Synthesis and anti-hypertensive ?-blocking activity evaluation of thiazole derivatives bearing pyrazole moiety

Article abstract of DOI:10.3987/COM-15-13290

A novel, facile reaction for the synthesis of series of thiazole derivatives has been developed from the reaction of the appropriate thiosemicarbazone derivatives and 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone in ethanol under reflux. The struc

Full text of DOI:10.3987/COM-15-13290

HETEROCYCLES, Vol. 91, No. 9, 2015
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HETEROCYCLES, Vol. 91, No. 9, 2015, pp. 1763 - 1773. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 21st July, 2015, Accepted, 11th August, 2015, Published online, 24th August, 2015
DOI: 10.3987/COM-15-13290
SYNTHESIS AND ANTI-HYPERTENSIVE α-BLOCKING ACTIVITY
EVALUATION OF THIAZOLE DERIVATIVES BEARING PYRAZOLE
MOIETY
Sobhi Gomha,*,1 Khaled Khalil,1 Hassan Abdel-aziz,2 and Mohamed Abdalla3
1) Chemistry department, Faculty of Science, Cairo University, Giza, 12613, Egypt.
2) Chemistry department, Faculty of Science, Cairo University, Bani Suef Branch,
Bani Suef, Egypt.
3) Research Unit, Saco Pharm. Co., 6th October City, Egypt.
*Corresponding author: E-mail: s.m.gomha@hotmail.com
Abstract – A novel, facile reaction for the synthesis of series of thiazole derivatives
has been developed from the reaction of the appropriate thiosemicarbazone
derivatives and 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone in ethanol
under reflux. The structures of the newly synthesized products were established on
the basis of spectral data (mass, IR, 1H and 13C NMR) and elemental analyses. The
pharmacological screening showed that many of the synthesized compounds exhibit
a good antihypertensive α-blocking activity and having low toxicity, as compared to
Minoxidil.
INTRODUCTION
Thiazoles are a familiar group of heterocyclic compounds possessing a wide variety of biological activities
as antimicrobial,1-3 antioxidant,4 antitubercular,5 anticonvulsant,6 anticancer,7 and anti-inflammatory8
agents. Moreover, many derivatives of thiazoles are used as selective cyclooxygenase-2 inhibitors,9 in
addition to their use as 5-HT3 receptor antagonists 10 and as potent and selective acetyl Co-A carboxylase-2
inhibitors.11 Furthermore, several pyrazole derivatives received great attention due to their biological and
pharmacological activities not only as potential inhibitors of HIV-1,12 pesticides,13 fungicides,14
antihypertensive agents 15 and anticancer activity.16 In addition, thiazoles have attracted more interest not
only due to their ability to enhance the lipid solubility but also they can easily metabolize through the
normal biochemical reactions.17 As a part of our research interest towards developing new routes for the
synthesis of a variety of heterocyclic systems with promising biological and pharmacological

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activities,18-26 we report in the present article the synthesis of a new series of 1,3-thiazoles bearing pyrazole
moiety as anti-hypertensive α-blocking agents and the results were reported against Minoxidil as reference.
RESULTS AND DISCUSSION
The thiosemicarbazones were synthesized by treatment of the corresponding carbonyl compound with
thiosemicarbazide in acid medium, unless otherwise indicated, according to the general procedure
previously described.
2-Bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone (4) was prepared via direct bromination of the
acetylpyrazole 3 with bromine in CHCl3 as previously reported in the respective literature.27
The reaction of 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone (4) with thiosemicarbazones
2a-r in refluxing ethanol, afforded the corresponding thiazoles 5a-r following Hantzsch thiazole
synthesis.28 The reaction proceeded through the reaction of 4 with equivalent amounts of each of
thiosemicarbazones 2a-r, to give the S-alkylated intermediates which cyclized in situ under the employed
reaction conditions with elimination of water molecule furnished in each case, one isolable product (as
tested by TLC). The reaction products were identified as thiazoles 5a-r (Scheme 1). Structures of the final
products were elucidated by studying their elemental analyses and spectral data. For example, the 1H NMR
spectrum of thiazoles 5a revealed the absence of NH2 protons of compound 2 and showed the signals at δ =
2.58 (s, 3H, CH3), 6.83-7.87 (m, 12H, Ar-H), 8.44 (s, 1H, CH=N), 10.36 (br s, 1H, NH). Also, its mass
spectrum showed peaks at m/z = 359 which matches with its molecular formula C20H17N5S.
In the IR spectrum of compounds 5a-r, the characteristic N–H stretching absorption band appeared around
1
the 3299-3092 cm-1 regions. H NMR spectra of compounds 5a-r revealed the presence of the –CH=N–
proton and the =N–NH– proton as two singlets at δ = 7.66-8.62 and 11.30-11.81 ppm, respectively. The
thiazole proton appeared as a multiplet at 6.45-8.14 ppm together with phenyl protons. In addition, EI-MS
spectra of 5a-r showed a molecular ion peak with intensities of 95-100%.

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O
S
R1
O
H2N
Me
N
NH2
R6
R5
R2
R3
Br2 / CHCl3
H
N
Me
N
NH2
S
R4
Ph
O
3
Br
HN
1a-r
R1
N
R6
R5
R2
R3
N
+
Me
N
Ph
4
R4
2a-r
EtOH, reflux
R1
R2
H
R3
N
N
N
N
N
S
Ph
R4
R6
Me
R5
5a-r
R3
R4
R1
R5
R6
R2
1,2,5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Me
OMe
H
H
H
H
H
H
OMe
H
Cl
H
H
Br
H
H
H
NO2
H
H
H
H
H
H
NO2
H
NMe2
H
H
H
H
H
OH
Cl
Cl
H
Cl
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
H
Me
OMe
Cl
H
H
H
H
H
H
NO2
OH
H
H
H
H
Scheme 1. Synthesis of thiazoles 5a-r

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HETEROCYCLES, Vol. 91, No. 9, 2015
Pharmacological screening
Antihypertensive α-blocking activity
The newly synthesized derivatives were subjected to α-blocking activity model screening using
α-sympatholytic activity in isolated vascular smooth muscle (Table 1). All the tested compounds showed
antihypertensive α-blocking activities and they are arranged in descending order of activities as follows:
5m > 5l > 5e > 5c > 5f > 5g > 5a > 5h > 5q > 5r > 5b > 5d > 5n > 5o > 5p > 5j > 5i > 5k.
It is worth to be mentioned that 5m and 5l compounds are more potent than Minoxidil, while, 5c and 5e are
of similar activity.
Table 1. The antihypertensive α-blocking activities of compounds 5a-r
Compound No.
IC50 μg/cm3
4.00
Compound No.
IC50 μg/cm3
21.56
23.78
3.91
Minoxidil
5j
5k
5l
5.93
5a
5b
5c
5d
5e
5f
9.45
4.17
3.79
5m
5n
5o
5p
5q
5r
12.65
4.13
16.54
18.67
20.86
6.54
5.45
5.56
5g
5h
5i
6.03
8.32
23.34
Structure activity relationship (SAR)
As shown in Table 1, the results of the antihypertensive α-blocking activities exhibited a clear structural
activity relation depending on the substitution at either aromatic ring or at the carbonyl carbon of
thiosemicarbazone moiety. It has been found that, the dichloro substitution at C-2 and C-6 has been
strongly affected the antihypertensive activity (IC50 μg/cm3 = 3.91), even more potent than Minoxidil
reference compound, as compared to the dichloro substitution at 2 and 4 carbons (IC50 μg/cm3 = 23.34). On
the other hand, mono aromatic substitutions with electron donating or electron withdrawing groups
exhibited more antihypertensive activity through aromatic substitution at C-4 (4-OMe; 4.17) rather than at
C-2 (2-OMe; 12.65). Moreover, mono substitution at C-4 with Cl and OMe groups led to similar activity to
Minoxidil. Interestingly, methyl substitution at carbonyl carbon of thiosemicarbazone, with unsubstituted

HETEROCYCLES, Vol. 91, No. 9, 2015
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benzene ring, strongly improved the antihypertensive activity (IC50 μg/cm3 = 3.79) more than the exhibited
activity of Minoxidil itself.
CONCCLUSIONS
This paper describes a facile and efficient synthesis of thiazole derivatives via cyclization reaction of
2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone with thiosemicarbazones. Structures of the final
1
products were elucidated by elemental analyses and FTIR, MS, H and 13C NMR spectra. The
pharmacological screening of the synthesized products showed potent antihypertensive α-blocking activity.
EXPERIMENTAL
Melting points were determined on a Gallenkamp apparatus and are uncorrected. IR spectra were recorded
in KBr using Pye-Unicam SP300 spectrophotometer. 1H and 13C NMR spectra were recorded in deuterated
1
13
DMSO-d6 using a Varian Gemini 300 NMR spectrometer (300 MHz for H NMR and 75 MHz for C
NMR) and the chemical shifts were related to that of the solvent DMSO-d6. Mass spectra were recorded on
a GCMS-Q1000-EX Shimadzu and GCMS 5988-A HP spectrometers, the ionizing voltage was 70 eV.
Elemental analyses of the products were carried out at the Microanalytical Centre of Cairo University, Giza,
Egypt. The starting WKLRVHPLFDUED]RQHVꢀ2a-c, 2e-j,29 2d,30 2m, 2p, 2r,31 2n, 2o,32 and 2q33 prepared as
previously described.
Synthesis of 2-(2-arylidenehydrazinyl)-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazole (5a-r).
General procedure:
A
mixture of thiosemicarbazone derivatives 2a-r (1 mmol) and
2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone (4) (0.263 g, 1 mmol) in EtOH (30 mL) was
refluxed for 2-4 h. (monitored by TLC). The formed precipitate was isolated by filtration, washed with
methanol, dried and recrystallized from appropriate solvent to give products 5a–r.
2-(2-Benzylidenehydrazinyl)-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazole (5a). Yield 67%; pale
o
1
yellow microcystals; mp 212-214 C (EtOH); IR (KBr): v 3431 (NH), 1608 (C=N) cm-1; H NMR
(DMSO-d6): δ 2.58 (s, 3H, CH3), 6.83-7.87 (m, 11H, Ar-H and thiazole-H5), 8.19 (s, 1H, pyrazole-H3),
8.44 (s, 1H, CH=N), 10.36 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 12.21(CH3), 113.7, 128.8, 129.1, 129.4,
133.8, 137.4, 137.8, 138.6, 138.9, 139.2, 139.5, 144.1, 145.7, 153.0, 165.9; MS m/z (%): 359 (M+, 27). Anal.
Calcd for C20H17N5S (359.45): C, 66.83; H, 4.77; N, 19.48; Found: C, 66.74; H, 4.58; N, 19.29%.
4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-(2-(4-methylbenzylidene)hydrazinyl)thiazole (5b). Yield
1
69%; pale yellow microcystals; mp 193-195 oC (EtOH); IR (KBr): v 3412 (NH), 1602 (C=N) cm-1; H
NMR (DMSO-d6): δ 2.18 (s, 3H, CH3), 2.57 (s, 3H, CH3), 6.91-7.97 (m, 10H, Ar-H and thiazole-H5), 8.25
(s, 1H, pyrazole-H3), 8.51 (s, 1H, CH=N), 10.36 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 12.21, 26.3 (CH3),
115.5, 125.2, 125.5, 127.4, 128.6, 129.1, 129.3, 130.7, 137.8, 138.1, 141.9, 144.7, 145.9, 162.0, 167.8; MS

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m/z (%): 373 (M+, 17). Anal. Calcd for C21H19N5S (373.47): C, 67.53; H, 5.13; N, 18.75; Found: C, 67.42;
H, 5.10; N, 18.69%.
2-(2-(4-Methoxybenzylidene)hydrazinyl)-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazole (5c). Yield
1
62%; brown microcystals; mp 172-174 oC (EtOH); IR (KBr): v 3417 (NH), 1600 (C=N) cm-1; H NMR
(DMSO-d6): δ 2.57 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 7.00-7.89 (m, 10H, Ar-H and thiazole-H5), 8.03 (s,
1H, pyrazole-H3), 8.52 (s, 1H, CH=N), 9.87 (br s, 1H, NH); MS m/z (%): 389 (M+, 23). Anal. Calcd for
C21H19N5OS (389.47): C, 64.76; H, 4.92; N, 17.98; Found: C, 64.69; H, 4.91; N, 17.66%.
2-(2-(2-Methoxybenzylidene)hydrazinyl)-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazole (5d). Yield
1
61%; brown microcystals; mp 164-166 oC (EtOH); IR (KBr): v 3411 (NH), 1603 (C=N) cm-1; H NMR
(DMSO-d6): δ 2.58 (s, 3H, CH3), 3.54 (s, 3H, OCH3), 7.51-7.97 (m, 10H, Ar-H and thiazole-H5), 8.14 (s,
1H, pyrazole-H3), 8.44 (s, 1H, CH=N), 9.83 (br s, 1H, NH); MS m/z (%): 389 (M+, 63). Anal. Calcd for
C21H19N5OS (389.47): C, 64.76; H, 4.92; N, 17.98; Found: C, 64.55; H, 4.90; N, 17.76%.
2-(2-(4-Chlorobenzylidene)hydrazinyl)-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazole (5e). Yield
1
69%; pale yellow microcystals; mp 213-215 oC (dioxane); IR (KBr): v 3436 (NH), 1605 (C=N) cm-1; H
NMR (DMSO-d6): δ 2.74 (s, 3H, CH3), 7.42-7.96 (m, 10H, Ar-H and thiazole-H5), 8.54 (s, 1H,
pyrazole-H3), 8.87 (s, 1H, CH=N), 10.06 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 13.2 (CH3), 110.7, 124.6,
124.9, 128.0, 128.9, 129.1, 130.6, 132.0, 137.2, 138.0, 139.1, 142.0, 145.3, 162.7, 164.6; MS m/z (%): 393
(M+, 44). Anal. Calcd for C20H16ClN5S (393.89): C, 60.98; H, 4.09; N, 17.78; Found: C, 60.78; H, 4.03; N,
17.63%.
2-(2-(4-Bromobenzylidene)hydrazinyl)-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazole (5f). Yield
1
66%; pale yellow microcystals; mp 251-253 oC (dioxane); IR (KBr): v 3427 (NH), 1603 (C=N) cm-1; H
NMR (DMSO-d6): δ 2.72 (s, 3H, CH3), 7.27-7.94 (m, 10H, Ar-H and thiazole-H5), 8.53 (s, 1H,
13
pyrazole-H3), 8.83 (s, 1H, CH=N), 10.21 (br s, 1H, NH); C NMR (DMSO-d6): δ 11.62 (CH3), 110.7,
114.7, 122.5, 125.0, 126.2, 128.2, 129.1, 132.2, 133.4, 137.5, 138.0, 139.1, 145.2,162.8, 165.8; MS m/z
(%): 438 (M+, 38). Anal. Calcd for C20H16BrN5S (438.34): C, 54.80; H, 3.68; N, 15.98; Found: C, 54.69; H,
3.62; N, 15.75%.
4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-(2-(4-nitrobenzylidene)hydrazinyl)thiazole (5g). Yield
66%; brown microcystals; mp 237-239 oC (dioxane); IR (KBr): v 3446 (NH), 1605 (C=N) cm-1; 1H NMR
(DMSO-d6): δ 2.55 (s, 3H, CH3), 6.98-7.95 (m, 10H, Ar-H and thiazole-H5), 8.12 (s, 1H, pyrazole-H3),
8.49 (s, 1H, CH=N), 10.09 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 12.0 (CH3), 112.6, 115.8, 124.1, 124.9,
126.9, 127.7, 129.1, 135.6, 136.3, 138.8, 139.2, 140.8, 147.0, 162.0, 165.4; MS m/z (%): 404 (M+, 18). Anal.
Calcd for C20H16N6O2S (404.45): C, 59.39; H, 3.99; N, 20.78; Found: C, 59.24; H, 3.91; N, 20.58%.
4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-(2-(3-nitrobenzylidene)hydrazinyl)thiazole (5h). Yield
1
66%; brown microcystals; mp 184-186 oC (EtOH); IR (KBr): v 3426 (NH), 1603 (C=N) cm-1; H NMR

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(DMSO-d6): δ 2.73 (s, 3H, CH3), 7.54-7.96 (m, 10H, Ar-H and thiazole-H5), 8.23 (s, 1H, pyrazole-H3),
8.50 (s, 1H, CH=N), 10.07 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 13.3 (CH3), 110.7, 123.2, 123.7, 124.5,
125.3, 126.9, 128.2, 129.6, 136.3, 137.9, 142.2, 148.7, 164.1, 166.1, 168.4; MS m/z (%): 404 (M+, 72). Anal.
Calcd for C20H16N6O2S (404.45): C, 59.39; H, 3.99; N, 20.78; Found: C, 59.32; H, 3.85; N, 20.69%.
N,N-Dimethyl-4-((2-(4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazol-2-yl)hydrazono)methyl)aniline
(5i). Yield 66%; brown microcystals; mp 206-208oC (EtOH); IR (KBr): v 3429 (NH), 1600 (C=N) cm-1; 1H
NMR (DMSO-d6): δ 2.70 (s, 3H, CH3), 3.15 (s, 6H, 2CH3), 6.77-7.88 (m, 10H, Ar-H and thiazole-H5), 8.30
(s, 1H, pyrazole-H3), 8.62 (s, 1H, CH=N), 9.66 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 11.9, 36.1 (CH3),
110.9, 111.1, 120.3, 124.5, 125.2, 129.4, 131.2, 131.8, 138.1, 138.6, 141.5, 144.3, 153.0, 163.1, 164.8; MS
m/z (%): 404 (M+, 72). Anal. Calcd for C22H22N6S (402.52): C, 65.65; H, 5.51; N, 20.88; Found: C, 65.65;
H, 5.51; N, 20.88%.
2-((2-(4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)thiazol-2-yl)hydrazono)methyl)phenol (5j). Yield 66%;
yellow microcystals; mp 226-228 oC (EtOH); IR (KBr): v 3447, 3318 (OH and NH), 1606 (C=N) cm-1; 1H
NMR (DMSO-d6): δ 2.71 (s, 3H, CH3), 5.40 (br s, 1H, OH), 6.94-7.76 (m, 10H, Ar-H and thiazole-H5),
8.26 (s, 1H, pyrazole-H3), 8.51 (s, 1H, CH=N), 10.14 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 13.2 (CH3),
110.8, 116.7, 118.8, 119.8, 125.1, 125.3, 129.1, 129.4, 129.5, 134.4, 138.0, 141.9, 145.1, 158.8, 161.8,
164.2, 167.6; MS m/z (%): 375 (M+, 36). Anal. Calcd for C20H17N5OS (375.45): C, 63.98; H, 4.56; N,
18.65; Found: C, 63.86; H, 4.52; N, 18.48%.
2-(2-(2,4-Dichlorobenzylidene)hydrazinyl)-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazole
(5k).
1
Yield 72%; yellow microcystals; mp 237-239 oC (EtOH); IR (KBr): v 3420 (NH), 1606 (C=N) cm-1; H
NMR (DMSO-d6): δ 2.73 (s, 3H, CH3), 7.40-7.99 (m, 9H, Ar-H and thiazole-H5), 8.17 (s, 1H, pyrazole-H3),
8.54 (s, 1H, CH=N), 10.55 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 13.3 (CH3), 125.0, 125.4, 127.3, 128.2,
128.3, 129.0, 129.5, 130.0, 130.9, 131.6, 131.7, 133.8, 133.9, 135.7, 150.9, 156.4, 169.9; MS m/z (%): 428
(M+, 38). Anal. Calcd for C20H15Cl2N5S (428.34): C, 56.08; H, 3.53; N, 16.35; Found: C, 56.03; H, 3.47; N,
16.25%.
2-(2-(2,6-Dichlorobenzylidene)hydrazinyl)-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazole (5l). Yield
74%; yellow microcystals; mp 249-251 oC (dioxane); IR (KBr): v 3434 (NH), 1604 (C=N) cm-1; 1H NMR
(DMSO-d6): δ 2.73 (s, 3H, CH3), 7.47-7.9 (m, 9H, Ar-H and thiazole-H5), 8.21 (s, 1H, pyrazole-H3), 8.50
13
(s, 1H, CH=N), 10.57 (br s, 1H, NH); C NMR (DMSO-d6): δ 13.3 (CH3), 124.1, 124.4, 127.3, 128.0,
128.7, 129.0, 129.9 130.3, 130.9, 132.1, 133.1, 133.8, 134.3, 135.3, 145.0, 156.4, 169.1; MS m/z (%): 428
(M+, 73). Anal. Calcd for C20H15Cl2N5S (428.34): C, 56.08; H, 3.53; N, 16.35; Found: C, 56.01; H, 3.40; N,
16.27%.
4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-(2-(1-phenylethylidene)hydrazinyl)thiazole (5m). Yield
1
68%; brown microcystals; mp 162-164 oC (EtOH); IR (KBr): v 3417 (NH), 1602 (C=N) cm-1; H NMR

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(DMSO-d6): δ 2.58 (s, 3H, CH3), 2.77 (s, 3H, CH3), 7.47-7.98 (m, 11H, Ar-H and thiazole-H5), 8.51 (s,
13
1H, pyrazole-H3), 10.63 (br s, 1H, NH); C NMR (DMSO-d6): δ 13.3, 15.9 (CH3), 110.7, 124.5, 125.0,
125.4, 125.8, 127.8, 128.1, 128.7, 129.0, 131.5, 136.5, 141.9, 164.1, 166.1, 168.4; MS m/z (%): 373 (M+,
47). Anal. Calcd for C21H19N5S (373.47): C, 67.53; H, 5.13; N, 18.75; Found: C, 67.46; H, 5.06; N,
18.59%.
4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-(2-(1-(p-tolyl)ethylidene)hydrazinyl)thiazole (5n). Yield
68%; yellowish-brown microcystals; mp 175-177 oC (EtOH); IR (KBr): v 3439 (NH), 1600 (C=N) cm-1; 1H
NMR (DMSO-d6): δ 2.28 (s, 3H, CH3), 2.54 (s, 3H, CH3), 2.74 (s, 3H, CH3), 6.91-7.88 (m, 10H, Ar-H and
thiazole-H5), 8.53 (s, 1H, pyrazole-H3), 10.60 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 13.3, 15.9 (CH3),
110.7, 124.5, 125.0, 125.4, 125.8, 127.8, 128.1, 128.7, 129.0, 131.5, 136.5, 141.9, 164.1, 166.1, 168.4; MS
m/z (%): 387 (M+, 30). Anal. Calcd for C22H21N5S (387.50): C, 68.19; H, 5.46; N, 18.07; Found: C, 68.08;
H, 5.35; N, 18.01%.
2-(2-(1-(4-Methoxyphenyl)ethylidene)hydrazinyl)-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazole
(5o). Yield 65%; yellowish-brown microcystals; mp 154-156 oC (dioxane); IR (KBr): v 3431 (NH), 1597
(C=N) cm-1; 1H NMR (DMSO-d6): δ 2.34 (s, 3H, CH3), 2.73 (s, 3H, CH3), 3.76 (s, 3H, OCH3), 7.23-7.88 (m,
10H, Ar-H and thiazole-H5), 8.53 (s, 1H, pyrazole-H3), 10.12 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 12.3,
21.1, 44.2 (CH3), 110.8, 124.7, 125.4, 126.5, 128.3, 129.7, 131.2, 138.1, 139.6, 142.0, 143.1, 145.8, 153.1,
165.2, 168.1; MS m/z (%): 387 (M+, 30). Anal. Calcd for C22H21N5OS (403.50): C, 65.49; H, 5.25; N, 17.36;
Found: C, 65.42; H, 5.19; N, 17.27%.
2-(2-(1-(4-Chlorophenyl)ethylidene)hydrazinyl)-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazole
(5p). Yield 68%; yellow microcystals; mp 183-185oC (dioxane); IR (KBr): v 3440 (NH), 1607 (C=N) cm-1;
1H NMR (DMSO-d6): δ 2.39 (s, 3H, CH3), 2.76 (s, 3H, CH3), 7.10-7.93 (m, 10H, Ar-H and thiazole-H5),
8.50 (s, 1H, pyrazole-H3), 10.52 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 12.9, 22.0 (CH3), 110.8, 121.4,
125.4, 126.0, 127.2, 129.2, 130.4, 134.6, 137.5, 141.3, 143.6, 141.5, 153.3, 164.2, 169.6; MS m/z (%): 407
(M+, 100). Anal. Calcd for C21H18ClN5S (407.92): C, 61.83; H, 4.45; N, 17.17; Found: C, 61.86; H, 4.39; N,
17.07%.
4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-(2-(1-(4-nitrophenyl)ethylidene)hydrazinyl)thiazole(5q).
Yield 62%; brown microcystals; mp 198-200 oC (dioxane); IR (KBr): v 3421 (NH), 1608 (C=N) cm-1; 1H
NMR (DMSO-d6): δ 2.32 (s, 3H, CH3), 2.75 (s, 3H, CH3), 7.03-7.89 (m, 10H, Ar-H and thiazole-H5), 8.53
(s, 1H, pyrazole-H3), 10.50 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 13.3, 21.4 (CH3), 110.3, 124.7, 125.4,
125.9, 127.4, 129.2, 131.5, 134.6, 137.6, 142.5, 143.8, 149.4, 150.3, 163.9, 169.0; MS m/z (%): 418 (M+,
63). Anal. Calcd for C21H18N6O2S (418.47): C, 60.27; H, 4.34; N, 20.08; Found: C, 60.21; H, 4.21; N,
19.93%.
4-(1-(2-(4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)thiazol-2-yl)hydrazono)ethyl)phenol (5r). Yield 66%;

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brown microcystals; mp 198-200oC (dioxane); IR (KBr): v 3414 (NH and OH), 1605 (C=N) cm-1; 1H NMR
(DMSO-d6): δ 2.30 (s, 3H, CH3), 2.80 (s, 3H, CH3), 4.11 (br s, 1H, OH), 7.02-7.97 (m, 10H, Ar-H and
thiazole-H5), 8.51 (s, 1H, pyrazole-H3), 10.38 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 12.6, 26.8 (CH3),
111.2, 115.3, 125.2, 125.8, 129.8, 130.3, 130.9, 138.5, 142.3, 145.2, 162.5, 163.5, 164.1, 166.6, 168.0; MS
m/z (%): 389 (M+, 31). Anal. Calcd for C21H19N5OS (389.47): C, 64.76; H, 4.92; N, 17.98; Found: C, 64.71;
H, 4.82; N, 17.74%.
Pharmacological assay
Anti-hypertensive α-blocking activity 34–38
Noradrenalin and other sympathomimetic drugs increase vascular smooth muscle tone by stimulation of
α-adrenergic receptors. Contractions can be antagonized by adrenergic α-receptor blocking agents, such as
phentolamine. Drugs can be tested for their capacity of reducing vascular smooth muscle contractions
induced by the adrenergic receptor-activating agent noradrenaline. Moreover, effects of peptides, such as
bradykinin, can be tested with strips of aorta or pulmonary artery.
Procedure
As donor animals, white guinea pigs of either sex weighing about 400 g are used. The vessels to be tested
are the thoracic aorta or the arteria pulmonalis. The animals are sacrificed by stunning and exsanguinations.
The pulmonary artery is quickly removed and cut into helical strips of 1–2 mm width and 15–20 mm length.
The strips are mounted in an organ bath with a preload of 1 g. Krebs-Henseleit buffer solution containing
o
11.5 M glucose is maintained at 37 C and oxygenated with 95% O2, 5% CO2. Isotonic or isometric
registration is performed. Changes in length are recorded isotonically using a lever transducer, isometric
force is measured with a force transducer.
Experimental course
Following an equilibration period of 60 min, contractions are induced by repeated administration of
(–)-noradrenalin HCl in concentrations of 2 x 10-6 M for testing the contractions of the pulmonary artery
and in concentrations of 2 x 10-8 M for testing the contractions of the aorta. After obtaining a state plateau of
identically sized contractions, cumulative doses of the test compound are added into the organ bath.
Concentrations are given when the response of the previous dose has reached a plateau.
Controls at the end of the experiment
If a compound does not show vaso relating activity at any dose, the sensitivity of the preparation is tested by
adding phentolamine (1 x 10-7 M). If a compound shows vaso relating activity, increasing the noradrenalin
concentration tests the reversibility of the relaxation.
Evaluation

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The contractile force is determined before and after drug administration. Percent inhibition of spas
Mogen-induced contraction by test drug is calculated as compared to the maximal contraction with a spas
Mogen alone (= 100%). IC50 values are determined from the individual dose response curves. IC50 is
defined as the dose of drug leading to a 50% relaxation of noradrenaline induced contraction.
The small values of IC50 for the selected compounds indicate that, for more anticancer effect higher
concentrations can be used.
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