Design, docking, and synthesis of some new pyrazoline and pyranopyrazole derivatives as anti-inflammatory agents

Article abstract of DOI:10.1002/jhet.1757

Design and synthesis of some novel pyrazoline and pyranopyrazole derivatives as potential anti-inflammatory agents are described. Most of the compounds were tested for their anti-inflammatory (in vitro and in vivo) and ulcerogenic activities. In all teste

Full text of DOI:10.1002/jhet.1757

450
Design, Docking, and Synthesis of Some New Pyrazoline and
Vol 51
Pyranopyrazole Derivatives as Anti-inflammatory Agents
c
c
Magda M. F. Ismail,a Nagy M. Khalifa,b,c Hoda H. Fahmy, Eman S. Nossier, and
*
Mohamed M. Abdullad
aDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
bDrug Exploration and Development Chair (DEDC), College of Pharmacy, King Saud University, Riyadh 11451
Saudi Arabia
cDepartment of Theraputical Chemistry, Pharmaceutical and Drug Industries Division, National Research Centre
Giza, Egypt
dResearch Unit, Saco Pharm. Co., 6th October City 11632, Egypt
*
E-mail: nkhalifa.c@ksu.edu.sa
Received February 28, 2012
DOI 10.1002/jhet.1757
Published online 19 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
Design and synthesis of some novel pyrazoline and pyranopyrazole derivatives as potential anti-
inflammatory agents are described. Most of the compounds were tested for their anti-inflammatory
(in vitro and in vivo) and ulcerogenic activities. In all tested compounds, it was found that pyrazolines,
2a, and pyrazolopyrano[2,3-d]pyrimidine 9 are the potent anti-inflammatory and selective cyclooxygenase-2
(COX-2) inhibitor. All compounds are mainly in the safe level. Docking study of 2a and 9 revealed higher
affinity for binding with the active site of COX-2 enzyme like SC-558, a selective COX-2 inhibitor.
J. Heterocyclic Chem., 51, 450 (2014).
INTRODUCTION
[6], rofecoxib (Vioxx) [7], and etoricoxib (Arroxin) (Fig. 1),
have shown excellent efficacy in humans with few side
effects. Pyrazolines are well known for their pronounced
anti-inflammatory activity. [8] Pyrano[2,3-c]pyrazole [9,10]
had been reported to display good anti-inflammatory activ-
ity. The present investigation aims to achieve two goals;
the first goal is design and synthesis of two novel series,
trisubstituted-2-pyrazolines with different substituents at
position 3 and 5, pyranopyrazoles and condensed pyranopyr-
azoles trying to obtain better and selective COX-2 inhibitors.
The second goal is evaluation of their anti-inflammatory and
ulcerogenic activities and use of docking technique to detect
the compounds with high affinity to the active site of COX-2
enzyme; therefore, it might be of the best activity. Accord-
ingly, docking of the designed compounds were performed
into COX-2 complexed with its bound inhibitor, SC-558:
4-[5-(4-bromophenyl)-3-(trifluoromethyl)pyrazol-1-yl]
benzenesulfonamide [11] (Fig. 1) using Molsoft ICM 3,4-8c
program was performed to predict the affinity and orientation
of these new series at the active site. The Internal Coordinate
Mechanic (ICM) score values combined with hydrogen
bonds formed with the surrounding amino acid residues are
the prediction of the correct binding geometry (affinity and
orientation) for each binder at the active site. This reflects
the picture about the COX-2 inhibitory activity.
Prostaglandins are endogenous substances involved in
different processes of physiological nature and are potent
mediators of inflammation. Prostaglandins are produced,
together with other prostanoids, in the arachidonic acid
metabolism, whose first step, consisting of the oxidative
conversion of arachidonic acid into prostaglandin H2, is
catalyzed by cyclooxygenase (COX) [1]. This enzyme exists
at least as two isoforms, one constitutive (COX-1) and the
other inducible (COX-2) [2]. COX-1 is found in platelets,
kidneys, and in the gastrointestinal (GI) tract and is believed
to be responsible for the homeostatic maintenance of the
kidneys and GI tract. The COX-2 enzyme is the inducible
isoform that is produced by various cell types upon exposure
to cytokines, mitogens, and endotoxins released during
injury [3]. The COX-2 enzyme, after being overexpressed
at the site of injury, is a catalyst for the production of the
prostaglandins that result in inflammation and pain at the
site. COX-1 is involved in the maintenance of the GI tract,
so all nonsteroidal anti-inflammatory drugs that are inhibi-
tors of both COX-2 and COX-1 have been found to cause
side effects associated with GI ulcers [4]. Thus, it was
thought that a more selective COX-2 inhibitor would have
reduced GI side effects [3]. Several COX-2 selective inhibi-
tors, including celecoxib (Celebrex) [5], valdecoxib (Bextra)
© 2013 HeteroCorporation

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Docking and Synthesis of Pyrazoline and Pyranopyrazole Derivatives
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Figure 1. Structures of marketed COX-2 inhibitors and selective COX-2 inhibitor, SC-558.
RESULTS AND DISCUSSION
pyrazol-1-(4H)-yl)-2-oxoethoxy]benzamides 4a–d. Pyrano
[2,3-c]pyrazole 4c was employed as key intermediate for
preparation of novel bicyclic and tricyclic derivatives.
Treatment of 4c with hydroxylamine hydrochloride/TEA
[16] gave the 5-carboxamidoxime 5. Also, 4c was allowed
to react with malononitrile in the presence of ethanolic
piperidine [16] to give the pyrazolopyranopyridine 6. On
reaction of 4c with triethylorthoformate, in the presence of
acetic anhydride [17], the expected product 7 was not
formed, and the product was identified as the corresponding
6-acetamido derivative 8. Moreover, the reaction of 4c with
either formic acid [18] and/or formamide [17] furnished
the pyranopyrazolopyrimidines 9 and 10, respectively.
Structures of target compounds, 4–10 were established on
the basis of their elemental and spectral data.
Chemistry. Synthesis of 1,3,5-trisubstituted pyrazoline
derivatives 1a–g and 2a–g (Scheme 1).
Claisen–Schmidt
condensation reaction of methylarylketones with different
aromatic or heterocyclic aldehydes in the presence of
10% alcoholic potassium hydroxide [12,13] gave the
respective yellow-orange colored a,b-unsaturated ketones
1a–g. Chalcones 1a–g were condensed with m-chlorophenyl
hydrazine hydrochloride in absolute ethanol in presence of
catalytic amount of anhydrous sodium acetate [14] to give
the respective pyrazolines 2a–g (Scheme 1). The spectral
and microanalytical data for compounds 1a–g and 2a–g
were consistent with their chemical structures.
Synthesis of pyrano[2,3-c]pyrazole derivatives 4–10
(Scheme 2).
The one-pot reaction of 2-[2-(3-methyl-5-
Molecular modeling and docking studies.
All docking
oxo-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy]benzamide
(3) [15] with different arylidene malononitriles/ piperidine
afforded the bifunctional compounds 2-[2-(6-amino-4-
(4-substituted-phenyl)-5-cyano-3-methylpyrano[2,3-c]
studies were performed using “Internal coordinate Mechanic
(Molsoft ICM 3.4-8C)”.
All compounds were evaluated through molecular
modeling and docking techniques using program. ICM
docking is probably the most accurate predictive tool of
binding geometry today [19].
Scheme 1. Synthesis of 1,3,5-trisubstituted pyrazoline derivatives 1a–g.
and 2a–g.
The aim of the flexible docking calculations is the
prediction of correct binding geometry for each binder.
The goal is to have an adequate 3D model of the receptor
pocket we are planning to dock compounds to. Usually,
dock the tested compounds to determine ICM scores.
To compare the binding affinity of the new pyrazolines
and pyranopyrazoles, we docked compounds 2–10 into the
empty binding site of the experimentally known crystal
structure of COX-2 (prostaglandin synthase-2), complexed
with a selective inhibitor, SC-558: 4-[5-(4-bromophenyl)-3-
(trifluoromethyl)pyrazol-1-yl]benzene sulfonamide [1CX2] [11].
As shown in Table 1 and Fig. 2, SC-558 (original
ligand) reveals ICM score of (ꢀ84.79) and forms three
strong H bonds with the hydrophilic pocket of COX-2,
one H bond with His 90, one H bond with Gln 192 in
addition to the H bond with Arg 513.
1,3,5-Trisubstituted pyrazoline 2a has a reasonable ICM
score (ꢀ78.91) and forms one strong H bond (1.76 A)
between oxygen of 5-OCH3 group and His90. In addition,
hydrophobic interactions between 3-thienyl and secondary
pocket contains Ser 530, Tyr 385, His 386, and Phe 518.
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M. M. F. Ismail, N. M. Khalifa, H. H. Fahmy, E. S. Nossier, and M. M. Abdulla
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Scheme 2. Synthesis of pyrano[2,3-c]pyrazole derivatives 4–10.
Moreover, hydrophobic interaction between 5-Ph and
Ser 353 was observed (Fig. 3), whereas other pyrazolines
2d, f, and g bind to the important amino acids in the
active site of COX-2, namely, Tyr 385, Trp 387, and Arg
120, respectively.
385. However, counterparts 4a–c having lower energy
(ꢀ101.61 to ꢀ102.06) bind to Trp 387 (Table 1).
Pharmacological activity. On the basis of the molecular
modeling, compounds 2a, 2d, 2f, 2g, 4a–d, 8, and 9 were
subjected for pharmacological screening.
Pyrazolopyrano[2,3-d]pyrimidine 9 forms three strong
H bonds with the hydrophilic pocket of COX-2 enzyme,
one H bond between ketone-O attached to pyrazole with
His 90 (2.27 A) and two H bonds between ketone-O and
pyran-O with Arg 513 (1.23, 2.46 A). In addition; such
interaction forces the 4-Cl-Ph moiety to adopt a specific
orientation at the top of the channel with Ser 353, Ser
530, Tyr 385, His 386, Phe 518, and Trp 387 (Fig. 4).
These interactions in compounds 2a and 9 are responsible
for the COX-2 selectivity and contributed to stabilize the
ligand–enzyme complexes (Figs 3 and 4).
Anti-inflammatory activity (in vitro and in vivo). All tested
compounds and celecoxib, as a reference drug, were
subjected to in vitro and in vivo anti-inflammatory studies
using human whole blood assay [20] and carrageenan-
induced rat paw edema (RPE) bioassay [21], respectively.
Most of the tested compounds at a dose level of 2.5 and
5 mg/kg showed significant anti-inflammatory activities
with prostaglandin inhibition (Table 2). Some general
features could be concluded from the pharmacological
screening as follows.
In pyrazoline derivatives, the anti-inflammatory activity
of the tested compounds using carrageenan-induced paw
edema method produced significant reduction of paw size
ranged from 88.16–92.27% as compared with that of
celecoxib (at dose 2.5 mg/kg). Moreover, compound 2f
Pyranopyrazole 4d has a reasonable ICM score of
ꢀ85.22 and forms 10 H bonds with active sites of the
enzyme: four H bonds with His 386, two H bonds with
Trp387 and His388, and another two H bonds with Tyr
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Docking and Synthesis of Pyrazoline and Pyranopyrazole Derivatives
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Table 1
Docking of compounds on cyclooxygenase-2.
Compounds
SC-558
ICM scores
No. of H bonds
3
Involved group of amino acid
Atom of ligand involved
Length of H bond (Å)
ꢀ84.79
His 90 . . . He 2r
Arg 513 . . . Hh 11
Gln 192 . . . Hn
His 90 . . . He 2
Lys 493 . . . Hz 1
Cys 47 . . .. Hn
Tyr 385 . . . O
O-1
O-1
O-2
O-1
N-2
N-1
H-8
—
2.24
2.36
1.57
1.76
1.88
2.77
2.46
—
2a
2b
2c
2d
2e
2f
ꢀ78.91
ꢀ82.22
ꢀ88.07
ꢀ88.89
ꢀ75.69
ꢀ86.38
1
1
1
1
0
2
—
His 207 . . . He 2
Trp 387 . . . Hn
Arg 120 . . . Hh 11
Asn 382 . . . Hd 21
Trp 387 . . . Hn
Asn 382 . . . Od 1
Asn 382 . . . O
Asn 382 . . . Hd 21
Trp 387 . . . Hn
Asn 382 . . . Od 1
Asn 382 . . . O
Trp 387 . . . Hn
Asn 382 . . . Hd 21
His 386 . . . Hd 1
His 386 . . . Hd 1
His 386 . . . He 2
His 386 . . . He 2
Trp 387 . . . Hn
His 388 . . . Hn
Thr 212 . . . Hg 1
Tyr 385 . . . O
N-1
O-3
N-3
N-5
O-3
H-2
H-2
N-5
O-3
H-2
H-2
O-3
O-4
O-3
O-1
O-2
O-4
O-5
O-5
O-4
H-2
H-3
N-1
H-7
H-11
O-3
O-1
O-2
O-2
O-2
O-1
N-1
H-12
2.75
2.22
2.35
2.31
2.77
2.63
2.76
2.31
2.77
2.63
2.76
2.66
1.60
2.06
2.43
2.54
2.69
2.52
2.49
2.74
1.09
1.13
2.38
1.84
1.76
2.56
2.08
2.58
2.27
1.23
2.46
2.38
2.46
2g
4a
ꢀ80.07
1
4
ꢀ102.06
4b
ꢀ102.06
4
4c
4d
ꢀ101.61
ꢀ85.22
1
10
Tyr 385 . . . O
Cys47 . . . Hn
Cys 41 . . . O
5
ꢀ110.40
2
6
8
ꢀ106.98
ꢀ98.48
1
3
Asp 125 . . . Od 2
His 207 . . . He 2
His 207 . . . He 2
His 207 . . . He 2
His 90 . . . He 2
Arg 513 . . . Hh 12
Arg 513 . . . Hh 12
Cys 47 . . . Hn
9
ꢀ90.17
3
2
10
ꢀ104.21
Gly 135 . . . O
Ulcerogenic activity. All tested compounds and celecoxib
as a reference drug were studied for ulcerogenic activity [22].
The animals tolerated the tested compounds quite well, and
no mortalities have been recorded among them. The ulcer
indices of all tested compounds are mainly in the safe level
(UI = 2.11–4.26) (Table 3).
displayed potent anti-inflammatory activity. This may be
due to the presence of electron-releasing groups at position
3 (4-methoxyphenyl) and position 5 (3,5-dimethoxyphenyl)
of pyrazoline nucleus.
In pyranopyrazole derivatives, 4d (RPEI% = 94.33),
bearing 2,5-dimethoxyphenyl group at position 4, is
the most potent anti-inflammatory than the other analogs
4a–c (RPEI% = 70.15–78.18), having 4-Cl-/4-Br-phenyl
group. Hence, it seems essential for activity to have an
electron-releasing group at position 4 of pyranopyrazole
nucleus.
EXPERIMENTAL
Melting points were measured in open capillary tubes using
Griffin apparatus (UK) and were uncorrected. The IR spectra
were recorded using potassium bromide disk technique on Schi-
madzu 435 IR spectrophotometer (Tokyo, Japan) at Microanalyt-
ical Unit, National Research Centre. The proton nuclear magnetic
resonance (1H NMR) spectra were performed on Varian Gemini
300 MHz spectrophotometer (PoloAlto, Ca, USA) using
In pyranopyrazole derivatives, it was found that pyrano-
pyrazole 4d showed good prostaglandin inhibitory
activity (PGEI% = 73.17) compared with that of celecoxib
(PGEI%= 92.88) at dose 2.5 mg/kg.
Journal of Heterocyclic Chemistry
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M. M. F. Ismail, N. M. Khalifa, H. H. Fahmy, E. S. Nossier, and M. M. Abdulla
Vol 51
Table 2
Anti-inflammatory activities (in vitro and in vivo) of the tested compounds
and reference standard at doses 2.5 and 5 mg/kg after 4 h.
In vitro
In vivo
%inhibition of
plasma PGE
%inhibition of RPE
2.5 mg/kg 5 mg/kg
Compound
no.
2.5 mg/kg
5 mg/kg
2a
2d
2f
2g
4a
4b
4c
4d
70.18
71.02
71.15
68.77
61.23
58.23
63.22
73.17
69.15
64.13
92.88
89.12
90.00
90.08
87.93
80.50
77.34
81.98
91.14
88.99
82.24
97.55
90.44
91.41
92.27
88.16
77.12
70.15
78.18
94.33
88.14
80.80
96.44
98.56
98.89
99.00
97.77
88.88
75.23
91.19
99.94
98.16
92.90
99.93
Figure 2. The proposed binding mode of ligand SC-558 inside the active site
COX-2. Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.
8
9
Celecoxib
tetramethylsilane (TMS) as internal standard. Chemical shift
values (d) are given using parts per million scale (ppm) at Micro-
analytical Unit, National Research Centre. Mass spectra were
recorded on Hewlett Packard 5988 spectrometer (California,
USA) at Microanalytical Unit, National Research Centre.
Elemental microanalyses were carried out at Microanalytical unit,
National Research Centre. All reactions were monitored by TLC
using precoated aluminum sheet silica gel Merck 60F254 and
were visualized by UV lamp. Chemical naming, calculation of
molecular weight (MW), and microanalyses of new compounds
were performed by ChemDraw program, whereas chemical
naming of compounds 4–10 was performed by ChemSketch pro-
gram. (E)-3-(benzo[d][1,3]dioxol-5-yl)-1-(thiophen-2-yl)prop-2-
en-1-one (1b) [23], (E)-3-(4-bromophenyl)-1-(1H-indol-3-yl)
prop-2-en-1-one (1c) [24], (E)-3-(4-chlorophenyl)-1-(1H-indol-
3-yl)prop-2-en-1-one (1d) [25], (E)-1,3-bis(4-chlorophenyl)
prop-2-en-1-one (1e) [26], (E)-3-(4-(dimethylamino)phenyl)-1-
(pyridin-2-yl)prop-2-en-1-one (1g) [27], and 2-[2-(3-methyl-5-
oxo-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy]benzamide (3) [15]
Figure 3. The proposed binding mode of 2a inside the active site COX-2.
Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.
were prepared following the procedures reported in the literature.
General method for the synthesis of a,b-unsaturated
ketones 1a–g. To a solution of the proper methyl aryl ketone,
namely, 2-acetyl thiophene and/or p-methoxy acetophenone
(0.01 mol) in ethanol (50mL), the appropriate aromatic aldehydes,
namely, 2,5- and 3,5-dimethoxy benzaldehyde (0.01 mol) were
added in the presence of 10% alcoholic potassium hydroxide
(5mL). The reaction mixture was stirred for 10–12h at room
temperature and stand overnight at the same temperature. The
solid obtained was filtered, washed with water, air dried, and
crystallized from the ethanol.
(E)-3-(2,5-Dimethoxyphenyl)-1-thien-2-yl)prop-2-en-1-one
(1a). Yield, 89%; mp 80–85ꢁC; IR (KBr) vmax/cmꢀ1: 3088
(CHAr), 1638 (C═O), 1573 (C═C). 1H NMR (DMSO-d6) (d,
ppm): 3.70 and 3.75 (2s, 6H, 2 OCH3), 6.32–8.17 (m, 6H, Ar-H
and thiophen protons), 7.71and 7.92 (dd, 2H, ethylenic protons).
MS m/z (%): 274 (15.5, M+.), 243 (82), 137 (6), 111 (100), 107
(4), 83 (27), 77 (39). Anal. Calcd For C15H14O3S (%): C, 65.67;
H, 5.14. Found: C, 65.8; H, 5.12.
Figure 4. The proposed binding mode of 9 inside the active site COX-2.
Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.
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Table 3
Ulcerogenic activity of the tested compounds and reference standard at dose 5 mg/kg.
Average no. of ulcers
Average no. of severity of ulcers
% of incidence of ulcer divided by
Ulcer index
Compound no.
X ꢂ SE
Y ꢂ SE
10
(UI)
2a
2d
2f
2g
4a
4b
4c
4d
2.10 ꢂ 0.29
1.913 ꢂ 0.26
1.414 ꢂ 0.19
1.71 ꢂ 0.22
1.10 ꢂ 0.061
2.88 ꢂ 0.34
2.56 ꢂ 0.322
1.64 ꢂ 0.21
1.66 ꢂ 0.20
1.12 ꢂ 0.073
1.88 ꢂ 0.20
1.33 ꢂ 0.17
1.23 ꢂ 0.13
1.00 ꢂ 0.06
1.17 ꢂ 0.15
0.71 ꢂ 0.021
2.01 ꢂ 0.23
1.81 ꢂ 0.22
1.10 ꢂ 0.11
1.12 ꢂ 0.12
0.81 ꢂ 0.029
1.33 ꢂ 0.18
5.60
5.10
3.90
4.44
2.90
5.93
5.91
4.3
4.10
3.70
2.90
3.12
2.11
4.26
4.22
3.00
3.05
2.21
3.00
8
9
4.35
3.01
4.05
Celecoxib
(E)-3-(3,5-Dimethoxyphenyl)-1-(4-methoxyphenyl)prop-2-en-
1-one (1f). Yield, 87%; mp 100–104ꢁC; IR (KBr) vmax/cmꢀ1
3076 (CHAr), 1659 (C═O), 1599 (C═C).1H NMR (DMSO-d6)
(d, ppm): 3.84 (s, 6H, 2 m.OCH3), 3.87 (s, 3H, p.OCH3),
6.58–8.17 (m, 7H, Ar-H), 7.64, 7.87 (dd, 2H, ethylenic protons).
MS m/z (%):298 (100.0, M+.), 267 (60), 163 (8), 135 (75), 107
(16). Anal. Calcd For C18H18O4 (%): C, 72.47; H, 6.08. Found: C,
72.18; H, 6.10.
451 (57.5, M+. + 2), 449 (100.0, M+.), 372 (0.5), 370 (2.1), 296
(2.7), 294 (9.5), 116 (1.7), 113 (2.6), 111 (7.4). Anal. Calcd For
C23H17BrClN3 (%): C, 61.28; H, 3.80; N, 9.32. Found: C, 61.53;
H, 3.78; N, 9.35.
3-(1-(3-Chlorophenyl)-5-(4-chlorophenyl)-4,5-dihydro-1H-
pyrazol-3-yl)-1H-indole (2d).
Yield, 68%; mp 160–162ꢁC;
IR (KBr) vmax/cmꢀ1 3437 (NH), 3068 (CHAr), 1652 (C═N),
1
1588.8 (C═C). H NMR (DMSO-d6) (d, ppm): 3.15 (dd, 1H,
1-(3-Chlorophenyl)-3,5-diaryl-2-pyrazoline derivatives 2a–g
CHA), 3.94 (dd, 1H, CHB), 5.45 (dd, 1H, CHx), 6.65–8.30
(m, 13H, Ar-H and indole protons), 11.55 (s, 1H, NH
exchangeable with D2O). MS m/z (%); 409 (12.1, M+. + 4),
407 (71.5, M+. + 2), 405 (100.0, M+.), 372 (0.5), 370 (1.3),
373 (0.2), 371 (0.7), 336 (0.4), 296 (5.0), 294 (15.1), 183
(1.3), 116 (3.4). Anal. Calcd For C23H17Cl2N3 (%): C, 67.99;
H, 4.22; N, 10.34. Found: C, 68.26; H, 4.23; N, 10.31.
General method.
To a solution of the proper chalcones 1a–g
(0.001mol) in absolute ethanol (15 mL), m-chlorophenyl hydrazine
hydrochloride (0.001mol, 0.18 g) and anhydrous sodium acetate
(0.001mol, 0.08g) in absolute ethanol (15mL) were added. The
reaction mixture was refluxed for 6–8 h. After cooling, the solid
obtained was filtered off, washed with ethanol, air dried, and
crystallized from ethanol.
1-(3-Chlorophenyl)-4,5-dihydro-5-(2,5-dimethoxyphenyl)-3-
(thiophen-2-yl)-1H-pyrazole (2a). Yield, 70%; mp 140–142ꢁC;
IR (KBr) vmax/cmꢀ1 3072 (CHAr), 1659 (C═N), 1592 (C═C).
1H NMR (DMSO-d6) (d, ppm): 3.13 (dd, 1H, CHA), 3.61 and
3.87 (2s, 6H, 2 OCH3), 3.93 (dd, 1H, CHB), 5.60 (dd, 1H, CHx),
6.56–7.61 (m, 10H, Ar-H and thiophene protons). MS m/z (%);
400 (17.3, M+. + 2), 398 (100.0, M+.), 369 (4), 367 (9), 338 (0.1),
336 (0.3), 287 (0.2), 263 (7), 261 (21), 113 (2), 111 (6). Anal.
Calcd For C21H19ClN2O2S (%): C, 63.23; H, 4.80; N, 7.02.
Found: C, 63.48; H, 4.82; N, 7.04.
1-(3-Chlorophenyl)-3,5-bis(4-chlorophenyl)-4,5-dihydro-1H-
pyrazole (2e). Yield, 73%; mp 120–122ꢁC; IR (KBr) vmax/cmꢀ1
:
3076 (CHAr), 1682 (C═N), 1592 (C═C). 1H NMR (DMSO-d6) (d,
ppm): 3.14 (dd, 1H, CHA), 3.90 (dd, 1H, CHB), 5.57 (dd, 1H, CHx),
6.75–7.95 (m, 12H, Ar-H). MS m/z (%); 404 (11.7, M+. + 4), 402
(41.9, M+. + 2), 400 (72.6, M+.), 293 (2.4), 291 (11.5), 289 (17.6),
113 (33.8), 111 (90.2), 75 (100.0). Anal. Calcd For C21H15Cl3N2
(%): C, 62.79; H, 3.76; N, 6.97. Found: C, 62.54; H, 3.77; N, 6.99.
1-(3-Chlorophenyl)-4,5-dihydro-5-(3,5-dimethoxyphenyl)-3-
(4-methoxyphenyl)-1H-pyrazole (2f). Yield, 69%; mp 105–107ꢁC;
1
IR (KBr) vmax/cmꢀ1 3045 (CHAr), 1682 (C═N), 1592 (C═C). H
NMR (DMSO-d6) (d, ppm): 3.10 (dd, 1H, CHA), 3.65 (s,
6H, 2 m.OCH3), 3.76 (s, 3H, p.OCH3), 3.90 (dd, 1H, CHB),
5.35 (dd, 1H, CHx), 6.40–7.70 (m, 11H, Ar-H). MS m/z
(%); 424 (37.6, M+. + 2), 422 (100.0, M+.), 287 (23.6), 285
(65.7), 137 (3.3), 113 (14.5), 111 (43.3), 107 (6.6). Anal.
Calcd For C24H23ClN2O3 (%): C, 68.16; H, 5.48; N, 6.62.
Found: C, 68.43; H, 5.45; N, 6.64.
5-(Benzo[d][1,3]dioxol-5-yl)-1-(3-chlorophenyl)-4,5-dihydro-
3-(thiophen-2-yl)-1H-pyrazole (2b). Yield, 87%; mp 100–102ꢁC;
IR (KBr) vmax/cmꢀ1: 3030 (CHAr), 1667 (C═N), 1593 (C═C). 1H
NMR (DMSO-d6) (d, ppm): 3.19 (dd, 1H, CHA), 3.93 (dd, 1H,
CHB), 5.44 (dd, 1H, CHx), 5.97 (s, 2H, CH2 of piperonal),
6.71–7.63 (m, 10H, Ar-H and thiophene protons). MS m/z (%);
384 (42.7, M+. + 2), 382 (83.5, M+.), 271 (3.1), 263 (22.0), 261
(35.1), 113 (21.2), 111 (79.4), 90 (100.0). Anal. Calcd For
C20H15ClN2O2S (%): C, 62.74; H, 3.95; N, 7.32. Found: C,
62.99; H, 3.93; N, 7.29.
4-(1-(3-Chlorophenyl)-4,5-dihydro-3-pyrid-2-yl)-1H-pyrazol-
5-yl)-N,N-dimethylbenzenamine (2g). Yield, 84%; mp 152–154ꢁC;
1
IR (KBr) vmax/cmꢀ1 3076 (CHAr), 1679 (C═N), 1594 (C═C). H
NMR (DMSO-d6) (d, ppm) 2.85 (s, 6H, N(CH3)2), 3.15 (dd,
1H, CHA), 3.90 (dd, 1H, CHB), 5.46 (dd, 1H, CHx), 6.65–8.57
(m, 12H, Ar-H and pyridine protons). MS m/z (%); 378 (36.2,
M+. + 2), 376 (90.6, M+.), 258 (30.1), 256 (79.7), 259 (10.3), 257
(33.0), 145 (10.0), 146 (100.0), 113 (16.1), 111 (57.4). Anal.
Calcd For C22H21ClN4 (%): C, 70.11; H, 5.62; N, 14.87. Found:
C, 69.83; H, 5.64; N, 14.91.
3-(5-(4-Bromophenyl)-1-(3-chlorophenyl)-4,5-dihydro-1H-
pyrazole-3-yl)-1H-indole (2c). Yield, 67%; mp 137–139ꢁC;
IR (KBr) vmax/cmꢀ1 3407 (NH), 3060 (CHAr), 1659 (C═N),
1591 (C═C). 1H NMR (DMSO-d6) (d, ppm): 3.15 (dd, 1H,
CHA), 3.95 (dd, 1H, CHB), 5.40 (dd, 1H, CHx), 6.67–8.25
(m, 13H, Ar-H and indole protons), 11.40 (s, 1H, NH exchangeable
with D2O). MS m/z (%); 455 (0.3, M+. + 6), 453 (10.2, M+. +4),
Journal of Heterocyclic Chemistry
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456
M. M. F. Ismail, N. M. Khalifa, H. H. Fahmy, E. S. Nossier, and M. M. Abdulla
Vol 51
2-[2-(6-Amino-4-(substitutedphenyl)-5-cyano-3-methylpyrano
[2,3-c]pyrazol-1-(4H)-yl)-2-oxoethoxy]benzamides (4a–d)
To a mixture of compound 3 (0.01 mol,
178 (2.4), 136 (100.0). Anal. Calcd For C23H21ClN6O5 (%):
C, 55.59; H, 4.26; N, 16.91. Found: C, 55.70; H, 4.27; N, 16.84.
2-[2-(5,7-Diamino-4-(4-chlorophenyl)-6-cyano-3-methylpyrazolo
[40,30:5,6]pyrano[2,3-b]pyridin-1(4H)-yl)-2-oxoethoxy]benzamide
(6). To a solution of compound 4c (0.01 mol, 4.6 g) in absolute
ethanol (20mL), malononitrile (0.01mol, 0.66 g) and piperidine
(0.3mL) were added. The reaction mixture was refluxed for 3 h,
concentrated, and cooled. The solid formed was filtered off,
dried, and crystallized from ethanol. Yield, 73%; mp> 300ꢁC; IR
(KBr) vmax/cmꢀ1 3464, 3355 and 3160 (3 NH2), 2212 (CꢃN),
1723 (CO-CH2), 1648 (CO-NH2), 1590 (C═C). 1H NMR
(DMSO-d6) (d, ppm): 2.83 (s, 2H, NH2 exchangeable with D2O),
2.85 (s, 3H, CH3), 5.51 (s, 3H, CH-pyran and CH2O), 5.59 (s, 2H,
NH2 exchangeable with D2O), 7.11–7.77 (m, 8H, Ar-H), 8.01
(s, 2H, NH2 exchangeable with D2O). Anal. Calcd For
C26H20ClN7O4 (%): C, 58.93; H, 3.80; N, 18.50. Found: C,
59.11; H, 3.79; N, 18.57.
General method.
2.75 g) in absolute ethanol (25mL), containing piperidine
(0.3mL), the proper arylidine malononitrile (0.01 mol) was added.
The reaction mixture was refluxed for 6 h and then concentrated,
cooled, and the solid formed was filtered off, washed with cold
diethyl ether and then recrystallized from dimethyl formamide.
2-[2-(6-Amino-4-(2-bromophenyl))-5-cyano-3-methylpyrano
[2,3-c]pyrazol-1(4H)-yl)-2-oxoethoxy]benzamide (4a). Yield,
55%; mp 230–233ꢁC; IR (KBr) vmax/cmꢀ1 3390, 3308 (2 NH2),
2190 (CꢃN), 1739 (CO-CH2), 1654 (CO-NH2), 1611 (C═C).
1H NMR (DMSO-d6) (d, ppm): 2.94 (s, 3H, CH3), 5.05 (s, 1H,
CH-pyran), 5.69 (s, 2H, OCH2), 6.95 (s, 2H, NH2
exchangeable with D2O), 7.14–7.93 (m, 8H, Ar-H), 12.14
(s, 2H, NH2 exchangeable with D2O). Anal. Calcd For
C23H18BrN5O4 (%): C, 54.34; H, 3.57; N, 13.78. Found: C,
54.45; H, 3.58; N, 13.75.
2-[2-(6-Amino-4-(4-bromophenyl)-5-cyano-3-methylpyrano
[2,3-c]pyrazol-1(4H)-yl)-2-oxoethoxy]benzamide (4b). Yield,
51%; mp 240–243ꢁC; IR (KBr) vmax/cmꢀ1 3416, 3292 (2 NH2),
2237 (CꢃN), 1731 (CO-CH2), 1673 (CO-NH2), 1597 (C═C).
MS m/z (%); 509 (2.7, M+. + 2), 414 (6.7), 296 (2.3), 219 (5.1),
203 (4.7), 121 (11.2), 120 (8.7), 81 (4.9), 79 (5.0), 80 (13.9),
62 (100.0). Anal. Calcd For C23H18BrN5O4 (%): C, 54.34;
H, 3.57; N, 13.78. Found: C, 54.18; H, 3.58; N, 13.82.
2-[2-(6-Acetamido-4-(4-chlorophenyl)-5-cyano-3-methylpyrano
[2,3-c]pyrazol-1(4H)-yl)-2-oxoethoxy]benzamide (8). A mixture
of 4c (0.007 mol, 3.2 g), triethylorthoformate (15 mL), and acetic
anhydride (5 mL) was heated under reflux for 4 h. After cooling,
the solid formed was filtered off and washed with water and
crystallized from ethanol. Yield, 54%; mp 155–158ꢁC; IR (KBr)
vmax/cmꢀ1 3418, 3334 (NH2 and NH), 2246 (CꢃN), 1729 (CO-
1
CH2), 1674 (COCH3), 1663 (CO-NH2), 1596 (C═C). H NMR
(DMSO-d6) (d, ppm): 2.29 (s, 3H, COCH3), 2.88 (s, 3H, CH3),
5.37 (s, 1H, CH-pyran), 5.71 (s, 2H, OCH2), 6.97–8.13 (m, 8H,
Ar-H), 8.49 (s, 2H, NH2 exchangeable with D2O), 9.20 (s, 1H, NH
exchangeable with D2O). Anal. Calcd For C25H20ClN5O5 (%): C,
59.35; H, 3.98; N, 13.84. Found: C, 59.46; H, 3.96; N, 13.88.
2-[2-(4-(4-Chlorophenyl)-3-methyl-5-oxo-5,6-dihydropyrazolo-
[40,30:5,6]pyrano-[2,3-d]pyrimidin-1(4H)-yl)-2-oxoethoxy]benzamide
(9). A solution of compound 4c (0.005 mol, 2.3 g), in formic
acid (10 mL), was refluxed for 4 h. The solid formed was
filtered off, dried, and crystallized from ethanol. Yield, 55%;
mp 207–210ꢁC; IR (KBr) vmax/cmꢀ1 3394, 3206 (NH2, NH),
1713 (CO-CH2), 1650 (CO-NH2), 1603 (C═C). 1H NMR
(DMSO-d6) (d, ppm): 2.88 (s, 3H, CH3), 4.75 (s, 1H, CH-pyran),
5.65 (s, 2H, OCH2), 7.66 (s, 1H, CH-pyrimidine), 7.06–7.92
(m, 8H, Ar-H), 8.10 (s, 2H, NH2 exchangeable with D2O), 13.40
(br.s, 1H, NH exchangeable with D2O). Anal. Calcd For
C24H18ClN5O5 (%): C, 58.60; H, 3.69; N, 14.24. Found: C,
58.83; H, 3.70; N, 14.18.
2-[2-(6-Amino-4-(4-chlorophenyl)-5-cyano-3-methylpyrano
[2,3-c]pyrazol-1(4H)-yl)-2-oxoethoxy]benzamide (4c). Yield,
62%; mp 226–228ꢁC; IR (KBr) vmax/cmꢀ1 3416, 3378 (2 NH2),
1
2237 (CꢃN), 1733 (CO-CH2), 1674 (CO-NH2), 1597 (C═C). H
NMR (DMSO-d6) (d, ppm): 2.84 (s, 3H, CH3), 4.03 (s, 2H, NH2
exchangeable with D2O), 4.24 (s, 1H, CH-pyran), 5.63 (s, 2H,
OCH2), 7.05–7.63 (m, 8H, Ar-H), 7.86 (s, 2H, NH2 exchangeable
with D2O). MS m/z (%); 465 (0.1, M+. + 2), 463 (0.3, M+.), 353
(7.9), 352 (0.6), 175 (0.9), 121 (3.7), 96 (0.5), 80 (5.9), 62
(100.0). Anal. Calcd For C23H18ClN5O4 (%): C, 59.55; H, 3.91;
N, 15.10. Found: C, 59.78; H, 3.92; N, 15.14.
2-[2-(6-Amino-5-cyano-4-(2,5-dimethoxyphenyl)-3-methylpyrano
[2,3-c]pyrazol-1(4H)-yl)-2-oxoethoxy]benzamide (4d).
Yield,
57%; mp 190–192ꢁC; IR (KBr) vmax/cmꢀ1 3433, 3325 (2 NH2),
1
2210 (CꢃN), 1739 (CO-CH2), 1641 (CO-NH2), 1591 (C═C). H
NMR (DMSO-d6) (d, ppm): 3.30 (s, 3H, CH3), 3.68, 3.72 (2s, 6H,
two OCH3), 5.02 (s, 3H, CH-pyran, OCH2), 6.86–7.93 (m, 7H,
Ar-H), 7.52 (s, 2H, NH2 exchangeable with D2O), 8.78 (s, 2H, NH2
exchangeable with D2O). MS m/z (%): 489 (0.7, M+.), 354 (1.3),
353 (2.9), 352 (1.3), 137 (2.7), 125 (100.0), 124 (1.5). Anal. Calcd
For C25H23N5O6 (%): C, 61.34; H, 4.74; N, 14.13. Found: C,
61.16; H, 4.75; N, 14.28.
2-[2-(5-Amino-4-(4-chlorophenyl)-3-methylpyrazolo[40,30:5,6]
pyrano[2,3-d] pyrimidin-1(4H)-yl)-2-oxoethoxy]benzamide
(10). A solution of 4c (0.005 mol, 2.3g) in formamide (20 mL)
was refluxed for 6 h. The reaction mixture was cooled, diluted
with water, and the resulting precipitate was collected by filtration
and crystallized from ethanol. Yield, 57%; mp 245–247ꢁC; IR (KBr)
2-[2-[6-Amino-4-(4-chlorophenyl)-5-(hydroxycarbamimidoyl)-
3-methylpyrano-[2,3-c]pyrazol-1(4H)-yl)-2-oxoethoxy]benzamide
v
max/cmꢀ1 3393, 3318 (2 NH2), 1728 (CO-CH2), 1646 (CO-NH2),
1
1602 (C═C). H NMR (DMSO-d6) (d, ppm): 2.87 (s, 3H, CH3),
5.02 (s, 1H, CH-pyrane), 5.63 (s, 2H, OCH2), 7.34–8.09 (m, 9H,
Ar-H and CH-pyrimidine), 9.92, 10.58 (2s, 4H, 2 NH2 exchangeable
with D2O). Anal. Calcd For C24H19ClN6O4 (%): C, 58.72; H, 3.90;
N, 17.12. Found: C, 58.49; H, 3.91; N, 17.19.
(5).
A mixture of compound 4c (0.01mol, 4.6 g) and
hydroxylamine hydrochloride (0.01 mol, 0.6 g) in absolute ethanol
(30 mL) containing few drops triethylamine was warmed until a
clear solution was obtained and then left overnight; the solid
formed was filtered off, dried, and crystallized from ethanol.
Yield, 69%; mp 200–203ꢁC; IR (KBr) vmax/cmꢀ1 3412 (OH),
3322, 3184 (two NH2), 1731 (CO-CH2), 1650 (CO-NH2), 1586
Molecular modeling and docking studies.
1CX2 and
4COX [19] were downloaded through the Protein Data Bank
PDB/ RCSB site and saved as *.pdb file. A set of synthesized
pyrazoline and pyranopyrazole derivatives to inhibit COX-2 were
compiled earlier. Molecular modeling of the target compounds
was built using ChemDraw Ultra version 9.0.3 and minimized
their energy through Chem3D Ultra version 9.0.3/MOPAC, Jop
1
(C═C). H NMR (DMSO-d6) (d, ppm): 2.82 (s, 3H, CH3), 5.01
(s, 1H, CH-pyran), 5.62 (s, 2H, OCH2), 7.07–8.24 (m, 8H, Ar-H),
8.31, 10.03, 10.23 (3s, 6H, 3 NH2 exchangeable with D2O), 11.00
(s, 1H, OH exchangeable with D2O). MS m/z (%); 498 (0.04,
M+. + 2), 496 (0.1, M+.), 385 (1.0), 209 (1.1), 194 (2.1), 193 (2.0),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
Docking and Synthesis of Pyrazoline and Pyranopyrazole Derivatives
457
Type: Minimum RMS Gradient of 0.010 kcal/mol and RMS
distance of 0.1Å and saved as MDL MolFile (*.mol). Docking
procedure was followed using the standard protocol implemented
in Molsoft ICM 3.4-8C program (Table 1).
a single or multiple lesions (erosion, ulcer, or perforation)
is considered to be positive. The number of ulcers and the
occurrence of hyperemia are noted to determine the ulcer
index (Table 3).
PHARMACOLOGY
CONCLUSION
From the previous results, it seems that ICM score of the
original ligand is lower than the ICM score of pyranopyra-
zolopyrimidine 9, which means that it has higher affinity
for binding with the active site of COX-2 enzyme. In
addition, the original ligand, SC-558, forms three H bonds
with Arg 513, Gln 192, and His 90, whereas pyrazoline 2a
binds with His 90 and pyranopyrazolopyrimidine 9 binds
with three H bonds: one with His 90 and two with Arg 513
in the active site of COX-2 enzyme. Therefore, these two
compounds are promising as selective COX-2 inhibitors.
Anti-inflammatory activity.
Human whole blood assay.
Heparinized blood samples were collected from the treated
rats (n = 8), and then, plasma were separated by
centrifugation of these samples at 12000 g for 2 min at 4ꢁC
and immediately stored frozen at 20ꢁC until use, where PG
was estimated by kits of immuno assay. The design’s
correlate-EIA prostaglandin E2
(PGE2) kit is a competitive
immuno assay for the quantitative determination of PGE2 in
biological fluids. The kit uses a monoclonal antibody to
PGE2 to bind, in a competitive manner, the PGE2 in the
sample. After
a
simultaneous incubation at room
temperature, the excess reagents were washed away, and the
substrate was added. After a short incubation time, the
enzyme reaction was stopped, and the yellow color
generated was read on a microplate reader (DYNATCH,
MR 5000) at 405 nm. The intensity of the bound yellow
color is inversely proportional to the concentration of PGE2
in either standard or samples (Table 2).
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M. M. F. Ismail, N. M. Khalifa, H. H. Fahmy, E. S. Nossier, and M. M. Abdulla
Vol 51
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