Molecular modeling and synthesis of new 1,5-diphenylpyrazoles as breast cancer cell growth inhibitors

Article abstract of DOI:10.1515/hc-2015-0156

New pyrazoles have been synthesized and evaluated as breast cancer cell growth inhibitors. Condensation of the substituted pyrazole-4-carbaldehyde 1 with acetophenone and chloroacetophenone afforded α, β-unsaturated ketones 2 and 3, respectively. Compounds 2 and 3 were subjected to different reactions using hydrazine hydrate, substituted hydrazine hydrate, hydroxylamine, o-phenylenediamine, malononitrile under different conditions affording 4-substituted pyrazole derivatives 4-28. Structure elucidation of these compounds was conducted using IR, ¹H NMR, ¹³C NMR, mass spectral data and elemental analysis. Antitumor activity of target compounds was tested against MCF-7 cell line (human breast cancer). Compounds 4, 10 and 20 show significant antitumor activity against breast cancer. Docking was performed with protein 1UYK to study the binding mode of the designed compounds.

Full text of DOI:10.1515/hc-2015-0156

Heterocycl. Commun. 2015; aop
Wafaa A. Ewes*, Sahar M.I. Badr, Hassan M. Eisa and Magda N.A. Nasr
Molecular modeling and synthesis of new
1,5-diphenylpyrazoles as breast cancer cell
growth inhibitors
DOI 10.1515/hc-2015-0156
A literature survey has revealed the importance of
pyrazole derivatives as potent anticancer agents [10–16]
including celecoxib (I in Figure 1) that is used in treatment
of breast cancer [17–24]. A variety of 1,5-diphenylpyrazole
derivatives (Figure 1) have been synthesized and their
cytotoxic properties evaluated [25–27]. Chalcone deriva-
tives (Figure 2) exhibit significant biological properties
Received July 24, 2015; accepted September 19, 2015
Abstract: New pyrazoles have been synthesized and
evaluated as breast cancer cell growth inhibitors. Con-
densation of the substituted pyrazole-4-carbaldehyde 1
with acetophenone and chloroacetophenone afforded α,
β-unsaturated ketones 2 and 3, respectively. Compounds 2
and 3 were subjected to different reactions using hydrazine
hydrate, substituted hydrazine hydrate, hydroxylamine,
o-phenylenediamine, malononitrile under different con-
ditions affording 4-substituted pyrazole derivatives 4–28.
Structure elucidation of these compounds was conducted
using IR, 1H NMR, 13C NMR, mass spectral data and elemental
analysis. Antitumor activity of target compounds was tested
against MCF-7 cell line (human breast cancer). Compounds
4, 10 and 20 show significant antitumor activity against
breast cancer. Docking was performed with protein 1UYK to
study the binding mode of the designed compounds.
CF3
CONHNH2
NC
N
N
N
N
Me
SO2NH2
I
II
Me
N
N
NC
N
N
HOOC
N
N
N
N
Keywords: anticancer; chalcone; pyrazole; pyridine.
Cl
SO2Me
III
IV
Introduction
Figure 1ꢀ1,5-Diphenylpyrazole derivatives I–IV as anticancer agents.
Breast cancer is the most popular malignancy and the
leading cause of death in women worldwide [1]. It has been
shown that inhibition of the enzyme aromatase is one of
the mechanisms of the most antitumor drugs especially in
the treatment of breast cancer [2–4]. Heat shock proteins
(HSP) are members of the molecular chaperones which
play an important role in the folding of a large number of
cellular proteins [5, 6]. The proliferative activity of breast
cancer cells leads to elevated HSP-90 expression [7, 8].
It has been found that the levels of HSP-90 decreased in
patients with clinical and biological response to aro-
matase inhibitors therapy [9].
O
N
N
O
N
MeO
N
H
OMe
MeO
V
VI
Cl
Me
MeO
O
O
N
*Corresponding author: Wafaa A. Ewes, Faculty of Pharmacy,
Department of Pharmaceutical Organic Chemistry, University of
Mansoura, Mansoura 35516, Egypt, e-mail: wafaa.ewes@yahoo.com
Sahar M.I. Badr, Hassan M. Eisa and Magda N.A. Nasr: Faculty
of Pharmacy, Department of Pharmaceutical Organic Chemistry,
University of Mansoura, Mansoura 35516, Egypt
OMe
N
Cl
O
VII
VIII
Figure 2ꢀChalcone derivatives V–VIII with known anticancer activity.
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ꢀꢀꢀꢁ
2ꢀ ꢀW.A. Ewes et al.: 1,5-Diphenylpyrazoles as breast cancer cell growth inhibitors
including antiproliferative activities [28–32]. It has been
reported that many heterocyclic compounds have a sig-
Results and discussion
nificant antitumor activity when linked to the pyrazole Chemistry
system [33–40].
Inspired by these finding, and in order to develop The synthetic pathways adopted for the preparation of the
new anticancer therapeutic agents, we were encouraged target new compounds are illustrated in Schemes 1 and 2.
to integrate a 1,5-diphenylpyrazole moiety as a main scaf- The starting material 1 was obtained via Vilsmeir Haack’s
fold with a chalcone moiety to form new hybrid molecules formylation using POCl3 [44, 45]. The α, β-unsaturated
[41–43].
carbonyl derivatives 2 and 3 were synthesized via
R
Me
N
O
N
b
N
N
4: R = H
5: R = Cl
R
Me
N
N
R
N
R′
c
N
Me
Me
N
OHC
O
N
N
a
N
6: R = H; R′= H
7: R = Cl; R′= H
8: R = Cl; R′= Ph
R
1
2: R = H
3: R = Cl
d
Me
N
O
N
N
9: R = H
10: R = Cl
e
NH
N
Me
N
N
R
11: R = H
12: R = Cl
Scheme 1ꢀThe synthesis of 3–12: (a) acetophenone or 4-chloroacetophenone, NaOH, absolute ethanol; (b) NH2NH2, AcOH; (c) R′-NHNH2,
absolute ethanol; (d) NH2OH·HCl, KOH; (e) o-phenylenediamine, Et3N, absolute ethanol.
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ꢂ3
W.A. Ewes et al.: 1,5-Diphenylpyrazoles as breast cancer cell growth inhibitorsꢂ
NH2
CN
N
Me
a
N
13: R = H
14: R = Cl
N
R
R
NH2
Me
CN
O
Me
O
N
N
b
15: R = H
16: R = Cl
N
N
R
2: R = H
3: R = Cl
OR'
CN
17: R = H; R′ = Me
18: R = H; R′ = Et
19: R = H; R′ = nPr
20: R = Cl; R′ = Me
21: R = Cl; R′ = Et
22: R = Cl; R′ = nPr
N
Me
c
N
N
R
Scheme 2ꢀThe synthesis of 13–22: (a) malononitrile, ammonium acetate, absolute ethanol; (b) malononitrile, DMF, pyridine; (c) malononi-
trile, sodium methoxide or sodium ethoxide or sodium propoxide, methanol, ethanol and n-propanol.
Table 1ꢀMolecular modeling results of 3–20 with amino acids of the enzyme 1UYK and their biological screening results against breast
cancer cell line (MCF-7).
Comp. no.ꢁ
Ec of interactionꢁ
ligand-protein
% inhibitionꢁ
IC 50b, μg/mLꢁ
Comp. no.ꢁ
Ec of interactionꢁ
ligand-protein
% inhibitionꢁ
IC 50b, μg/mL
3
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
-40.264ꢃ
-34.761ꢃ
-37.322ꢃ
-30.629ꢃ
-35.633ꢃ
-32.328ꢃ
-33.727ꢃ
-39.095ꢃ
-29.938ꢃ
-35.397ꢃ
33.982ꢃ
78.174aꢃ
30.857ꢃ
25.53ꢃ
ꢃ
13ꢃ
14ꢃ
15ꢃ
16ꢃ
17ꢃ
18ꢃ
19ꢃ
20ꢃ
21ꢃ
22ꢃ
-31.271ꢃ
-29.997ꢃ
-42.784ꢃ
-33.386ꢃ
-30.134ꢃ
-29.425ꢃ
-29.530ꢃ
-30.324ꢃ
-29.072ꢃ
-36.324ꢃ
55.288ꢃ
54.672ꢃ
48.686ꢃ
40.597ꢃ
43.615ꢃ
37.013ꢃ
25.861ꢃ
66.437aꢃ
41.855ꢃ
35.488ꢃ
4
11.7ꢃ
5
ꢃ
6
ꢃ
7
67.877aꢃ
56.28ꢃ
25.9ꢃ
8
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
9
16.848ꢃ
50.244ꢃ
58.489ꢃ
38.773ꢃ
10
11
12
29.5
aCompounds showing significant antitumor activity; bIC50 for active antitumor compounds; cenergy (kJ/mol).
Claisen-Schmidt condensation [46, 47] of compound 1 7 shows an exchangeable signal at 7.63 ppm for NH group.
with a ketone (Scheme 1). The IR spectrum of 3 reveals a The mass spectrum of compound 8 shows a molecu-
Cꢀ=ꢀO band of carbonyl group at 1658 cm-1. The reaction of lar ion peak at m/z 489 corresponding to the molecular
+
compounds 2 and 3 with hydrazine hydrate in the presence formula C31H25ClN4 and a peak at 490 (M +2) due to the
of acetic acid yielded N-acetylpyrazole derivatives 4 and presence of the isotopic chlorine atom. Hydroxylamine
5, respectively. A similar reaction conducted in ethanol hydrochloride was also allowed to react with chalcones
gave the N-substituted pyrazoles 6 and 7. Moreover, 2 and 3 to form isoxazoline derivatives 9 and 10, respec-
reaction of chalcone 3 with phenylhydrazine afforded tively. The 1H NMR spectrum of the compound 9 is charac-
1
compounds 8. H NMR spectrum of 4 shows a doublet at terized by the presence of a doublet at 3.5 ppm for CH2 and
3.85 ppm and a triplet at 5.12 ppm corresponding to the a triplet at 5.9 ppm for CH of the isoxazoline ring. Reac-
pyrazoline CH2 and CH, respectively. 1H NMR spectrum of tion of o-phenylenediamine with chalcones 2 and 3 gave
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4ꢀ ꢀW.A. Ewes et al.: 1,5-Diphenylpyrazoles as breast cancer cell growth inhibitors
the corresponding 1,5-benzodiazepines 11 and 12. The IR in the presence of sodium alkoxide in an alcohol gave the
spectrum of 11 shows a significant band at 3350 cm-1 attrib- corresponding 2-alkoxypyridine-3-carbonitriles derivatives
uted to N-H group and the disappearance of an absorption 17–22. IR spectrum of 13 reveals the presence of a stretch-
band assigned to the carbonyl group. 13C NMR spectrum of ing band at 3415 cm-1 attributed to NH2 group. The 1H NMR
12 shows signals at 38.7, 40.4, 121.1, 124.8 ppm correspond- of 14 displays a signal at 6.27 ppm corresponding to NH2
ing to the benzodiazepine carbon atoms and a signal at group while compound 15 shows characteristic 2 signals
14.2 ppm corresponding to the CH3 group.
at 6.56 and 6.83 ppm corresponding to the pyran protons.
Pyridine-3-carbonitriles and pyran-3-carbonitriles
were prepared as shown in Scheme 2. Malononitrile was
allowed to react with compounds 2 and 3 in the presence of Antitumor activity
ammonium acetate to give pyridine-3-carbonitrile deriva-
tives 13 and 14, respectively. A similar reaction conducted All synthesized compounds were tested for their cytotoxic
in DMF in the presence of piperidine, afforded the corre- activity against MCF-7 (human breast cancer cell line)
sponding pyran-3-carbonitriles derivatives 15 and 16. Fur- using the method of Skehan [48, 49]. The results are pre-
thermore, reaction of chalcones 2 and 3 with malononitrile sented in Table 1. A series of 1,5-diphenylpyrazoles was
synthesized and evaluated in vitro for antitumor activity
against MFC-7 cell line. Compounds 4, 7 and 20 exhibit
strong activity (Table 1). Compounds 5, 8, 11, 13–17 and 22
show moderate activity. Compounds 12 and 18 show weak
activity. Compounds 9 and 19 show very weak activity.
1,5-Benzodiazepine derivative 11, pyridine-3-carbonitriles
13 and 14 and pyran derivatives 15 and 16 are moderately
active in comparison to the starting compounds 2 and 3.
The introduction of a propyl chain in compounds 19, 22
causes reduction in activity in comparison with the other
pyridine-3-carbonitriles 17, 18, 20 and 21.
Molecular modeling
The molecular operating environment (MOE) [50] based
molecular docking was done for the target compounds
Figure 3ꢀDocking of 4 in 1UYK binding side.
Figure 4ꢀDocking of 7 in 1UYK binding side.
Figure 5ꢀDocking of 16 in 1UYK binding side.
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W.A. Ewes et al.: 1,5-Diphenylpyrazoles as breast cancer cell growth inhibitorsꢂ ꢂ5
1-(4-Chlorophenyl)-3-[(3-methyl)-1,5-diphenyl-1H-pyrazol-4-yl]
prop-2-en-1-one (3)ꢁA mixture of compound 1 (2.6 g, 0.01 mol),
chloroacetophenone (0.01 mol) and sodium hydroxide (0.025 mol) in
absolute ethanol (20 mL) was heated under reflux for 2 h. The solid
obtained was collected by filtration, dried and crystallized from etha-
nol: light brown solid; yield 85%; mp 155–156°C; IR: 1590 (Cꢀ=ꢀN), 1606
(Cꢀ=ꢀC), 1658 cm-1 (Cꢀ=ꢀO); 1H NMR: δ 2.41 (s, 3H, CH3), 6.8 (d, 1H, J ꢀ=ꢀ 16.3
+
Hz), 7.2 (d, 1H, J ꢀ=ꢀ 16.3 Hz), 7.17–7.44 (m, 14H, Ar-H); MS: m/z 399 [M ].
General procedure for the preparation of
compounds 4 and 5
A solution of compound 2 or 3 (0.001 mol) and hydrazine hydrate (0.1
mL, 0.002 mol) in glacial acetic acid (15 mL) was heated under reflux
for 6–9 h. Cold water was added to the hot mixture and the product
extracted using ethyl acetate was crystallized from ethanol.
1-[5-(3-Methyl-1,5-diphenyl-1H-pyrazol-4-yl)-3-phenyl-4,5-dihy-
dro-1H-pyrazol-1-yl]ethan-1-one (4)ꢁYield 70%; mp 118–120°C;
Figure 6ꢀDocking of 20 in 1UYK binding side.
1
IR: 1645 (Cꢀ=ꢀN), 1675 cm-1 (Cꢀ=ꢀO); H NMR: δ 1.92 (s, 3H, CH3), 2.03 (s,
3H, COCH3), 3.85 (d, 2H, CH2 pyrazoline), 5.12 (t, 1H, CH pyrazoline),
+
3–22 on heat shock proteins (HSP) obtained from the
protein data bank (code, 1UYK.pdb) with the help of
PharmMapper software [51]. When examining the protein-
ligand interaction for the protein molecule 1UYK [52], it
was found that the main amino acids involved in binding
to the ligand are Asn (51), Asp (93) and Phe (138). The
selected complexes calculated as part of this work are
shown in Figures 3–6.
7.15–7.57 (m, 15H, Ar-H); MS: m/z 421 [M +1]. Anal. calcd for C27H24N4O:
C, 77.12; H, 5.75; N, 13.32. Found: C, 77.03; H, 5.53; N, 13.12.
1-[3-(4-Chlorophenyl)-5-(3-methyl-1,5-diphenyl-1H-pyrazol-4-yl)-
4,5-dihydro-1H-pyrazol-1-yl]ethan-1-one (5)ꢁYield (67%); mp 122–
124°C; IR: 1620 (Cꢀ=ꢀN), 1680 cm-1 (Cꢀ=ꢀO); 1H NMR: δ 1.89 (s, 3H, CH3), 2.32
(s, 3H, COCH3), 3.57 (d, 2H, CH2 pyrazoline), 4.56 (t, 1H, CH pyrazoline),
+
+
7.10–7.97 (m, 14H, Ar-H); MS: m/z 455 [M +1], 456 [M +2]. Anal. calcd for
C27H23ClN4O: C, 71.28; H, 5.10; N, 12.30. Found: C, 71.16; H, 5.36; N, 12.04.
Preparation of 3-methyl-1,5-diphenyl-4-[3-(substituted
phenyl)-4,5-dihydropyrazol-5-yl)]-1H-pyrazoles 6–8
Conclusion
There is a strong correlation between molecular modeling
and biological screening results which confirm that the
structural modification of the lead structure affects the
activity in a predictable manner.
A mixture of compound 2 or 3 (0.005 mol) with hydrazine hydrate (0.02
mol) or phenylhydrazine (0.005 mol) in absolute ethanol was heated
under reflux for a period of time indicated below and then concentrated
in vacuo. On cooling the separated solid was filtered and crystallized
from ethanol.
3-Methyl-1,5-diphenyl-4-(3-phenyl-4,5-dihydro-1H-pyrazol-
5-yl)-1H-pyrazole (6)ꢁCompound 6 was prepared from 2 and hydra-
zine hydrate, reaction time 6 h: yield 56%; mp 135–137°C; IR: 1599
(Cꢀ=ꢀN), 3305 cm-1 (N-H); 1H NMR: δ 1.8 (s, 3H, CH3), 2.7 (d, 2H, CH2 pyra-
zoline), 3.3 (t, 1H, CH pyrazoline), 6.7–8 (m, 15H, Ar-H), 7.63 (s, 1H,
Experimental
Chemistry
+
NH D2O exchangeable); MS: m/z 378 [M ]. Anal. calcd for C25H22N4: C,
Melting points are uncorrected and were recorded in open capillaries
on an electro-thermal melting point apparatus. IR spectra were
recorded on a Mattson 5000 FT-IR spectrometer in KBr disks at the
79.34; H, 5.86; N,14.80. Found: C, 79.71; H, 5.66; N, 14.64.
Faculty of Science, Mansoura University. H NMR (200 MHz) and 13C
1
4-[3-(4-Chlorophenyl-4,5-dihydro-1H-pyrazol-5-yl]-3-methyl-
1,5-diphenyl-1H-pyrazole (7)ꢁCompound 7 was prepared from 3
and hydrazine hydrate, reaction time 6 h: yield 69%; mp 183–185°C;
IR: 1593 (Cꢀ=ꢀN), 3365 cm-1 (N-H); 1H NMR: δ 1.9 (s, 3H, CH3), 2.5 (d, 2H,
CH2 pyrazoline), 3.9 (t, 1H, CH pyrazoline), 7.00–8.02 (m, 14H, Ar-H),
NMR (50 MHz) spectra were obtained on a Gemini Varian spectro-
meter using TMS as internal standard, at the Micro-analytical Unit
of Cairo University. Mass spectral analyses were performed on a JOEL
JMS-600H spectrometer at Cairo University. Microanalyses were per-
formed at the Micro-analytical Unit of Cairo University. All reagents
were purchased from the Aldrich Chemical Company. Compounds 1,
2 were synthesized according to reported methods [53, 54].
+
+
7.36 (s, 1H, NH D2O exchangeable); MS: m/z 413 [M +1], 414 [M +2].
Anal. calcd for C25H21ClN4: C, 72.72; H, 5.13; N, 13.57. Found: C, 72.47;
H, 5.37; N, 13.34.
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4-[3-(4-Chlorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-5-yl]- 2-Amino-4-(3-methyl-1,5-diphenyl-1H-pyrazol-4-yl)-6-phe-
3-methyl-1,5-diphenyl-1H-pyrazole (8)ꢁCompound
8 was pre- nylpyridine-3-carbonitrile (13)ꢁYield 64%; mp 131–133°C; IR: 1598
pared from 3 and phenylhydrazine, reaction time 20 h; yield 63%; (Cꢀ=ꢀN), 2227 (CN), 3415 cm-1 (NH2); 1H NMR: δ 2.41(s, 3H, CH3), 6.32 (s, 2H,
mp 110–112°C; IR: 1599 (Cꢀ=ꢀN), 1605 cm-1 (Cꢀ=ꢀC); 1H NMR: δ 11.37 NH2), 7.19 (s, 1H, H-pyridine), 7.31–8.30 (m, 15H, Ar-H); 13C NMR: 19.3,
(s, 3H, CH3), 3.35 (d, 2H, CH2 pyrazoline), 5.55 (t, 1H, CH pyrazoline), 89.1, 103.4, 116.7, 121.4, 123.7, 124.8, 126.7, 128.5, 130.7, 132.4, 134.6, 136.3,
+1
+
+
6.46–8.02 (m, 19H, Ar-H); MS: m/z 489 [M ], 490 [M ]. Anal. calcd for 140.0, 143.8, 150.2, 154.7, 156.3, 163.7; MS: m/z 428 [M +1]. Anal. calcd for
C31H25ClN4: C, 76.14; H, 5.15; N, 11.46. Found: C, 76.34; H, 5.39; N, 11.74. C28H21N5: C, 78.67; H, 4.95; N, 16.38. Found: C, 78.87; H, 4.65; N, 16.63.
2-Amino-6-(4-chlorophenyl)-4-(3-methyl-1,5-diphenyl-1H-pyra-
zol-4-yl)pyridine-3-carbonitrile (14)ꢁYield 70%; mp 146–148°C;
Preparation of 5-(3-methyl-1,5-diphenyl-1H-pyrazol-4-yl)-
IR: 1630 (Cꢀ=ꢀN), 2223 (CN), 3350 cm-1 (NH2); 1H NMR: δ 2.34 (s, 3H, CH3),
3-(substituted phenyl)-4,5-dihydroisoxazoles 9 and 10
6.27 (s, 2H, NH2), 7.11 (s, 1H, H-pyridine), 7.29–8.37 (m, 14H, Ar-H); MS:
+
+
m/z 462 [M +1], 463 (M +2], 3.4%). Anal. calcd for C28H20ClN5: C, 72.80;
A mixture of compound 2 or 3 (0.03 mol), absolute ethanol (15 mL),
hydroxylamine hydrochloride (0.2 g, 0.003 mol) and potassium
hydroxide (0.2 g, 0.004 mol) was heated under reflux for 10 h. Afer
cooling, the precipitate was filtered and crystallized from ethanol.
H, 4.36; N, 15.16. Found: C, 72.53; H, 4.10; N, 15.42.
Preparation of compounds 15 and 16
5-(3-Methyl-1,5-diphenyl-1H-pyrazol-4-yl)-3-phenyl-4,5-dihy-
1
droisoxazole (9)ꢁYield 60%; mp 103–105°C; H NMR: δ 2.5 (s, 3H,
A mixture of malononitrile (0.001 mol) compound 2 or 3 (0.001 mol),
and a few drops of piperidine in DMF (15 mL) was stirred at room
temperature. The precipitated product was washed with DMF and
crystallized from ethanol.
CH3), 3.5 (d, 2H, CH2 isoxazoline H-4), 5.9 (t, 1H, CH isoxazoline),
7.03–7.89 (m, 15H, Ar-H); 13C NMR: δ 21.2, 46.6, 80.4, 119.4, 121.2, 123.7,
124.0, 126.7, 129.5, 131.6, 135.0, 136.5, 139.4, 142.7, 144.3, 146.7, 149.4,
+
153.4, 159.2; MS: m/z 379[M ]. Anal. calcd for C27H23ClN4O: C, 79.13; H,
5.58; N, 11.07. Found: C, 79.45; H, 5.76; N, 11.37.
2-Amino-4-(3-methyl-1,5-diphenyl-1H-pyrazol-4-yl)-6-phenyl-
4H-pyran-3-carbonitrile (15)ꢁYield 56%; mp 120–122°C; IR: 1593
(Cꢀ=ꢀN), 2230 (CN), 3400 cm-1 (NH2); 1H NMR: δ 2.41(s, 3H, CH3), 6.30 (s,
2H, NH2), 6.56 (d, 1H, J ꢀ=ꢀ 3.8 Hz), 6.83 (d, 1H, J ꢀ=ꢀ .8 Hz), 7.31–8.30 (m,
3-(4-Chlorophenyl)-5-(3-methyl-1,5-diphenyl-1H-pyrazol-4-yl)-
1
4,5-dihydroisoxazole (10)ꢁYield 54%; mp 113–115°C; H NMR: δ 2.1
+
(s, 3H, CH3), 3.3(d, 2H, CH2 isoxazoline), 5.2 (t, 1H, CH isoxazoline),
15H, Ar-H); MS: m/z 430 [M . Anal. calcd for C28H22N4O: C, 78.12; H,
+
+
7.01–7.52 (m, 14H, Ar-H); MS: m/z 414 [M +1], 415 [M +2]. Anal. calcd for
5.15; N, 13.01. Found: C, 78.43; H, 5.36; N, 13.31.
C25H20ClN3O: C, 72.55; H, 4.87; N, 10.15. Found: C, 72.20; H, 4.63; N, 10.42.
2-Amino-6-(4-chlorophenyl)-4-(3-methyl-1,5-diphenyl-1H-
pyrazol-4-yl)-4H-pyran-3-carbonitrile (16)ꢁYield 59%; mp 126–
128°C; IR: 1587 (Cꢀ=ꢀN), 2218 (CN), 3365 cm-1 (NH2); 1H NMR: δ 2.34 (s, 3H,
CH3), 6.11 (s, 2H, NH2), 6.34 (d, 1H, J ꢀ=ꢀ 3.6 Hz), 6.75 (d, 1H, J ꢀ=ꢀ 3.6 Hz),
Preparation of compounds 11 and 12
+
+
7.25–8.20 (m, 14H, Ar-H); MS: m/z 464 [M ], 466 [M +2]. Anal. calcd for
A mixture of 2 or 3 (2.44 g, 0.01 mol), o-phenylenediamine (1.08 g, 0.01
mol) and triethylamine (3 mL) in absolute ethanol (15 mL) was heated
under reflux for 15 h. The reaction mixture was cooled to 0°C and the
resultant precipitate was filtered and crystallized from ethanol.
C28H21ClN4O: C, 72.33; H, 4.55; N, 12.05. Found: C, 72.63; H, 4.67; N, 12.35.
Preparation of compounds 17–22
2-(3-Methyl-1,5-diphenyl-1H-pyrazol-4-yl)-4-phenyl-2,3-dihy-
dro-1H-1,5 benzodiazepine (11)ꢁYield 59%; mp 178–180°C; IR: 1593
A mixture of chalcone 2 or 3 (0.001 mol), malononitrile (0.001 mol)
and a solution of sodium alkoxide (15 mL, 0.014 mol of sodium in
100 mL of the appropriate alcohol, namely, methanol, ethanol or
n-propanol) was stirred at room temperature for the period of time
indicated below. The product was crystallized from ethanol/DMF.
+
(Cꢀ=ꢀN), 3350 cm-1 (N-H); MS: m/z 454 [M . Anal. calcd for C31H26N4: C,
81.91; H, 5.77; N, 12.33. Found: C, 81.78; H, 5.47; N, 12.13.
4-(4-Chlorophenyl)-2-(3-methyl-1,5-diphenyl-1H-pyrazol-4-yl)-
2,3-dihydro-1H-1,5-benzodiazepine (12)ꢁYield 63%; mp 186–
188°C; IR: 1592 (Cꢀ=ꢀN), 3375 cm-1 (N-H); 13C NMR: δ 14.2, 38.7, 40.4,
115.7, 119.2, 121.1, 124.8, 126.1, 127.7, 128.6, 130.0, 130.1, 135.7, 136.4, 137.7,
2-Methoxy-4-(3-methyl-1,5-diphenyl-1H-pyrazol-4-yl)-6-phe-
nylpyridine-3-carbonitrile (17)ꢁCompound 17 was prepared from 2
and malononitrile in sodium methoxide and methanol, reaction time
2 h; yield 70%; mp 105–107°C; IR: 1560 (Cꢀ=ꢀN), 2220 cm-1 (CN);1H NMR:
δ 2.47 (s, 3H, CH3), 4.27 (s, 3H, OCH3), 7.48 (s, 1H, pyridine-H), 6.73–
+
138.8, 140.2, 144.9, 146.4, 148.7, 153.2, 165.4; MS: m/z 489 [M +1], 490
+
[M +2]. Anal. calcd for C31H25ClN4: C, 76.14; H, 5.15; N, 11.46. Found: C,
76.34; H, 5.37; N, 11.27.
+
7.88 (m, 15H, Ar-H); MS: m/z 443 [M +1]. Anal. calcd for C29H22N4O: C,
78.71; H, 5.01; N, 12.66. Found: C, 78.48; H, 5.39; N, 12.48.
Preparation of compounds 13 and 14
2-Ethoxy-4-(3-methyl-1,5-diphenyl-1H-pyrazol-4-yl)-6-phe-
A solution of chalcone 2 or 3 (0.005 mol), malononitrile (0.005 mol) nylpyridine-3-carbonitrile (18)ꢁCompound 18 was prepared from
and ammonium acetate (0.04 mol) in ethanol was heated under 2 and malononitrile in sodium ethoxide and ethanol, reaction time
reflux for 6 h. On cooling, the precipitated solid was filtered, dried 3 h; yield 67%; mp 101–103°C; IR: 1569 (Cꢀ=ꢀN), 2227 cm-1 (CN); 1H NMR:
and crystallized from ethanol.
δ 1.36 (t, 3H, O-CH2CH3), 2.01 (s, 3H, CH3), 4.10 (q, 2H, O-CH2CH3), 7.49
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W.A. Ewes et al.: 1,5-Diphenylpyrazoles as breast cancer cell growth inhibitorsꢂ
+
(wt/vol) sulforhodamine B (SRB) stain dissolved in 1% acetic acid.
Unbound dye was washed with 1% acetic acid and protein bound dye
was extracted with Tris EDTA (Meter Tech. Σ 960, USA). The optical
density (O.D.) of each well was measured spectrophotometrically at
564 nm with an ELIZA microplate reader (Meter Tech. Σ 960, USA).
The percentage of cell survival was calculated as follows: Survival
fractionꢀ=ꢀO.D. (treated cells)/O.D. (control cells). The IC50 values were
calculated using different concentrations of the tested compounds.
The relation between surviving fraction and compound concentra-
tion was plotted to obtain the survival curve (Table 1).
(s, 1H, pyridine-H), 7.23–7.85 (m, 15H, Ar-H); MS: m/z 457 [M +1]. Anal.
calcd for C30H24N4O: C, 78.92; H, 5.30; N, 12.27. Found: C, 78.69; H, 5.67;
N, 12.42.
4-(3-Methyl-1,5-diphenyl-1H-pyrazol-4-yl)-6-phenyl-2-pro-
poxypyridine-3-carbonitrile (19)ꢁCompound 19 was prepared
from 2 and malononitrile in sodium propoxide and n-propanol, reac-
tion time 4 h; yield 64%; mp 138–140°C; IR: 1567 (Cꢀ=ꢀN), 2230 cm-1
1
(CN); H NMR: δ 0.8 (t, 3H, OCH2CH2CH3), 1.89 (m, 2H, OCH2CH2CH3),
2.16 (s, 3H, CH3), 4.56 (t, 2H, OCH2CH2CH3), 7.58 (s, 1H, pyridine-
+
H), 7.13–8.08 (m, 15H, Ar-H); MS: m/z 471 [M +1]. Anal. calcd for
C31H26N4O: C, 79.12; H, 5.57; N, 11.91. Found: C, 79.37; H, 5.32; N, 11.61.
Molecular docking
6-(4-Chlorophenyl)-2-methoxy-4-(3-methyl-1,5-diphenyl-
1H-pyrazol-4-yl)pyridine-3-carbonitrile (20)ꢁCompound 20 was
prepared from 3 and malononitrile in sodium methoxide and metha-
nol,reactiontime1h;yield61%;mp123–125°C;IR:1570(Cꢀ=ꢀN),2219cm-1
(CN); 1H NMR: δ 2.41 (s, 3H, CH3), 4.34 (s, 3H, OCH3), 7.44 (s, 1H, pyri-
The docking studies and modeling calculations were done using
‘MOE version 2008.10 release of Chemical Computing Group’s’ which
was operated under Windows XP operating system installed on an
Intel Pentium IV PC with a 2.8 MHz processor and 512 RAM. The
tested compounds were built in 2D using ChemBiooffice suite and
geometric optimization was done using Hyperchem, then subjected
to docking simulation. The X-ray crystallographic structure of heat
shock protein enzyme was obtained from the Protein Data Bank;
code ‘1UYK.pdb’.
+
+
dine-H), 6.88–7.37 (m, 14H, Ar-H); MS: m/z 476 [M ], 478 [M +2]. Anal.
calcd for C29H21ClN4O: C, 73.03; H, 4.44; N, 11.75. Found: C, 73.37; H,
4.28; N, 11.98.
6-(4-Chlorophenyl)-2-ethoxy-4-(3-methyl-1,5-diphenyl-1H-pyra-
zol-4-yl)pyridine-3-carbonitrile (21)ꢁCompound 21 was prepared
from 3 and malononitrile in sodium ethoxide and ethanol, reaction
time 2.5 h; yield 66%; mp 140–142°C; IR: 1564 (Cꢀ=ꢀN), 2217 cm-1 (CN); 1H
NMR: δ 1.15 (t, 3H, O-CH2CH3), 2.15 (s, 3H, CH3), 4.32 (q, 2H, O-CH2CH3),
7.68 (s, 1H, pyridine-H), 7.11–7.52 (m, 14H, Ar-H); MS: m/z 491 [M +1],
[M +2]. Anal. calcd for C30H23ClN4O: C, 73.39; H, 4.72; N, 11.41. Found:
Acknowledgments: The authors wish to thank Faculty of
pharmacy, Mansoura University for using his laboratory
equipments and funding this work.
+
+
C, 73.70; H, 4.58; N, 11.69.
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