Synthesis and Structure–Activity Relationship Study of Novel Pyrazolylthiazoles as Potential Anti-Breast Cancer Agents

Article abstract of DOI:10.1002/jhet.2794

A novel series of pyrazolylthiazole has been synthesized from the reaction of 5-(4-fluorophenyl)-3-aryl-4,5-dihydropyrazole-1-carbothioic acid amide derivatives with different reagents. The mechanism and structures of all the novel products were assured o

Full text of DOI:10.1002/jhet.2794

Month 2017
Synthesis and Structure–Activity Relationship Study of Novel
Pyrazolylthiazoles as Potential Anti-Breast Cancer Agents
a
a
b,c
Eman M. H. Abbas, Dina H. Dawood, Thoraya A. Farghaly, Fatma A. El-hag,a and Mamdouh M. Alid
*
aDepartment of Chemistry of Natural and Microbial Products, National Research Centre, Dokki 12622, Giza, Egypt
bDepartment of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
cChemistry Department, Faculty of Applied Science, Umm Al-Qura University, Makkah Almukkarramah, 21955,
Saudi Arabia
dBiochemistry Department, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki 12622,
Giza, Egypt
*
E-mail: dinanrc@yahoo.com
Additional Supporting Information may be found in the online version of this article.
Received June 15, 2016
DOI 10.1002/jhet.2794
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
A novel series of pyrazolylthiazole has been synthesized from the reaction of 5-(4-fluorophenyl)-3-aryl-
4,5-dihydropyrazole-1-carbothioic acid amide derivatives with different reagents. The mechanism and
structures of all the novel products were assured on the foundation of spectral information and elemental
analyses. The antitumor activity of all the synthesized compounds was estimated versus MCF-7 cell line.
The outcomes showed that some of the tested samples revealed powerful activity against human breast
cancer cell line. In addition, the relation between the structure and the activity has been discussed.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
indicating the use of pyrazole PEG as a robust tool for new
anticancer medication development. Many reports showed
that the substituted pyrazole ring with heterocycles
possessing sulfur and/or nitrogen atoms showed extremely
potent and efficient antitumor activity [12]. One of the most
powerful heterocyclic compounds is 1,3-thiazole ring,
which exhibited potent anticancer activity against various
types of cancer [13–15]. Also, pyrazolylthiazoles showed
Thediscoveryofnewcompoundsmayleadtostylingnew,
robust, eclectic, and least toxic anticancer agents, which
continue to exist as a major challenge for pharmaceutical
chemistry researchers. In the last decennium, several
researchers have published a large series of pyrazole
derivatives having potent antitumor activities [1–11],
© 2017 Wiley Periodicals, Inc.

E. M. H. Abbas, D. H. Dawood, T. A. Farghaly, F. A. El-hag, and M. M. Ali
Vol 000
anticancer activity against human malignant hepatoma
HepG2, MCF-7, and human lung cancer [16]. Moreover,
the fluorinated compounds in many reports showed potent
biological activities [17]. From the aforementioned findings
and in resumption of our efforts to synthesize novel
anticancer agents [18–22], this work strives to synthesize a
new series of fluorinated pyrazolylthiazole that is foreseen
to have antitumor activity.
According to the values of the previous coupling constants
that are in accordance with the literature reports [24,25],
the structure of compound 3a was drawn as illustrated
in Scheme 1. Mass spectrum of pyrazolylthiazole
derivative 4a revealed the existence of the molecular ion
peak at m/z 399. Also, the infrared spectra of thiazoles 3–5
were free from any absorption bands characteristic for NH2
groups.
Other six derivatives of pyrazolylthiazoles 7a–f were
prepared from the reaction of the carbothioic acid amides
2a and 2b with chloroacetic acid and substituted
benzaldehydes in acetic acid under reflux (Scheme 2). The
structuresof7a–fwereassuredbyspectroscopicinformation
and alternative synthetic method. Consequently,
cyclization of carbothioic acid amide 2 with ethyl
bromoacetate in absolute ethanol and anhydrous sodium
acetate (NaOAc) gave the pyrazolylthiazole derivatives 6a
and 6b followed by condensation with benzaldehyde
derivatives to give products conforming in all respects
(melting point, blended melting point, and infrared
spectra) with 7 (Scheme 2).
RESULTS AND DISCUSSION
Chemistry.
5-(4-Fluorophenyl)-3-aryl-4,5-dihydro-
pyrazole-1-carbothioic acid amides 2 were prepared as
previously reported [23] from condensation of
thiosemcarbazide with substituted chalcone 1 in boiling
ethyl alcohol in the presence of a base catalyst (Scheme 1).
The carbothioic acid amides 2a and 2b were seemed to be
beneficial synthons for supplementary synthesis of
different heterocyclic compounds. Consequently, reaction
of compounds 2 with various halogenated ketones,
namely, chloroacetone, phenacyl bromide, and 4-
bromophenacyl bromide, afforded the new thiazole
derivatives 3–5 (Scheme 1). The structures of compounds
3–5 were elucidated on the basis of spectroscopic data. For
example, the 1H NMR spectrum of substituted thiazole 3a
showed a singlet peak of the methine proton of thiazole
ring at δ 6.42 ppm and three doublet of doublet at 3.23,
3.96, and 5.58 ppm for the protons of CH2 and CH of the
pyrazoline ring with coupling constants 17.5, 12.2, and 6.2.
Moreover, compounds 8a and 8b were synthesized via
the cyclization of compounds 2a and 2b with ethyl-2-
1
bromopropionate (Scheme 3). The H NMR spectrum of
the latter thiazolone derivative 8b showed the existence
of a quartet signal at δ 4.15ppm for the thiazole-H5 in
addition to the aliphatic and aromatic protons.
The reaction between the key intermediates 2a and 2b
and ethyl-2-chloroacetoacetate in ethyl alcohol containing
anhydrous NaOAc gave thiazole derivatives 10a and 10b
Scheme 1. Preparation of compounds 3–5.
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DOI 10.1002/jhet

Month 2017
Novel Pyrazolylthiazoles as Potential Anti-Breast Cancer Agents
Scheme 2. Preparation of compounds 7a–f.
derivatives 2 with acetyl hydrazonoyl chloride derivatives
12 in dioxan in the existence of a base catalyst yielded
only one isolated product (Scheme 5). The spectroscopic
information confirmed the reaction product 14 via the
intermediate 13 with elimination of water molecule
(Scheme 5).
In an identical way, when pyrazoles 2 were allowed to react
with the ethyl(N-arylhydrazono)chloroacetates 15 in boiling
dioxane in the presence of a base catalyst, it yielded in each
case a single product, namely, 5-[(4-chloro-phenyl)-hyd
razono]-2-[3,5-disubstituted-4,5-dihydropyrazol-1-yl]-thiazol-
4-one 17a and 17b (Scheme 6). The structure of compounds
14a–h and 17a and 17b was proved on the basis of spectral
data and elemental analyses (see Experimental section).
Biological activity. Cytotoxicity versus human breast cancer
MCF-7 cell line. The antiproliferative activity of the target
thiazoles was screened against human breast MCF-7 cancer
cell line using Sulforhodamine-B (SRB) assay, and the
Scheme 3. Preparation of compounds 8a and 8b.
Scheme 5. Preparation of compounds 14a–h.
1
in good yields (Scheme 4). The H NMR spectrum of
pyrazolylthiazole derivative 10a revealed the triplet and
quartet signals at δ 1.21 and 4.15ppm, respectively,
assignable to the ethyl group, increment to signals of
other prospective protons.
Next, the reactivity of the carbothioic acid amide
derivatives 2 with diverse types of hydrazonoyl chlorides
was rated. Thus, heating the carbothioic acid amide
Scheme 4. Preparation of compounds 10a and 10b.
Scheme 6. Preparation of compounds 17a and 17b.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. M. H. Abbas, D. H. Dawood, T. A. Farghaly, F. A. El-hag, and M. M. Ali
reference drug is tamoxifen. The results depicted in Table 1
Vol 000
and Figure 1 revealed that some of the tested compounds
showed significant activity against the breast carcinoma cell
line (MCF7) in comparison with tamoxifen. It was revealed
that compounds 14g, 7c, 7d, 14f, 7e, 5a, 6b, and 14d are
equipotent to tamoxifen (IC50 =8.00μg/mL) with IC50 =8.10,
8.11, 8.33, 8.65, 8.77, 9.30, 9.60, and 9.90μg/mL,
respectively.
Structure–activity relationship.
In the case of 5-(4-
fluorophenyl)-3-phenyldihydropyrazole, it was found that
the introduction of 4-methylthiazole moiety 3a
(IC50 =30.80 Æ 3.60μg/mL) or 4-phenylthiazole moiety
4a (IC50 = 27.80Æ 2.90μg/mL) resulted in the decrease in
Figure 1. IC50 of the most potent compounds (5a, 6b, 7c–e, 14d, 14f, and
14g) and tamoxifen. [Color figure can be viewed at wileyonlinelibrary.com]
the activity compared with tamoxifen (IC50
=
8.00Æ 0.94μg/mL). However, an increment in activity
was spotted by the submission of 4-(4-bromophenyl)
thiazole 5a (IC50 = 9.30Æ 0.99μg/mL). On the other
hand, the introduction of thiazol-4-one moiety 6a
displayed moderate activity (IC50 = 17.00 Æ1.85). Among
the 5-arylidinethiazol-4-one derivatives, 7a, 7c, and 7e
Cl atoms, respectively, were the most potent
derivatives. They displayed lower IC50 values than the
congeners
endowed
with
methyl
group
14c
(IC50 = 28.00Æ 3.00μg/mL) and the unsubstituted
phenyl derivative 14a (IC50 =32.10 Æ 3.32μg/mL).
Regarding the 3,5-bis(4-fluorophenyl)dihydropyrazole,
it was observed that the 4-methylthiazole 3b, 4-
phenylthiazole 4b, and 4-(4-bromophenyl)thiazole 5b
(IC50 = 11.40Æ 1.34, 12.60 Æ2.10, and 11.50 Æ1.43 μg/
mL, respectively) demonstrated a good activity compared
with tamoxifen (IC50 = 8.00Æ 0.94μg/mL). Furthermore,
the introduction of thiazol-4-one moiety 6b displayed
remarkable antitumor activity (IC50 = 9.60 Æ1.13 μg/mL).
On the other hand, the 5-arylidinethiazol-4-one derivatives
7b and 7f showed no activity, while compound 7d
(IC50 = 8.33Æ 0.87μg/mL) was found to be equipotent to
the reference drug.
Moreover, both 5-methyl-thiazol-4-one 8b and 5-[(4-
chlorophenyl)hydrazono]thiazol-4-one 17b derivatives
showed dramatic decrease in activity (IC50 = 42.70Æ 5.30
and 52.60 Æ4.00 μg/mL, respectively), while the
pyrazolylthiazole ester derivative 10b lacked any
antitumor activity.
exhibited remarkable antitumor activity (IC50
=
11.60 Æ1.22, 8.11 Æ 0.82, and 8.77 Æ1.00 μg/mL,
respectively). Moreover, it was noticed that the 5-
methylthiazol-4-one
8a
and
5-[(4-chlorophenyl)
hydrazono]thiazol-4-one 17a derivatives lack any
antitumor activity.
It is deserving to note that rising the hydrophilic
character by the insertion of a thiazole ring carrying
methyl and ester groups as in compound 10a
(IC50 =65.20 Æ 6.85μg/mL) led to a decrease in the
antitumor activity.
Within the synthesized 5-arylazothiazoles series,
compounds 14e (IC50 = 10.00 Æ 1.11μg/mL) and 14g
(IC50 =8.10 Æ0.80 μg/mL) substituted by the OCH3 and
Table 1
Effect of the synthesized compounds (3–8, 10, 14, and 17) on MCF-7
cell line.
Considering the 5-arylazothiazoles series, compounds
14d (IC50 = 9.90 Æ1.22 μg/mL) and 14f (IC50 = 8.65Æ
0.90 μg/mL) substituted by the electron-donating CH3
and OCH3 atoms, respectively, were found to be more
potent than compound 14h substituted by the electron-
withdrawing Cl atom (IC50 = 31.32 Æ3.50 μg/mL). On the
other hand, the unsubstituted phenyl derivative 14b
lacked any activity.
Compound
IC50 (μg/mL)
Compound
IC50 (μg/mL)
3a
3b
4a
4b
5a
5b
6a
6b
7a
7b
7c
7d
7e
7f
30.80 Æ 3.60
11.40 Æ 1.34
27.80 Æ 2.90
12.60 Æ 2.10
9.30 Æ 0.99
11.50 Æ 1.43
17.00 Æ 1.85
9.60 Æ 1.13
11.60 Æ 1.22
NA
8b
10a
10b
14a
14b
14c
14d
14e
14f
14g
14h
17a
17b
42.70 Æ 5.30
65.20 Æ 6.85
NA
32.10 Æ 3.32
NA
28.00 Æ 3.00
9.90 Æ 1.22
10.00 Æ 1.11
8.65 Æ 0.90
8.10 Æ 0.80
31.32 Æ 3.50
NA
8.11 Æ 0.82
8.33 Æ 0.87
8.77 Æ 1.00
NA
CONCLUSION
52.60 Æ 4.00
Recently, from this report we can conclude that a new
series of pyrazolylthiazole derivatives was prepared from
DMSO
Tamoxifen
—
8a
NA
8.00 Æ 0.94
the
reaction
of
5-(4-fluorophenyl)-3-aryl-4,5-
Data were expressed as M Æ SE of four independent experiments. NA is
no activity.
dihydropyrazole-1-carbothioic acid amide derivatives
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Novel Pyrazolylthiazoles as Potential Anti-Breast Cancer Agents
with different reagents. All the synthesized compounds
were estimated for their antitumor activity versus breast
cancer cell line. Eight derivatives of the tested
compounds showed efficient activity versus MCF-7. The
study of the relation between the structure and activity
disclosed that the antitumor efficiency of these
compounds is evidenced to be exceedingly linked to the
kind of the substituent at position-4 and position-5 of the
thiazole ring, also position-3 of the pyrazole rings.
ppm): 1.98 (s, 3H, CH3), 3.14 (dd, 1H, HA, J = 17.6,
6.0 Hz), 3.95 (dd, 1H, HB, J = 17.6, 12.0 Hz), 5.58 (dd,
1H, Hx, J = 12.1, 6.0 Hz), 6.42 (s, 1H, H5-thiazole ring),
7.11–7.91 (m, 8H, Ar–Hs). MS m/z (%): 357 (M++2,
25), 356 (M++1, 3), 355 (M+, 75), 122 (13), 113 (100),
95 (36), 77 (34). Anal. Calcd for C19H15F2N3S (355.40):
C, 64.21; H, 4.25; N, 11.82. Found: C, 64.25; H, 4.28; N,
11.90%.
2-[5-(4-Fluorophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl]-4-
phenylthiazole (4a).
Yellow crystals, mp 133–135°C,
yield (75%). IR (cmÀ1): 1603 (C=N). 1H NMR (d6-
DMSO, δ ppm): 3.32 (dd, 1H, HA, J =17.5, 5.9 Hz), 4.05
(dd, 1H, HB, J = 17.5, 12.3Hz), 5.66 (dd, 1H, Hx,
J = 12.3, 5.9 Hz), 7.16–7.84 (m, 15H, Ar–Hs + H5-
thiazole ring). MS m/z (%): 401 (M+ + 2, 10), 400
(M+ +1, 30), 399 (M+, 100), 224 (15), 175 (69), 147
(16), 134 (37), 122 (53), 96 (19), 77 (63). Anal. Calcd for
C24H18FN3S (399.48): C, 72.16; H, 4.54; N, 10.52.
Found: C, 72.31; H, 4.64; N, 10.43%.
EXPERIMENTAL
All melting points were uncorrected and measured using
Electrothermal IA 9000 apparatus (Stuart Scientific, UK).
Infrared spectra were measured by Nexus 670 FT-IR FT-
Raman spectrometer using KBr discs. The nuclear
magnetic resonance NMR spectra were recorded on
1
Varian Mercury 300 or 400MHz for H NMR and 75 or
2-[3,5-Di(4-fluorophenyl)-4,5-dihydropyrazol-1-yl]-4-
100MHz for 13C NMR spectrometer using TMS as the
internal standard. The mass spectra were recorded on
GCMS-QP 1000EX Shimadzu gas chromatography MS
spectrometer (Shimadzu, Japan). The IR, MS, NMR
spectra, and elemental analyses were performed at Micro-
analytical Laboratory, Central Services Laboratory, Cairo
University, Egypt. The reactions were pursued by TLC
(aluminum sheets, Merck), and the spots were disclosed
by exposure to UV lamp. Compounds 2a and 2b, 6a and
6b, and hydrazonoyl chlorides 12 and 15 were prepared
as previously described in literature [23,26,27].
phenylthiazole (4b).
Yellow crystals, mp 165–167°C,
yield (78%). IR (cmÀ1): 1600 (C=N). 1H NMR (d6-
DMSO, δ ppm): 3.32 (dd, 1H, HA, J=17.1, 6.2Hz), 4.00
(dd, 1H, HB, J=17.1, 12.2Hz), 5.66 (dd, 1H, Hx, J=12.2,
6.2Hz), 7.16–7.80 (m, 14H, Ar–Hs+H5-thiazole ring).
MS m/z (%): 419 (M+ +2, 34), 418 (M+ +1, 22), 417 (M+,
100), 122 (14), 95 (16), 77 (27). Anal. Calcd for
C24H17F2N3S (417.47): C, 69.05; H, 4.10; N, 10.07.
Found: C, 69.18; H, 4.22; N, 10.13%.
4-(4-Bromophenyl)-2-[5-(4-fluorophenyl)-3-phenyl-4,5-dihy-
dropyrazol-1-yl]thiazole (5a).
Buff crystals, mp 204–
Synthesis of 2-[3,5-disubstituted-4,5-dihydro-pyrazol-1-yl]-
4-substituted-thiazoles (3a, b–5a, b).
206°C, yield (80%). IR (cmÀ1): 1574 (C=N). H NMR
(d6-DMSO, δ ppm): 3.10 (dd, 1H, HA, J= 17.6, 6.0Hz),
3.85 (dd, 1H, HB, J = 17.6, 12.5 Hz), 5.89 (dd, 1H, Hx,
J = 12.5, 6.0 Hz), 7.12–8.06 (m, 14H, Ar–Hs + H5-
thiazole ring). MS m/z (%): 479 (M+ + 1, 99), 478 (M+,
30), 477 (100), 375 (8), 253 (23), 224 (30), 173 (87), 155
(10), 122 (97), 77 (60). Anal. Calcd for C24H17BrFN3S
(478.38): C, 60.26; H, 3.58; N, 8.78. Found: C, 60.40; H,
3.63; N, 8.83%.
1
General method:
Pyrazole-1-carbothioic acid amide derivatives 2a and 2b
(5 mmol) were refluxed with each of chloroacetone,
phenacyl bromide, or p-bromophenacyl bromide (5mmol)
in ethyl alcohol (20 mL) in the presence of anhydrous
NaOAc (0.82 g, 10 mmol) for 8–10 h. Upon cooling, the
solid formed was filtered, washed with water, dried, and
recrystallized from ethyl alcohol to afford the thiazole
derivatives 3–5.
2-[3,5-Di(4-fluorophenyl)-4,5-dihydropyrazol-1-yl]-4-(4-bro-
2-[5-(4-Fluorophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl]-4-
methylthiazole (3a). Buff crystals, mp 180–182°C, yield
mophenyl)thiazole (5b).
Buff crystals, mp 194–196°C,
yield (82%). IR (cmÀ1): 1602 (C=N). 1H NMR (d6-
DMSO, δ ppm): 3.22 (dd, 1H, HA, J =17.4, 6.2 Hz), 3.98
(dd, 1H, HB, J = 17.3, 12.0Hz), 5.65 (dd, 1H, Hx,
J = 12.0, 6.2 Hz), 7.16–7.61 (m, 13H, Ar–Hs + H5-
thiazole ring). 13C NMR (d6-DMSO, δ ppm): 43.3 (C-4,
pyrazoline ring), 64.2 (C-5, pyrazoline ring), 105.9,
115.8, 115.9, 116.5, 121.1, 128.0, 129.3, 132.0, 134.2,
138.3, 149.8, 152.7, 162.6, 163.0, 164.6, 165.0. MS m/z
(%): 498 (M+ + 2, 21), 497 (M+ + 1, 16), 496 (M+, 79),
122 (100), 94 (25), 76 (53). Anal. Calcd for
C24H16BrF2N3S (496.37): C, 58.07; H, 3.25; N, 8.47.
Found: C, 58.21; H, 3.39; N, 8.55%.
1
(75%). IR (cmÀ1): 1600 (C=N). H NMR (d6-DMSO, δ
ppm): 2.01 (s, 3H, CH3), 3.23 (dd, 1H, HA, J =17.5,
6.2Hz), 3.96 (dd, 1H, HB, J= 17.5, 12.2Hz), 5.58 (dd,
1H, Hx, J =12.2, 6.2 Hz ), 6.42 (s, 1H, H5-thiazole ring),
7.13–7.80 (m, 9H, Ar–Hs). MS m/z (%): 339 (M+ + 2, 2),
338 (M+ + 1, 28), 337 (M+, 100), 224 (13), 122 (24), 113
(57), 104 (13), 96 (10), 77 (18). Anal. Calcd for
C19H16FN3S (337.41): C, 67.63; H, 4.78; N, 12.45.
Found: C, 67.66; H, 4.80; N, 12.51%.
2-[3,5-Di(4-fluorophenyl)-4,5-dihydropyrazol-1-yl]-4-
methylthiazole(3b). Buffcrystals,mp122–124°C,yield
(77%). IR (cmÀ1): 1596 (C=N). 1H NMR (d6-DMSO, δ
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. M. H. Abbas, D. H. Dawood, T. A. Farghaly, F. A. El-hag, and M. M. Ali
Vol 000
Synthesis of 5-arylidine-2-[3,5-disubstituted-4,5-dihydro
pyrazol-1-yl]-thiazol-4-one (7a–f).
7.26–7.99 (m, 13H, Ar–Hs+ benzylic proton). 13C NMR (d6-
DMSO, δ ppm): 44.0 (C-4, pyrazoline ring), 63.8 (C-5, pyrazoline
ring), 116.4, 116.8, 128.2, 129.5, 130.6, 130.7, 132.6, 136.8, 139.0,
153.8,161.2,162.2,163.2,163.7,164.1,170.9,179.6.MS m/z(%):
465(M++2,2),464(M++1,1),463(M+,7),152(100), 122(8),95
(24), 77 (41). Anal. Calcd for C25H16F3N3OS (463.47): C, 64.79;
Method A: Glacial
acetic acid solution (10 mL) of pyrazole-1-carbothioic
acid amide derivatives 2a and 2b (5 mmol) were boiled
with chloroacetic acid (0.47 g, 5 mmol) and anhydrous
NaOAc (0.82g, 10 mmol) and the appropriate aromatic
aldehyde (5 mmol) in the presence of acetic anhydride
(5 mL) for 3h. After the solution was cooled, it was
poured onto cold water. The solid formed was collected
by filtration and crystallized from acetic acid to give the
thiazol-4-ones 7a–f. Method B: The appropriate aromatic
H,3.48;N,9.07.Found:C,64.82;H,3.52;N,9.19%.
2-[5-(4-Fluorophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl]-5-(4-
methoxybenzylidene)thiazol-4-one (7e). Yellow crystals, mp
220–222°C, yield (73%). IR (cmÀ1): 1711 (C=O) and
1
1590 (C=N). H NMR (d6-DMSO, δ ppm): 3.34 (dd, 1H,
HA, J= 17.3, 6.5Hz), 3.79 (s, 3H, OCH3), 4.13 (dd, 1H,
HB, J=17.3, 12.0Hz), 5.89 (dd, 1H, Hx, J=12.0, 6.5Hz),
7.07–7.99 (m, 14H, Ar–Hs+benzylic proton). MS m/z,
(%): 457 (M+, 26), 164 (100), 149 (32), 122 (13), 121
(17), 96 (3), 77 (9). Anal. Calcd for C26H20FN3O2S
(457.52): C, 68.25; H, 4.41; N, 9.18. Found: C, 68.38; H,
aldehyde (5mmol) was added to
a
mixture of
pyrazolylthiazolones 6a and 6b (5 mmol), acetic
anhydride (5 mL), and anhydrous NaOAc (0.82g,
10mmol) in acetic acid (10 mL). The latter solution was
refluxed for 3 h, and then after the solution was cooled, it
was poured onto cold water. The solid formed was
collected by filtration and crystallized from acetic acid to
give the thiazol-4-ones 7a–f.
5-Benzylidene-2-[5-(4-fluorophenyl)-3-phenyl-4,5-dihydropyrazol-
1-yl]thiazol-4-one (7a). Yellow crystals, mp 150–152°C, yield
4.43; N, 9.27%.
2-[3,5-Di(4-fluorophenyl)-4,5-dihydropyrazol-1-yl]-5-(4-methoxy
benzylidene)thiazol-4-one(7f). Yellowcrystals,mp236–238°C,
1
yield (75%). IR (cmÀ1): 1711 (C=O) and 1590 (C=N). H
(75%). IR (cmÀ1): 1711 (C=O) and 1590 (C=N). 1H NMR (d6-
DMSO, δ ppm): 3.31(dd, 1H, HA, J=17.7, 6.3Hz), 4.10 (dd,
1H, HB, J=17.7, 12.0Hz), 5.86 (dd, 1H, Hx, J=12.0, 6.3 Hz),
7.18–7.71 (m, 15H, Ar–Hs + benzylic proton). MS m/z (%):
429 (M+ + 2, 1), 428 (M+ +1, 3), 427 (M+, 10), 324 (16), 134
(100), 122 (17), 90 (11), 77 (13). Anal. Calcd for
C25H18FN3OS (427.49): C, 70.24; H, 4.24; N, 9.83. Found: C,
NMR (d6-DMSO, δ ppm): 3.39 (dd, 1H, HA, J= 17.1,
6.3Hz), 3.78 (s, 3H, OCH3), 4.09 (dd, 1H, HB, J= 17.1,
12.2Hz), 5.88 (dd, 1H, Hx, J= 12.2, 6.3 Hz), 7.16–8.01
(m, 13H, Ar–Hs+ benzylic proton). MS m/z, (%): 477
(M+ +2, 2), 476 (M+ +1, 2), 475 (M+, 28), 164 (100), 149
(36), 122 (32), 95 (11), 77 (10). Anal. Calcd for
C26H19F2N3O2S (475.51): C, 65.67; H, 4.03; N, 8.84. Found:
C, 65.74; H, 4.17; N, 8.70%.
70.37; H, 4.36; N, 9.68%.
5-Benzylidene-2-[3,5-di(4-fluorophenyl)-4,5-dihydropyrazol-1-
yl]thiazol-4-one (7b). Yellow crystals, mp 148–150°C, yield
Synthesis of 2-[3,5-disubstituted-4,5-dihydropyrazol-1-yl]-5-
methylthiazol-4-one (8a and 8b). General method: Pyrazole-1-
(72%). IR (cmÀ1): 1711 (C=O) and 1590 (C=N). 1H NMR
(d6-DMSO, δ ppm): 3.33 (dd, 1H, HA, J=17.6, 6.1Hz),
4.16 (dd, 1H, HB, J=17.6, 12.2Hz), 5.89 (dd, 1H, Hx,
J=12.2, 6.1Hz), 7.18–7.62 (m, 14H, Ar–Hs+benzylic
proton). MS m/z (%): 447 (M+ +2, 1), 446 (M+ +1, 2), 445
(M+, 5), 134 (100), 121 (14), 77 (37). Anal. Calcd for
C25H17F2N3OS (445.48): C, 67.40; H, 3.85; N, 9.43. Found:
carbothioic acid amide derivatives 2a and 2b (5 mmol) were
refluxed with ethyl-2-bromopropionate (0.9 mL, 5mmol) and
anhydrous NaOAc (0.82 g, 10 mmol) in ethyl alcohol (20 mL)
for 6 h. The precipitate formed after cooling was filtered then
washed with cold water, dried, and recrystallized from ethyl
alcohol to afford the thiazole derivatives 8a and 8b.
2-[5-(4-Fluorophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl]-
5-methylthiazol-4-one (8a).
White crystals, mp 180–
C, 67.56; H, 3.97; N, 9.54%.
5-(4-Fluorobenzylidene)-2-[5-(4-fluorophenyl)-3-phenyl-4,5-
dihydropyrazol-1-yl]thiazol-4-one (7c). Yellow crystals, mp
182°C, yield (78%). IR (cmÀ1): 1695 (C=O) and 1602
1
(C=N). H NMR (d6-DMSO, δ ppm): 1.41 (d, 3H, CH3),
90–92°C, yield (70%). IR (cmÀ1): 1698 (C=O) and 1604
3.48 (dd, 1H, HA, J=17.5, 6.4Hz), 4.06 (dd, 1H, HB,
J=17.5, 12.1Hz), 4.17 (q, 1H, CH), 5.82 (dd, 1H, Hx,
J=12.1, 6.4Hz), 7.17–7.85 (m, 9H, Ar–Hs). 13C NMR
(d6-DMSO, δ ppm): 19.2 (CH3), 43.9 (C-4, pyrazoline ring),
49.5 (C-5, thiazole ring), 63.4 (C-5, pyrazoline ring), 116.3,
127.8, 128.5, 129.5, 130.3, 132.1, 137.0, 161.1, 163.1,
176.4, 190.1. MS m/z, (%): 355 (M+ +2, 1), 354 (M+ +1, 3),
353 (M+, 11), 320 (22), 250 (15), 122 (100), 96 (19), 77
(20). Anal. Calcd for C19H16FN3OS (353.41): C, 64.57; H,
1
(C=N). H NMR (d6-DMSO, δ ppm): 3.31 (dd, 1H, HA,
J =17.0, 6.0Hz), 4.10 (dd, 1H, HB, J =17.0, 12.5Hz ),
5.89 (dd, 1H, Hx, J =12.5, 6.0 Hz), 7.21–8.00 (m, 14H,
Ar–Hs +benzylic proton). MS m/z (%): 447 (M+ +2, 3),
446 (M+ + 1, 4), 445 (M+, 7), 342 (76), 152 (100), 122
(27), 80 (75), 64 (35). Anal. Calcd for C25H17F2N3OS
(445.48): C, 67.40; H, 3.85; N, 9.43. Found: C, 67.52; H,
3.76; N, 9.60%.
2-[3,5-Di(4-fluoro-phenyl)-4,5-dihydropyrazol-1-yl]-5-(4-fluorobenzy
4.56; N, 11.89. Found: C, 64.61; H, 4.59; N, 11.92%.
2-[3,5-Di(4-fluorophenyl)-4,5-dihydropyrazol-1-yl]-5-methylthiazol-4-
one (8b). White crystals, mp 192–193°C, yield (75%). IR
lidene)thiazol-4-one (7d).
Yellow crystals, mp 106–108°C,
yield (74%). IR (cmÀ1): 1711 (C=O) and 1590 (C=N). 1H NMR
(d6-DMSO, δ ppm): 3.32 (dd, 1H, HA, J= 17.6, 6.1 Hz), 4.13
(dd, 1H, HB,J= 17.6, 12.2 Hz), 5.96 (dd, 1H, Hx,J=12.2, 6.1Hz),
(cmÀ1): 1695 (C=O) and 1602 (C=N). 1H NMR (d6-DMSO, δ
ppm): 1.41 (d, 3H, CH3), 3.33 (dd, 1H, HA, J=17.6, 6.1Hz),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Novel Pyrazolylthiazoles as Potential Anti-Breast Cancer Agents
4.03 (dd, 1H, HB, J=17.6, 12.0Hz), 4.15 (q, 1H, CH), 5.77 (dd,
1H, Hx, J=12.0, 6.1Hz), 7.16–7.86 (m, 8H, Ar–Hs). MS m/z,
(%): 373 (M++2, 1), 372 (M++ 1, 1), 371 (M+, 3), 122 (100),
95 (22), 76 (67). Anal. Calcd for C19H15F2N3OS (371.40): C,
61.44; H, 4.07; N, 11.31. Found: C, 61.56; H, 4.23; N, 11.41%.
Synthesis of 2-[3-substituted-5-phenyl-4,5-dihydropyrazol-1-
yl]-4-methylthiazole-5-carboxylic acid ethyl ester (10a and
10b). General method: Pyrazole-1-carbothioic acid amide
derivatives 2a and 2b (5 mmol) were refluxed with ethyl-2-
chloro acetoacetate 9 (0.82 mL, 5 mmol) and anhydrous
NaOAc (0.82g, 10 mmol) in ethyl alcohol (20 mL) for 7h.
The solid product was formed after cooling was collected by
filtration, dried, and recrystallized from ethyl alcohol to
{2-[3,5-Di(4-fluorophenyl)-4,5-dihydropyrazol-1-yl]-4-methylthiazol-
5-yl}-phenyldiazene (14b).
Orange crystals, mp 195–196°C,
yield (85%). IR (cmÀ1): 1603 (C=N). H NMR (d6-DMSO,
δ ppm): 2.45 (s, 3H, CH3), 3.27 (dd, 1H, HA, J=17.6,
6.1Hz), 4.02 (dd, 1H, HB, J= 17.6, 12.2 Hz), 5.82 (dd, 1H,
Hx, J=12.4, 6.1Hz), 7.16–7.86 (m, 13H, Ar–Hs). MS m/z
(%): 461 (M++2, 6), 460 (M++1, 2), 459 (M+, 18), 135
(27), 122 (74), 77 (100). Anal. Calcd for C25H19F2N5S
(459.51): C, 65.34; H, 4.17; N, 15.24. Found: C, 65.48; H,
1
4.29; N, 15.36%.
{2-[5-(4-Fluorophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl]-4-
methylthiazol-5-yl}-p-tolyldiazene (14c). Red crystals, mp
170–173°C, yield (82%), IR (cmÀ1): 1611 (C=N). 1H
NMR (d6-DMSO, δ ppm): 2.27 (s, 3H, CH3), 2.46 (s,
3H, CH3), 3.32 (dd, 1H, HA, J= 17.2, 6.2 Hz), 4.01
(dd, 1H, HB, J = 17.2, 12.2Hz), 5.83 (dd, 1H, Hx,
J = 12.2, 6.2 Hz), 6.88–7.81 (m, 13H, Ar–Hs). MS m/z
(%): 457 (M+ + 2, 4), 456 (M+ +1, 4), 455 (M+, 12),
122 (15), 80 (100). Anal. Calcd for C26H22FN5S
(455.55): C, 68.55; H, 4.87; N, 15.37. Found: C,
afford pyrazolylthiazoles 10a and 10b.
2-[5-(4-Fluorophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl]-4-
methylthiazole-5-carboxylic acid ethyl ester (10a). Yellow
crystals, mp 85–87°C, yield (68%). IR (cmÀ1): 1698
1
(C=O) and 1601 (C=N). H NMR (d6-DMSO, δ ppm):
1.21 (t, 3H, CH3), 2.31 (s, 3H, CH3), 3.39 (dd, 1H, HA,
J = 17.6, 6.4 Hz), 3.90 (dd, 1H, HB, J = 17.6, 12.4 Hz),
4.15 (q, 2H, CH2), 5.76 (dd, 1H, Hx, J = 12.4, 6.4 Hz),
7.14–7.76 (m, 9H, Ar–Hs). MS m/z (%): 411 (M+ + 2,
8), 410 (M+ + 1, 27), 409 (M+, 100), 185 (78), 149
(14), 122 (89), 95 (16), 77 (70). Anal. Calcd for
C22H20FN3O2S (409.48): C, 64.53; H, 4.92; N, 10.26.
68.42; H, 4.95; N, 15.48%.
{2-[3,5-Di(4-fluorophenyl)-4,5-dihydropyrazol-1-yl]-4-methylthiazol-
5-yl}-p-tolyldiazene (14d).
Orange crystals, mp 166–168°C,
yield (87%). IR (cmÀ1): 1603 (C=N). H NMR (d6-DMSO,
δ ppm): 2.29 (s, 3H, CH3), 2.46 (s, 3H, CH3), 3.36 (dd,
1H, HA, J=17.6, 6.6Hz), 4.03 (dd, 1H, HB, J=17.6,
12.6Hz), 5.81 (dd, 1H, Hx, J= 12.6, 6.5 Hz), 6.88–7.94 (m,
12H, Ar–Hs). MS m/z (%): 475 (M++2, 14), 474 (M++1,
12), 473 (M+, 47), 121 (43), 91 (100), 77 (65). Anal. Calcd
for C26H21F2N5S (473.54): C, 65.95; H, 4.47; N, 14.79.
1
Found: C, 64.61; H, 4.97; N, 10.30%.
2-[3,5-Di(4-fluorophenyl)-4,5-dihydropyrazol-1-yl]-4-methylthiazole-5-
carboxylic acid ethyl ester (10b). Yellow crystals, mp 124–126°C,
yield (70%). IR (cmÀ1): 1673 (C=O) and 1602 (C=N). 1H NMR
(d6-DMSO, δ ppm): 1.21 (t, 3H, CH3), 2.31 (s, 3H, CH3), 3.13
(dd, 1H, HA, J= 17.0, 6.0Hz), 4.04 (dd, 1H, HB, J=17.0,
12.2 Hz), 4.15 (q, 2H, CH2), 5.76 (dd, 1H, Hx, J=12.0,
6.0 Hz), 7.14–7.87 (m, 8H, Ar–Hs). MS m/z (%): 429 (M++2,
3), 428 (M++ 1, 1), 427 (M+, 10), 122 (100), 77 (32). Anal.
Calcd for C22H19F2N3O2S (427.47): C, 61.81; H, 4.48; N,
9.83. Found: C, 61.94; H, 4.51; N, 9.87%.
Found: C, 65.99; H, 4.64; N, 14.61%.
{2-[5-(4-Fluorophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl]-
4-methylthiazol-5-yl}-(4-methoxyphenyl)diazene (14e). Orange
crystals, mp 145–147°C, yield (84%). IR (cmÀ1): 1599
1
(C=N). H NMR (d6-DMSO, δ ppm): 2.40 (s, 3H, CH3),
3.32 (dd, 1H, HA, J= 17.6, 6.1 Hz), 3.78 (s, 3H, OCH3), 3.86
(dd, 1H, HB, J= 17.6, 12.4Hz), 5.82 (dd, 1H, Hx, J=12.5,
6.1Hz), 6.99–7.64 (m, 13H, Ar–Hs). MS m/z (%): 473
(M+ + 2, 2), 472 (M+ +1, 3), 471 (M+, 10), 134 (12), 122
(45), 94 (230), 77 (57), 59 (100). Anal. Calcd for
C26H22FN5OS (471.55): C, 66.22; H, 4.70; N, 14.85. Found:
Reaction of compounds 2a and 2b with hydrazonoyl chlorides
12 and 15. General method: The appropriate hydrazonoyl
chlorides 12 or 15 (10mmol) were added to a dioxan
(30 mL) solution of pyrazole derivatives 2a and 2b
(10mmol) containing triethylamine (1.01mL, 10mmol), and
the reaction mixture was refluxed for 8 h. The cold solution
was poured onto acidified cold water by concentrated
hydrochloric acid. The precipitated produced was filtered off
and crystallized from the ethanol to give products 14a–h and
C, 66.34; H, 4.81; N, 14.96%.
{2-[3,5-Di(4-fluorophenyl)-4,5-dihydropyrazol-1-yl]-4-methylthiazol-
5-yl}-(4-methoxyphenyl)diazene (14f). Orange crystals, mp 175–
1
177°C, yield (85%). IR (cmÀ1): 1600(C=N). H NMR (d6-
DMSO, δ ppm): 2.46 (s, 3H, CH3), 3.31 (dd, 1H, HA,
J= 17.6, 6.1 Hz), 3.76 (s, 3H, OCH3), 4.07 (dd, 1H, HB,
J= 17.6, 12.2 Hz), 5.83 (dd, 1H, Hx, J= 12.4, 6.1 Hz), 7.02–
7.91 (m, 12H, Ar–Hs). 13C NMR (d6-DMSO, δ ppm):
16.4 (CH3), 44.0 (C-4, pyrazoline ring), 56.0 (OCH3), 63.0
(C-5, pyrazoline ring), 115.1, 116.1, 116.2, 123.8, 127.5,
128.6, 129.8, 137.8, 141.4, 146.8, 155.6, 156.1, 160.8,
161.1, 163.0, 164.3. MS m/z (%): 491 (M++2, 9), 490
(M++1, 32), 489 (M+, 100), 242 (17), 135 (15), 122 (55),
107 (74), 95 (14), 77 (50). Anal. Calcd for C26H21F2N5OS
17a and 17b.
{2-[5-(4-Fluorophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl]-4-methylthiazol-
5-yl}-phenyldiazene (14a). Orange crystals, mp 185–187°C, yield
(80%). IR (cmÀ1): 1633 (C=N). H NMR (d6-DMSO, δ ppm):
1
2.46 (s, 3H, CH3), 3.39 (dd, 1H, HA, J= 17.6, 6.2 Hz), 4.05 (dd,
1H, HB, J=17.6, 12.4Hz), 5.84 (dd, 1H, Hx, J=12.5, 6.2Hz),
7.16–7.80 (m, 14H, Ar–Hs). MS m/z (%): 443 (M++2, 1), 442
(M++ 1, 1), 441 (M+, 4), 122 (23), 62 (100). Anal. Calcd for
C25H20FN5S (441.52): C, 68.01; H, 4.57; N, 15.86. Found: C,
68.05; H, 4.60; N, 15.90%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. M. H. Abbas, D. H. Dawood, T. A. Farghaly, F. A. El-hag, and M. M. Ali
Vol 000
(489.54): C, 63.79; H, 4.32; N, 14.31. Found: C, 63.82; H,
4.50; N, 14.37%.
(4-Chlorophenyl)-{2-[5-(4-fluorophenyl)-3-phenyl-4,5-dihydropyrazol-
Cell lines and culturing. The breast MCF-7 cancer cell
line that was utilized in the anticancer activity screening
was provided from the American Type Culture Collection
(Rockville, MD, USA). It was preserved in Dulbecco’s
modified Eagle’s medium equipped with 10% heat
inactivated fetal calf serum (GIBCO), streptomycin
(100 μg/mL), and penicillin (100 U/mL) at 37°C in atmo-
sphere containing 5% CO2. Cell at a concentration of
0.50 ×106 was grown in a flask in 5 mL of culture medium.
1-yl]-4-methylthiazol-5-yl}diazene (14g).
Orange crystals, mp
220–222°C, yield (85%). IR (cmÀ1): 1598 (C=N). 1H
NMR (d6-DMSO, δ ppm): 2.53 (s, 3H, CH3), 3.30 (dd,
1H, HA, J= 16.9, 6.0 Hz), 4.07 (dd, 1H, HB, J=16.9,
12.3Hz), 5.84 (dd, 1H, Hx, J= 12.3, 6.0 Hz), 7.16–7.80
(m, 13H, Ar–Hs). MS m/z (%): 477 (M+ +2, 1), 476
(M+ + 1, 2), 475 (M+, 5), 122 (15), 95 (52), 76 (74),
59 (100). Anal. Calcd for C25H19ClFN5S (475.97): C,
63.09; H, 4.02; N, 14.71. Found: C, 63.11; H, 4.17; N,
The antiproliferative assay.
The antiproliferative
activity was evaluated in vitro utilizing the SRB stain assay
according to the reported standard method [28]. Twenty-
four hours before treatment with the tested compounds, the
cell was plated in 96-well microtiter plate (104 cells/ well)
to allow attachment of the cell to the wall of the plate. The
dimethylsulfoxide was used in dissolving the tested
compounds and then diluted with saline to the appropriate
volume. Different concentrations of tested compounds (0–
100 μg/mL) were added to the cell. Triplicate wells were
prepared for each dose. Monolayer cell was incubated with
the compounds for 48h at 37°C and in atmosphere of 5%
CO2. After 48h, the cell was fixed, washed, and stained
with 0.4% (w/v) SRB dissolved in 1% acetic acid. The
unbound dye was washed with 1% acetic acid, and the
attached stain was recovered with Tris-EDTA buffer.
ELISA reader was used to measure the color intensity. The
survival curve was obtained by plotting the relation
between surviving fraction and drug concentration. The
IC50 was calculated (Table 1).
14.59%.
{2-[3,5-Di(4-fluorophenyl)-4,5-dihydropyrazol-1-yl]-4-methylthiazol-5-
yl}-(4-chlorophenyl)diazene (14h). Brown crystals, mp 120–122°C,
yield(88%).IR(cmÀ1):1601(C=N).1HNMR(d6-DMSO, δppm):
2.53 (s, 3H, CH3), 3.32 (dd, 1H, HA,J= 17.6, 6.1 Hz), 4.05 (dd, 1H,
HB, J=17.6, 12.1 Hz), 5.86(dd, 1H, Hx,J= 12.1, 6.1 Hz), 7.16–7.84
(m, 12H, Ar–Hs). MSm/z(%):495(M++2, 8), 494(M++1,6),493
(M+, 20), 242(12), 122(49), 113(36), 95(28), 77 (930). Anal. Calcd
forC25H18ClF2N5S(493.96):C, 60.79;H, 3.67;N, 14.18. Found:C,
60.81; H, 3.71; N, 14.22%.
5-[(4-Chlorophenyl)hydrazono]-2-[5-(4-fluorophenyl)-3-phe
nyl-4,5-dihydropyrazol-1-yl]-thiazol-4-one (17a).
Yellow
crystals, mp 155–158°C, yield (80%). IR (cmÀ1): 3356
(NH), 1711 (C=O), and 1590 (C=N). 1H NMR (d6-
DMSO, δ ppm): 3.14 (dd, 1H, HA, J= 17.6, 6.1 Hz), 3.86
(dd, 1H, HB, J =17.6, 12.2Hz), 5.87 (dd, 1H, Hx,
J =12.4, 6.1Hz ), 7.11–7.82 (m, 13H, Ar–Hs), 10.57 (s,
1H, NH, D2O exchangeable). MS m/z (%): 479 (M+ + 2,
4), 478 (M+ + 1, 2), 477 (M+, 15), 122 (38), 77 (23), 64
(100%). Anal. Calcd for C24H17ClFN5OS (477.94): C,
Statistical analysis.
The results are reported as
mean Æstandard error (SE) for at least four times
60.31; H, 3.59; N, 14.65. Found: C, 60.44; H, 3.68; N,
14.80%.
experiments.
2-[3,5-Di(4-fluorophenyl)-4,5-dihydropyrazol-1-yl]-5-[(4-chlorop
henyl)hydrazono]thiazol-4-one (17b).
Yellow crystals, mp
REFERENCES AND NOTES
199–200°C, yield (82%). IR (cmÀ1): 3356 (NH), 1709
(C=O), and 1574 (C=N). 1H NMR (d6-DMSO, δ ppm): 3.12
(dd, 1H, HA, J=17.6, 6.5 Hz), 3.93 (dd, 1H, HB, J=17.6,
12.2 Hz), 5.94 (dd, 1H, Hx, J=12.3, 6.4Hz), 7.09–8.02 (m,
12H, Ar–Hs), 10.53 (s, 1H, NH, D2O exchangeable). MS m/z
(%): 497 (M+ +2, 3), 496 (M+ +1, 2), 495 (M+, 10), 122
(100). Anal. Calcd for C24H16ClF2N5OS (495.93): C, 58.12;
H, 3.25; N, 14.12. Found: C, 58.29; H, 3.40; N, 14.26%.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet