Design, Synthesis, and Evaluation of Some Novel Heterocycles Bearing Pyrazole Moiety as Potential Anticancer Agents

Article abstract of DOI:10.1002/jhet.3544

1,3-Diphenylpyrazole-4-carboxylaldehyde and o-hydroxyacetophenone were exploited as starting materials for the synthesis of novel substituted chalconated pyrazole derivative. The proclivity of this compound towards carbon and nitrogen nucleophiles such as malononitrile, diethyl malonate, ethyl cyanoacetate, ethyl acetoacetate, semicarbazide, thiosemicarbazide, and hydroxylamine has been investigated. The structures of all synthesized compounds were ascertained by analytical and spectral data. The antitumor activity of the target synthesized compounds was tested against a panel of two human tumor cell lines, namely, hepatocellular carcinoma (liver) HepG2 and mammary gland breast MCF-7.

Full text of DOI:10.1002/jhet.3544

Month 2019
Design, Synthesis, and Evaluation of Some Novel Heterocycles Bearing
Pyrazole Moiety as Potential Anticancer Agents
Nancy Abdelgawad, Mahmoud F. Ismail, Mohamed H. Hekal,*
and Magda I. Marzouk
Chemistry Department, Faculty of Science, Ain Shams University, Abbassia, Cairo 11566, Egypt
*
E-mail: mohahekal2007@yahoo.com
Received November 9, 2018
DOI 10.1002/jhet.3544
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
1,3-Diphenylpyrazole-4-carboxylaldehyde and o-hydroxyacetophenone were exploited as starting mate-
rials for the synthesis of novel substituted chalconated pyrazole derivative. The proclivity of this compound
towards carbon and nitrogen nucleophiles such as malononitrile, diethyl malonate, ethyl cyanoacetate, ethyl
acetoacetate, semicarbazide, thiosemicarbazide, and hydroxylamine has been investigated. The structures of
all synthesized compounds were ascertained by analytical and spectral data. The antitumor activity of the tar-
get synthesized compounds was tested against a panel of two human tumor cell lines, namely, hepatocellular
carcinoma (liver) HepG2 and mammary gland breast MCF-7.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
central core for a variety of pharmacologically important
compounds. Their true importance may be explained in
two branches: the biological activity associated with them
and their synthetic utility for the preparation of
pharmacologically important heterocyclic derivatives.
Chalcones of various classes have been extensively
studied owing to their wide range of pharmacological
activities such as antileishmanial [18], antimalarial
[19,20], antifungal [21], invasive [22], antitrypanosomal
[23], antibacterial [24], anti-inflammatory [25], and
anticancer activity [26,27]. Chalcones are widely spread in
nature as in fruits, species, soy-based food stuff, vegetable,
In the last few decades, anticancer drugs have been
sophisticated from chemically synthesized compounds.
Recently,
a large number of interesting pyrazole
derivatives have been synthesized [1]. The pyrazole-
tethered heterocyclic compounds have received senior
attention owing to their diverse chemotherapeutic potential
[
2–4]. The important pyrazole-based drugs available in the
market are apixaban, celecoxib, deracoxib, tolpiprazole,
fipronil, lonazolac, remogliflozin etabonate, and many
more. Ruxolitinib and crizotinib are important pyrazole-
tethered anticancer drugs [5]. Some pyrazole-based drugs
are depicted in Figure 1. Pyrazole derivatives show
anticancer activity due to their inhibition of various targets
such as EGFR [6], IGF-1R [7], tubulin [8], B-raf [9,10],
mTOR [11], HDAC [12,13], ALK [14], topoisomerase II
0
and tea. Their 2 -hydroxy derivatives play an important
role in the flavonoid synthesis and biosynthesis as both
precursors and products [28].
[15], JAK2 [16], ROS 1 [17], among others. Hence,
RESULTS AND DISCUSSION
incorporation of the pyrazole moiety is an important
synthetic strategy in rational drug development process.
The chalcones are α,β-unsaturated ketones that acts as a
As a continuation of our efforts in respect of
synthesizing biologically active heterocyclic compounds
©
2019 Wiley Periodicals, Inc.

N. Abdelgawad, M. F. Ismail, M. H. Hekal, and M. I. Marzouk
Vol 000
Figure 1. Pyrazole-based drugs. [Color figure can be viewed at wileyonlinelibrary.com]
especially those with anticipated cytotoxic activity [29,30],
we aimed to synthesize new series of pyran, chromone, and
pyridine derivatives bearing pyrazole moiety in the hope
that new anticancer agents might be detected. The
spectrum that showed signals for OH, olefinic, and
aromatic protons. The higher coupling constant (J) for the
olefinic protons H and H is in a good agreement with
its existence as the E-configurated isomer (cf.
experimental section). Because chalcones are versatile
synthon for the preparation of five-membered and six-
membered ring systems [32], the proclivity of compound
a
b
substituted chalconated pyrazole derivative
synthesized by Claisen–Schmidt condensation reaction
31]. Thus, the reaction of o-hydroxyacetophenone with
,3-diphenylpyrazole-4-carboxylaldehyde in methanolic
potassium hydroxide at room temperature for 12 h
furnished (E)-3-(1,3-diphenyl-1H-pyrazol-4-yl)-1-(2-
hydroxyphenyl)prop-2-en-1-one (Scheme 1). The
1 was
[
1
1
with different carbon nucleophiles such as
malononitrile, diethyl malonate, ethyl cyanoacetate, and
ethyl acetoacetate has been investigated. Therefore, cyclic
condensation of 1 with malononitrile under different
reaction conditions afforded pyran and pyridine
derivatives 2–4 (Scheme 1).
1
structure of compound 1 was substantiated from the
complete analysis of IR and mass spectra beside the
correct analytical data. Further support for the suggested
Reaction of pyrazole derivative 1 with malononitrile in
refluxing methanol in the presence of sodium methoxide
1
structure of compound 1 was gained from its H NMR
Scheme 1
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Some Novel Heterocycles Bearing Pyrazole Moiety as Potential Anticancer
Agents
yielded pyran derivative 2. The structure of compound 2
was confirmed by complete analysis of IR, H NMR, and
mass spectra beside the correct elemental analysis. Thus,
conditions was also investigated as shown in Scheme 2.
Therefore, reaction of 1 with diethyl malonate in boiling
ethanol in the presence of ammonium acetate afforded the
1
1
the IR spectrum showed absorption bands for NH at
corresponding pyridinone derivative 5. Screening of H
2
ꢀ
1
ꢀ1
1
3
347, 3224 cm and CꢁN at 2214 cm . Moreover, H
NMR spectrum (DMSO-d ) of compound 5 revealed the
6
NMR spectrum of 2 (DMSO-d ) showed signals that is
presence of signals downfield for (NH) proton as a
6
consistent with the proposed structure at δ (ppm): 11.20
singlet at 12.62 ppm, (OH) proton as a singlet at
(
br s, 1H, OH, exchangeable with D O), 8.97 (s, C H
9.31 ppm, C -H of the pyrazole moiety as a singlet at
2
5
5
pyrazole), 7.97–7.15 (m, 14Harom.), 6.32 (s, 2H, NH2,
8.50 ppm, aromatic protons (15H) as a multiplet in the
region of δ 8.01–7.31 ppm besides the existence of
quartet signal at 4.32 ppm and triplet signal at 1.21 ppm
characteristic for ethyl protons of ester group that is
consistent with the structure 5.
exchangeable with D O), 5.31 (d, 1H, C H pyran), 3.91
2
5
(
d, 1H, C H pyran).
4
While refluxing the reaction mixture of 1 and
malononitrile in methanol in the presence of ammonium
acetate afforded the corresponding pyridine derivative 3.
In contrast, 4-(1,3-diphenyl-1H-pyrazol-4-yl)-6-(2-
hydroxyphenyl)-2H-pyran-2-one 6 was obtained as a sole
product in a fairly good yield upon treatment of
compound 1 with diethyl malonate in boiling ethanol in
the presence of catalytic amount of piperidine. The
formation of 6 could be postulated as follows (Scheme 3).
Refluxing of compound 1 with ethyl cyanoacetate in
boiling ethanol in the presence of a catalytic amount of
piperidine afforded on a hot crystalline product with the
molecular formula C H N O and not the pyrone
Studying the spectroscopic data of compound
3
confirmed its proposed structure. Thus, the IR spectrum
ꢀ
1
displayed broad νOH at 3404 cm with absorption band
ꢀ
1
ꢀ1
for NH at 3340, 3236 cm , υ
at 2214 cm and
2
CꢁN
ꢀ
1 1
υ
(
at 1649 cm . H NMR spectrum of compound 3
DMSO-d ) displayed singlet at δ (ppm) 13.35 integrated
C¼N
6
for one proton of OH that disappeared with D O, singlet
2
for one proton at δ 8.95 corresponding to C -H of the
5
pyrazole moiety, the deshielded aromatic protons (15H)
was shown downfield at δ 7.96–6.90 ppm as well as a
broad singlet at δ 7.15 ppm integrated for two protons of
NH that is exchangeable with D O. On the other hand,
21 17 3 2
derivative. The carbanion underwent nucleophilic
addition reaction to the double bond of compound 1 via
Michael type addition reaction to give a substance where
structure should be either compound 7 (route a) or
compound 8 (route b). The actual structure of the product
was assigned as compound 8 based on the spectroscopic
2
2
cyclic condensation of α-enone 1 with malononitrile in
refluxing methanol in the presence of catalytic amount of
piperidine produced 2-imino-2H-chromene derivative 4
1
(Scheme 1). Structure of the synthesized compound 4
data (Scheme 2). The H NMR spectrum of this product
was ascertained from its analytical and spectral data.
In this study, reaction of chalconated pyrazole derivative
revealed the absence of phenolic OH proton and the
presence of a triplet signal at 1.28 ppm and a quartet
signal at 4.30 ppm characteristic for ethyl protons of ester
1
with diethyl malonate under two different reaction
Scheme 2
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N. Abdelgawad, M. F. Ismail, M. H. Hekal, and M. I. Marzouk
Vol 000
Scheme 3
Scheme 4
group that ruled out the expected structure 7 and confirm
the structure 8. Moreover, the IR spectrum of this product
It was reported that the reaction of chalcone derivatives
with hydroxylamine, o-phenylenediamine, and/or
displayed the absorption bands for υ
(sharp band) at
CꢁN
ꢀ
1
ꢀ1
2220 cm and υ
(ester) at 1723 cm . Also, the
thiosemicarbazide yielded the corresponding oxazole,
pyrazole, and benzodiazepine derivatives, respectively.
Thus, when compound 1 was subjected to react with
hydroxylamine in boiling acetic acid in the presence of
fused sodium acetate afforded the unexpected compound
that identified as 1,3-diphenyl-1H-pyrazole-4-carbonitrile 12
[33] rather than 11. The spectroscopic data are in good
agreement with the proposed structure. Thus, the
C¼O
highest recorded peak in the mass spectrum at m/z = 343
attributable for the correct molecular ion peak for
molecular formula C H N O . Furthermore, the strong
2
1 17 3 2
evidence for the structure 8 is forthcoming from authentic
sample prepared from the reaction of 1,3-
diphenylpyrazole-4-carboxylaldehyde
with
ethyl
cyanoacetate in boiling ethanol in the presence of a
catalytic amount of piperidine (TLC, mp, and IR
comparison).
Treatment of 1 with ethyl acetoacetate in boiling
ethanol with few drops of piperidine afforded an
ꢀ
1
appearances of a sharp absorption band at 2224 cm for
CN in the IR spectrum confirms the unexpected structure of
compound 12. The conversion of compounds 1 to 12 could
be explained according the following mechanism (Scheme 5).
The reaction of α-enone 1 with o-phenylenediamine in
boiling ethanol furnished the unexpected product 2-(1,3-
unexpected
product
with
molecular
formula
C H N O (M = 476) that was identified as ethyl
3
2
28
2
4
r
0
5
-(1,3-diphenyl-1H-pyrazol-4-yl)-2 -hydroxy-3-oxo-3,4-
dihydro-[1,1 -biphenyl]-4-carboxylate 9. Furthermore, the
strong clue for this structure is forthcoming from H NMR
diphenyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole
13
0
1
Scheme 5
spectrum that completely accord with the assigned
structure 9 and ruled out 10 as shown in Figure 2.
As
a precursor to construct more heterocyclic
compounds incorporating pyrazole moiety, compound 1
was allowed to react with different nitrogen nucleophiles,
namely, hydroxylamine, o-phenylenediamine, and
semicarbazide hydrochloride as shown in Scheme 4.
1
Figure 2. H NMR spectrum of compound 9.
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Month 2019
Some Novel Heterocycles Bearing Pyrazole Moiety as Potential Anticancer
Agents
1
instead of benzodiazepine derivative 14. The spectroscopic
data are in accordance with the assigned structure (cf.
experimental section). On the other hand, treatment of 1
with semicarbazide hydrochloride in the presence of
fused sodium acetate in refluxing acetic acid gave
pyrazole derivative 15 (Scheme 4). Formation of 15 can
be explained via Michael addition reaction of α,β-
unsaturated carbonyl, cyclization followed by acylation
base 19 rather than 20 as shown in Scheme 6. The H
NMR spectrum of compound 19 revealed the presence of
signals downfield for (NH) proton as a singlet at
11.33 ppm, C -H of the pyrazole moiety as a singlet at
5
9.18 ppm, (CH¼) proton as a singlet at 8.22 ppm,
aromatic protons (10H) as a multiplet in the region of
7.91–7.36 ppm and (NH ) protons as a broad singlet at
7.69 ppm that ruled out the expected structure 20 and
confirm the structure 19. Moreover, the IR spectrum of
2
ꢀ
1
[
34]. The IR spectrum of 15 exhibited ν at 3177 cm
NH
ꢀ
1
1
and νCO at 1676 cm . Moreover, H NMR and mass
spectra were in consistent with the assigned structure.
Meanwhile, reaction of 1 with thiosemicarbazide in
boiling dioxane also yielded the unexpected product with
molecular formula C H N O that was identified as
this product showed the absorption bands for NH at
2
ꢀ
1
ꢀ1
3330, 3257 cm , NH at 3159 cm , and C¼N at
ꢀ
1
1618 cm . Furthermore, the ample evidence for the
structure 19 is forthcoming from authentic sample
prepared from the reaction of 1,3-diphenylpyrazole-4-
carboxylaldehyde with thiosemicarbazide in boiling
dioxane (TLC, mp, and IR comparison).
3
2 28 2 4
2-(1,3-diphenyl-1H-pyrazol-4-yl)chroman-4-one
16
(Scheme 6) that obtained via intramolecular addition of
phenolic OH group on β-carbon of α,β-unsaturated
carbonyl group. Furthermore, IR and H NMR spectra
are completely matched with the assigned structure 16
and lack of 17 (cf. experimental section).
Protection of phenolic OH group via alkylation of the
Cytotoxicity and antitumor evaluation.
In vitro
1
cytotoxicity of all the synthesized compounds was
determined by the MTT [(3-(4,5-dimethyl-2-thiazolyl)
2,5-diphenyl-2H-tetrazolium bromide)] assay against a
panel of two different human cancer cell lines, namely,
MCF-7 (human breast) and hepatocellular carcinoma
(HePG-2). From the IC50 values that represent the
compounds concentrations required to produce a 50%
inhibition of cell growth after 72 h of incubation,
compared with untreated controls (Table 1). All the tested
compounds showed cytotoxic activity ranged from very
strong to weak activity. As for the activity against
hepatocellular carcinoma (HePG-2), the highest cytotoxic
activity was displayed by compounds 3, 9, and 16
that showed IC50 8.96 ± 0.7, 6.93 ± 0.5, and
10.27 ± 1.0 μM/mL, respectively. Remarkably strong
inhibitory activity was also seen for compounds 2 and
chalconated pyrazole
1
with ethyl iodide in
dimethylformamide in the presence of anhydrous
potassium carbonate yielded the O-alkylated product 18
(Scheme 6). The structure of compound 18 was
confirmed from the analytical and spectroscopic data. The
1
H NMR spectrum of 18 is in accordance with the
suggested structure as it revealed the absence of phenolic
proton and showed signals corresponding to ethyl,
olefinic, and aromatic protons (cf. experimental section).
Another attempt to construct pyrazole derivative through
reaction of compound 18 with thiosemicarbazide in boiling
dioxane was not successful because it afforded Schiff-like
Scheme 6
Journal of Heterocyclic Chemistry
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N. Abdelgawad, M. F. Ismail, M. H. Hekal, and M. I. Marzouk
Vol 000
Table 1
•
Compound 2 showed very strong activity against MCF-7
Cytotoxicity (IC50) of the tested compounds on different cell lines.
and strong activity against HePG-2; this is due to the
presence of NH group available to form hydrogen bond
with either one of the nucleobases of the DNA and
causes it damage.
• Compound 9 showed very strong activity against MCF-7
and HePG-2 due to the introduction of cyclohexa-2,4-
dien-1-one ring and ester groups.
2
In vitro cytotoxicity IC50 (μM)•
Compound
HePG2
56.97 ± 3.2
MCF-7
1
2
3
4
5
6
8
9
61.91 ± 3.8
5.87 ± 0.4
11.82 ± 1.2
79.62 ± 4.3
19.28 ± 1.7
22.62 ± 1.9
29.95 ± 2.5
7.38 ± 0.7
68.34 ± 4.0
34.06 ± 2.9
15.17 ± 1.4
4.17 ± 0.2
18.23 ± 1.6
8.96 ± 0.7
94.83 ± 5.2
27.46 ± 2.1
31.50 ± 2.4
21.78 ± 1.8
6.93 ± 0.5
75.31 ± 4.1
42.11 ± 2.9
10.27 ± 1.0
4.50 ± 0.3
•
•
•
Compound 3 showed very strong activity against HePG-
2 and strong activity against MCF-7 due to the presence
of CN, OH, and NH groups.
2
Compound 16 showed strong activity against both MCF-
1
1
1
2
5
6
7
and HePG-2; this is due to the presence of chromanone
and pyrazole rings.
DOX
Compound 5 showed strong activity against MCF-7; this
is due to the presence of OH and NH and also the for-
mation of intramolecular hydrogen bond between the
ester group and the NH group of the DNA that increases
its lipophilicity.
IC50 (μg/mL): 1–10 (very strong), 11–20 (strong), 21–50 (moderate), 51–
00 (weak), above 100 (non-cytotoxic). DOX, doxorubicin
1
1
6. Also, compounds 5, 6, 8, and 15 showed moderate
activity, and compounds 1, 4, and 12 had weak activity.
As for the activity against mammary gland (breast)
MCF-7 cell line, compound 2 showed very strong
activity with IC50 5.87 ± 0.4 μM/mL, while compounds
EXPERIMENTAL
Chemistry. All melting points were taken on a Griffin
and Geory melting point apparatus and are uncorrected. IR
spectra were recorded on Pye Unicam SP1200
spectrophotometer using the KBr wafer technique.
NMR experiments were run at 300 on a Varian Mercury
VX-300 NMR spectrometer using tetramethylsilane as
internal standard in dimethyl sulfoxide (DMSO-d6).
Chemical shifts are quoted as δ. EI–MS were measured
on a Schimadzu GC–MS operating at 70 eV. Elemental
analyses were carried out at the Microanalytical Unit,
Faculty of Science, Ain Shams University, using a
Perkin-Elmer 2400 CHN elemental analyzer, and
satisfactory analytical data (±0.4) were obtained for all
3, 5, and 16 showed strong activity towards with IC50
11.82 ± 1.2, 19.28 ± 1.7, and 15.17 ± 1.4 μM/mL,
respectively. On the other hand, compounds 6, 8, and 15
showed moderate activity, while compounds 1, 4, and 12
showed weak activity as shown in Figure 3.
1
H
Structure–activity relationship.
By comparing the
experimental cytotoxicity of the compounds reported in
this study to their structures, the following structure–
activity relationship was postulated.
•
All the tested compounds showed cytotoxic activity
ranged from very strong to weak activity; this is due to
the presence of pyrazole ring.
Figure 3. Cytotoxic activity of the tested compounds on different cell lines. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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Some Novel Heterocycles Bearing Pyrazole Moiety as Potential Anticancer
Agents
compounds. The homogeneity of the synthesized
compounds was controlled by thin layer chromatography
using aluminum sheet silica gel F254 (Merck). The
pharmacological activity assays were carried out at
Pharmacology Department, Faculty of Pharmacy, El-
Mansoura University, El-Mansoura, Egypt.
(E)-4-(2-(1,3-Diphenyl-1H-pyrazol-4-yl)vinyl)-2-imino-2H-
chromene-3-carbonitrile (4).
1
A mixture of 1 (1 g,
0 mmol) and malononitrile (0.18 g, 10 mmol) in
methanol (20 mL) in the presence of catalytic amount of
piperidine was refluxed for 8 h. The reaction mixture was
poured onto ice and acidified with dilute acetic acid. The
precipitated solid was filtered off, washed several times
with cooled water, and then recrystallized from ethanol to
give 4 as yellow crystals; mp 274–276°C, yield: 36%. IR
(
E)-3-(1,3-Diphenyl-1H-pyrazol-4-yl)-1-(2-hydroxyphenyl)
prop-2-en-1-one (1). A mixture of 1,3-diphenylpyrazole-
-carboxylaldehyde (1 g, 10 mmol) and o-
4
ꢀ
1
1
hydroxyacetophenone (0.55 g, 10 mmol) was stirred in
absolute methanol (20 mL) in the presence of potassium
hydroxide (50%) for 12 h. The precipitated solid was
filtered off, washed several times with cooled water,
dried, and then recrystallized from benzene to give 1 as
(
ν/cm ): 3163 (NH), 2203 (CꢁN), 1636 (C¼N).
H
NMR (DMSO-d ) δ (ppm): 7.1–8.12 (m, 14H
+ 1H,
arom.
6
NH), 7.55 (d, 1H, H , J = 16.4), 8.68 (d, 1H, H ,
a
b
J = 17.1), 9.22 (s, 1H, C -Hpyrazole). MS m/z (%): 415
5
+.
(M + 1, 23). Anal. Calcd for C H N O (414.47): C,
27 18 4
ꢀ
1
yellow crystals; mp 170–172°C, yield: 95%. IR (ν/cm ):
78.24; H, 4.38; N, 13.52. Found: C, 78.11; H, 4.27; N,
1
br 3443 (OH), 1672 (C¼O), 1636 (C¼N). H NMR
1
3.64.
(
DMSO-d ) δ (ppm): 6.99–7.98 (m, 14H
), 7.80 (d,
arom.
Ethyl 4-(1,3-diphenyl-1H-pyrazol-4-yl)-6-(2-hydroxyphenyl)-
6
2
-oxo-1,2-dihydropyridine-3-carboxylate (5). A mixture of
1
H, H , J = 15.3), 8.35 (d, 1H, H , J = 14.4), 9.46 (s,
a
b
1
H, C -H
), 12.57 (br s, 1H, OH, exchangeable
1 (1 g, 10 mmol), diethylmalonate (0.44 g, 10 mmol),
and ammonium acetate (0.5 g) in absolute ethanol
5
pyrazole
+
.
with D O). MS m/z (%): 366 (M , 54). Anal. Calcd for
2
(20 mL) was refluxed for 10 h. The reaction mixture was
C H N O (366.42): C, 78.67; H, 4.95; N, 7.65. Found:
2
4 18 2 2
C, 78.31; H, 5.22; N, 7.52.
poured onto ice and acidified with dilute acetic acid. The
precipitated solid was filtered off, washed several times
with cooled water, and then recrystallized benzene to
give 5 as yellow crystals; mp 180–182°C, yield: 62%, IR
2
-Amino-4-(1,3-diphenyl-1H-pyrazol-4-yl)-6-(2-
hydroxyphenyl)-4H-pyran-3-carbonitrile (2). A mixture of 1
1 g, 10 mmol), malononitrile (0.18 g, 10 mmol) in
methanol (20 mL), and sodium methoxide (0.5 g Na in
0 mL methanol) was refluxed for 8 h. The reaction
(
ꢀ
1
(ν/cm ): 3400 (OH), 3149 (NH), 1720 (C¼Oester), 1674
1
lactam 6
3
(C¼O
). H NMR (DMSO-d ) δ (ppm): 1.23 (t, 3H,
mixture was poured onto ice and acidified with dilute
acetic acid. The precipitated solid was filtered off,
washed several times with cooled water, and then
recrystallized from toluene to give 2 as brown crystals;
CH CH ), 4.32 (q, 2H, CH CH ), 7.31–8.50 (m,
2
3
2
3
15Harom.), 9.31 (s, 1H, C Hpyrazole), 9.99 (br s, 1H, NH,
5
exchangeable with D O), 12.60 (s, 1H, OH,
2
+.
exchangeable with D O). MS m/z (%): 478 (M + 1, 12).
2
ꢀ
1
mp 125–127°C, yield: 73%, IR (ν/cm ): 3347, 3224
Anal. Calcd for C H N O (477.52): C, 72.94; H, 4.86;
29 23 3 4
1
(
NH ), 2214 (CꢁN). H NMR (DMSO-d ) δ (ppm): 3.91
N, 8.80. Found: C, 72.87; H, 4.89; N, 8.79.
4-(1,3-Diphenyl-1H-pyrazol-4-yl)-6-(2-hydroxyphenyl)-2H-
2
6
(d, 1H, C H
), 5.31 (d, 1H, C H ), 6.32 (br s, 2H,
5 pyran
4
pyran
NH , exchangeable with D O), 7.15–7.97 (m, 14Harom.),
pyran-2-one (6).
A mixture of 1 (1 g, 10 mmol) and
2
2
diethylmalonate (0.44 g, 10 mmol) in absolute ethanol
(20 mL) in the presence of catalytic amount of piperidine
was refluxed for 8 h. The reaction mixture was poured
onto ice and acidified with dilute acetic acid. The
precipitated solid was filtered off, washed several times
with cooled water, and then recrystallized from ethanol to
give 6 as buff crystals; mp 275–277°C, yield: 58%. IR
8
.97 (s, 1H, C H
), 11.20 (br s, 1H, OH,
pyrazole
5
+
.
exchangeable with D O). MS m/z (%): 430 (M ꢀ2, 40).
2
Anal. Calcd for C H N O (432.48): C, 74.98; H, 4.66;
27 20 4 2
N, 12.95. Found: C, 75.03; H, 4.75; N, 13.11.
2
-Amino-4-(1,3-diphenyl-1H-pyrazol-4-yl)-6-(2-
hydroxyphenyl)nicotinonitrile (3).
A mixture of 1 (1 g,
0 mmol) and malononitrile (0.18 g, 10 mmol) in
methanol (20 mL) in the presence of ammonium acetate
0.7 g, 10 mmol) was refluxed for 10 h. The precipitated
1
ꢀ
1
1
(
δ
ν/cm ): 3451 (OH), 1662 (C¼O). H NMR (DMSO-d )
6
(
(ppm): 7.28–8.12 (m, 16H
), 8.34 (s, 1H,
arom.
solid was filtered off, washed several times with cooled
water, dried, and then recrystallized from dioxane to give
3
C H
), 9.60 (br s, 1H, OH, exchangeable with
pyrazole
5
+.
D O). MS m/z (%): 404 (M ꢀ2, 10). Anal. Calcd for
2
as buff crystals; mp 315–317°C, yield: 75%. IR (ν/
C H N O (406.44): C, 76.83; H, 4.46; N, 6.89. Found:
26 18 2 3
ꢀ
1
cm ): br 3404 (OH), 3340, 3236 (NH ), 2214 (CꢁN),
C, 76.79; H, 4.50; N, 6.92.
Ethyl (Z)-2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acrylate
2
1
1
649 (C¼N). H NMR (DMSO-d ) δ (ppm): 6.90–7.96
6
(m, 15H
), 7.15 (br s, 2H, NH , exchangeable with
(8).
A mixture of 1 (1 g, 10 mmol) and ethyl
arom.
2
D O), 8.95 (s, 1H, C -H ), 13.35 (br s, 1H, OH,
pyrazole
cyanoacetate (0.31 g, 10 mmol) in ethanol (20 mL) in the
presence of catalytic amount of piperidine was refluxed
for 10 h. The white solid that separated on hot was dried
and then recrystallized from petroleum 60–80°C to give 8
2
5
+
.
exchangeable with D O). MS m/z (%): 429 (M , 100).
2
Anal. Calcd for C H N O (429.48): C, 75.51; H, 4.46;
2
7 19 5
N, 16.31. Found: C, 75.21; H, 4.27; N, 16.65.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Abdelgawad, M. F. Ismail, M. H. Hekal, and M. I. Marzouk
Vol 000
ꢀ
1
as white crystals; mp 130–132°C, yield: 33%. IR (ν/cm ):
10 mmol) in acetic acid (20 mL) in the presence of fused
sodium acetate (1 g) was heated under reflux for 7 h. The
solid product that deposited was collected by filtration,
washed with cold water, dried, and then recrystallized
from toluene to give 15 as yellow crystals; mp 177–
1
1
723 (C¼O), 2220 (CꢁN). H NMR (DMSO-d ) δ (ppm):
6
1
.28 (t, 3H, CH CH ), 4.28 (q, 2H, CH CH ), 7.57–7.95
2
3
2
3
(
m, 10Harom.), 8.13 (s, 1H, CH
), 9.20 (s, 1H,
olefinic
). MS m/z (%): 343 (M , 15). Anal. Calcd for
+
.
C H
5
pyrazole
ꢀ
1
C H N O (343): C, 73.45; H, 4.99; N, 12.24. Found:
179°C, yield 75%. IR (ν/cm ): 3177 (NH), 2979 (CH
3
),
2
1 17 3 2
1
br 1676 (C¼O). H NMR (DMSO-d ) δ (ppm): 2.12 (s,
C, 73.52; H, 5.03; N, 12.36.
6
0
3
H, COCH ), 7.34–8.22 (m, 15H
), 8.89 (s, 1H,
arom.
Ethyl
5-(1,3-diphenyl-1H-pyrazol-4-yl)-2 -hydroxy-3-oxo-
,4-dihydro-[1,1 -biphenyl]-4-carboxylate (9). A mixture of
3
0
3
C Hpyrazole), 10.99 (br s, 1H, NH, exchangeable with
5
1
(1 g, 10 mmol) and ethyl acetoacetate (0.35 mL,
D O), 11.17 (br s, 1H, OH, exchangeable with D O). MS
2
2
+.ꢀ
10 mmol) in absolute ethanol (20 mL) in the presence
m/z (%): 462 (M 1, 30). Anal. Calcd for C H N O
27 21 5 3
of catalytic amount of piperidine was refluxed for 8 h.
The buff solid that separated after slow evaporation of
the solvent was dried and then recrystallized from
ethanol to give 9 as buff crystals; mp 253–255°C,
(463.50): C, 69.97; H, 4.57; N, 15.11. Found: C, 70.01;
H, 4.61; N, 15.25.
2
-(1,3-Diphenyl-1H-pyrazol-4-yl)chroman-4-one (16).
A
mixture of 1 (1 g, 10 mmol) and thiosemicarbazide (0.3 g,
0 mmol) in dioxane was heated under reflux for 6 h. The
ꢀ
1
1
yield: 78%, IR (ν/cm ): br 3441 (OH), 2918, 2849
CH , CH ), 1731 (C¼O ), 1657 (C¼O
solid product that deposited was collected by filtration,
washed with cold water, dried, and then recrystallized
from petroleum 60–80°C to give 16 as brown crystals; mp
(
3
2
ester
cyclohex-2,4-
1
).
H NMR (DMSO-d ) δ (ppm): 1.08 (t, 3H,
6
dienone
CH CH ), 4.17 (q, 2H, CH CH ), 3.84 (s, 1H,
2
3
2
3
ꢀ
1
1
82–184°C, yield 81%. IR (ν/cm ): 2920, 2850 (CH2,
C H
2
), 6.28 (s, 1H, C Hcyclohex-2,4-dienone),
6
cyclohex-2,4-dienone
1
CH), 1681 (C¼O). H NMR (DMSO-d ) δ (ppm): 2.98 (d,
6
.37 (s, 1H, C Hcyclohex-2,4-dienone), 6.83–8.47 (m,
6
4
1
H, H , J = 11.4 Hz), 3.44 (dd, 1H, H , J = 13.2 Hz), 5.75
a b
1
5Harom.), 12.40 (br s, 1H, OH, exchangeable with
+
.
(
1
d, 1H, H , J = 10.5 Hz), 7.06–7.94 (m, 14Harom.), 8.86 (s,
H, C Hpyrazole). MS m/z (%): 338 (M + 2, 5). Anal.
5
D O). MS m/z (%): 476 (M , 22). Anal. Calcd for
c
2
+.
C H N O (476.53): C, 75.62; H, 5.08; N, 5.88.
3
0 24 2 4
Calcd for C H N O (336.42): C, 78.67; H, 4.95; N,
Found: C, 75.83; H, 5.11; N, 5.97.
,3-Diphenyl-1H-pyrazole-4-carbonitrile (12). A mixture
of 1 (1 g, 10 mmol) and hydroxylamine hydrochloride
0.69 g, 10 mmol) in acetic acid (20 mL) in the presence
24 18 2 2
1
7.65. Found: C, 78.62; H, 4.97; N, 7.73.
(
E)-3-(1,3-Diphenyl-1H-pyrazol-4-yl)-1-(2-ethoxyphenyl)
prop-2-en-1-one (18). A mixture of 1 (1 g, 10 mmol) and
ethyl iodide (0.4 g, 10 mmol) in dimethylformamide
(
of fused sodium acetate (0.5 g) was heated under reflux
for 6 h. The solid product that deposited was collected by
filtration, washed with cold water, dried, and then
recrystallized from petroleum 60–80°C to give 12 as
(20 mL) in the presence of anhydrous potassium
carbonate (1 g) was stirred in an ice bath for 15 h. The
solid product that deposited was collected by filtration,
washed with cold water, dried, and then recrystallized
from petroleum 60–80°C to give 18 as buff crystals; mp
ꢀ
1
yellow crystals; mp 120–122°C, yield 81%. IR (ν/cm ):
1
2
224 (CꢁN), 1597 (C¼N). H NMR (DMSO-d ) δ
6
ꢀ
1
9
CH
(
0–92°C, yield 63%. IR (ν/cm ): 2972, 2866 (CH2,
(ppm): 7.42–8.00 (m, 10H
), 9.43 (s, 1H, C Hpyrazole).
arom. 5
MS m/z (%): 247 (M + 2, 34). Anal. Calcd for
1
+
.
3
), 1672 (C¼O). H NMR (DMSO-d
) δ (ppm): 1.28
6
t, 3H, CH CH ), 4.10 (q, 2H, CH CH ), 7.33–8.00 (m,
2
3
2
3
C H N (245.29): C, 78.35; H, 4.52; N, 17.13. Found:
1
6 11 3
1
4Harom. + 2H
), 9.22 (s, 1H, C Hpyrazole). MS m/z
olefinic 5
C, 78.45; H, 4.57; N, 17.26.
+.
(%): 394 (M , 12). Anal. Calcd for C H N O
2
-(1,3-Diphenyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole
26 22 2 2
(
13).
A mixture of 1 (1 g, 10 mmol) and o-
(394.47); C, 79.17; H, 5.62; N, 7.10. Found: C, 79.26; H,
5.84; N, 7.15.
phenylenediamine (0.3 mL, 10 mmol) in ethanol was
heated under reflux for 8 h. The solid product that
deposited was collected by filtration, washed with cold
water, dried, and then recrystallized from toluene to give
1
(
(
E)-2-((1,3-Diphenyl-1H-pyrazol-4-yl)methylene)hydrazine-
-carbothioamide (19). A mixture of 18 (3.9 g, 10 mmol)
and thiosemicarbazide (0.9 g, 10 mmol) in dioxane
30 mL) was heated under reflux for 5 h. The solid
1
(
3 as pale yellow crystals; mp 270–272°C, yield 67%. IR
ꢀ
1
1
product that deposited was collected by filtration, washed
with cold water, dried, and then recrystallized from
ethanol to give 19 as yellow crystals; mp 224–226°C,
ν/cm ): 3130 (NH), 1528 (C¼N). H NMR (DMSO-d )
6
δ
C H
(ppm): 7.19–8.00 (m, 14H
), 9.09 (s, 1H,
arom.
), 12.60 (br s, 1H, NH, exchangeable with
pyrazole
5
ꢀ
1
+
.
yield 53%. IR (ν/cm ): 3330, 3257, 3159 (NH , NH),
2
D O). MS m/z (%): 336 (M , 17). Anal. Calcd for
C H N (336.40): C, 78.55; H, 4.79; N, 16.66. Found:
C, 78.52; H, 4.83; N, 16.57.
N-Acetyl-5-(2-hydroxyphenyl)-1 ,3 -diphenyl-1H,1’H-[3,4 -
bipyrazole]-1-carboxamide (15).
2
1
1
618 (C¼N). H NMR (DMSO-d ) δ (ppm): 7.36–7.91
6
2
2 16 4
(m, 10H
), 7.69 (br s, 2H, NH , exchangeable with
arom. 2
0
0
0
D O), 8.22 (s, 1H, CH¼), 9.18 (s, 1H, C Hpyrazole), 11.33
2
5
A mixture of 1 (1 g,
0 mmol) and semicarbazide hydrochloride (0.4 g,
(br s, 1H, NH, exchangeable with D
322 (M + 1, 25). Anal. Calcd for C17H N S (321.40):
15 5
2
O). MS m/z (%):
+.
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Some Novel Heterocycles Bearing Pyrazole Moiety as Potential Anticancer
Agents
C, 63.53; H, 4.70; N, 21.79; S, 9.98. Found: C, 63.64; H,
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Cytotoxicity assay.
The cytotoxic activity of 11
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fetal bovine serum. Antibiotics added were 100 units/mL
penicillin and 100 μg/mL streptomycin at 37°C in a 5%
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2
[
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[
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6
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet