.61 (d, 2 H, J =
8 Hz, aromatic-H), 8.54 (m, 2 H, pyridine-H). MS m/z (%): 361
(M+, 60), 327 (38), 301 (72), 288 (25), 223 (30), 192 (18), 178
(94), 144 (100), 137 (15), 103 (31).
34
35
General procedure for the synthesis of 9–35
3-Phenyl-1-(4-phenyl-2-thiazolyl)-5-(3-pyridyl)-2-pyrazoline (9)
Clonidine
Control
DMSO
P < 0.001
To a suspension of compound 7 a (2.82 g, 0.01 mol) in ethanol
(15 mL) phenacyl bromide (1.99 g, 0.01 mol) was added and
heated to reflux for 1 h. After cooling, the precipitate was col-
lected by suction filtration and purified by flash chromatography
on silica gel with methanol-diethyl ether (50:50, v/v).The prod-
uct was crystallized from chloroform to yield (1.54 g, 41 %) of
compound 9. mp 155–157 °C. 1H-NMR (CDCl3): δ = 3.40 (dd,
ternal standard. Mass spectra were obtained using a Finnigan-
MAT TSQ-70 spectrophotometer at 70 eV.The IR spectra were
obtained using a Nicolet FT-IR Magna 550 spectrograph (KBr
disks). Elemental analyses were within 0.4 % of theoretical
values for C, H and N.
1 H, JAB = 16 Hz, JAX = 8 Hz, HA), 4.19 (dd, 1 H, JAB = 16 Hz, JBX
=
8 Hz, HB), 5.80 (dd, 1 H, JAX = 8 Hz, JBX = 12 Hz, HX), 6.91 (s,
1 H, thiazole-H), 7.57 (m, 10 H, aromatic-H), 7.94 (m, 1 H, pyri-
dine-H), 8.54 (m, 1 H, pyridine-H), 8.72 (m, 1 H, pyridine-H),
9.02 (m, 1 H, pyridine-H). MS m/z (%): 382 (M+, 100), 349 (10),
304 (10), 278 (20), 266 (15), 248 (31), 220 (22), 174 (60), 134
(60), 104 (38).
3-Phenyl-5-(3-pyridyl)-1-thiocarbamoyl-2-pyrazoline (7 a)
To a suspension of azachalcon 6 a (2.09 g, 0.01 mol) and sodi-
um hydroxide (1 g, 0.025 mol) in ethanol (15 mL), thiosemicar-
bazide (0.9 g, 0.01 mol) was added. The mixture was refluxed
for 1 h. The solution was poured into ice-water. The resulting
precipitate was filtered off and recrystallized from methanol-
ether (10:1, v/v) to yield 1.2 g (45 %) of compound 7 a as white
crystals. mp 162–164 °C. IR: νmax = 3426, 3288, 1588, 1460,
1347 cm–1. 1H-NMR (CDCl3): δ = 3.22 (dd, 1 H, JAX = 3.6 Hz,
JAB = 16 Hz, HA), 3.89 (dd, 1 H, JAB = 16 Hz, JBX = 12 Hz, HB),
6.07 (dd, 1 H, JAX = 3.6 Hz, JBX = 12 Hz, HX), 6.15 (brs, 1 H, NH),
7.1 (brs, 1 H, NH), 7.27 (m, 1 H, pyridine-H), 7.46 (m, 3 H, aro-
matic-H), 7.54 (m, 1 H, pyridine-H), 7.73 (m, 2 H, aromatic-H),
8.54 (m, 2 H, pyridine-H). MS m/z (%): 282 (M+, 100), 268 (8),
249 (53), 222 (25), 193 (15), 177 (33), 146 (60), 137 (10), 104
(19).
Compounds 10–35 were prepared similarly (Table 1).
Acknowledgement
This work was partially supported by a grant from the re-
search council of the Tehran University of Medical Sci-
ences.
References
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203–205 °C (methanol-ether), IR: νmax = 3425, 3285, 1586,
© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

34 Bagheri et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 25–34
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