Synthesis, biological evaluation and docking analysis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones as potential cyclooxygenase-2 (COX-2) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2014.08.050

As a part of our continued efforts to discover new COX inhibitors, a series of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones were synthesized and evaluated for in vitro COX inhibitory potential. Within this series, seven compounds (3a-d, 3h, 3k and 3

Full text of DOI:10.1016/j.bmcl.2014.08.050

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, biological evaluation and docking analysis
of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones
as potential cyclooxygenase-2 (COX-2) inhibitors
Jagdeep Grover a, Vivek Kumar b, M. Elizabeth Sobhia b, Sanjay M. Jachak a,
⇑
a Department of Natural Products, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar (Mohali) 160062, Punjab, India
b Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar 160062, Punjab, India
a r t i c l e i n f o
a b s t r a c t
Article history:
As a part of our continued efforts to discover new COX inhibitors, a series of 3-methyl-1-phenylchro-
meno[4,3-c]pyrazol-4(1H)-ones were synthesized and evaluated for in vitro COX inhibitory potential.
Within this series, seven compounds (3a–d, 3h, 3k and 3q) were identified as potential and selective
Received 24 May 2014
Revised 17 July 2014
Accepted 21 August 2014
Available online xxxx
COX-2 inhibitors (COX-2 IC50’s in 1.79–4.35
l
M range; COX-2 selectivity index (SI) = 6.8–16.7 range).
M; COX-1 IC50 >30 M) and selective
Compound 3b emerged as most potent (COX-2 IC50 = 1.79
l
l
COX-2 inhibitor (SI >16.7). Further, compound 3b displayed superior anti-inflammatory activity
(59.86% inhibition of edema at 5 h) in comparison to celecoxib (51.44% inhibition of edema at 5 h) in car-
rageenan-induced rat paw edema assay. Structure–activity relationship studies suggested that N-phenyl
ring substituted with p-CF3 substituent (3b, 3k and 3q) leads to more selective inhibition of COX-2. To
corroborate obtained experimental biological data, molecular docking study was carried out which
revealed that compound 3b showed stronger binding interaction with COX-2 as compared to COX-1.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
3-Methyl-1-phenylchromeno[4,3-c]pyrazol-
4(1H)-ones
Cyclooxygenase-2
Anti-inflammatory
Molecular docking
Cyclooxygenase (COX) or prostaglandin endoperoxide synthase
(PGHS), catalyzes the conversion of arachidonic acid to inflamma-
tory mediators such as prostaglandins (PGs), prostacyclins and
thromboxanes. COX exists in mainly two isoforms: COX-1 and
COX-2.1 Nonsteroidal anti-inflammatory drugs (NSAIDs), widely
used for relief of fever, pain and inflammation, act by inhibiting
COX catalyzed biosynthesis of inflammatory mediators.1,2
However, the therapeutic use of classical NSAIDs is associated with
well-known side effects at the gastrointestinal level (mucosal
damage, bleeding)3 and, less frequently, at the renal level.4 Two
decades after the discovery of COX isoforms, it was recognized that
selective inhibition of COX-2 might be endowed with improved
anti-inflammatory properties and reduced gastrointestinal toxicity
profiles than classical NSAIDs. Overall, these selective COX-2 inhib-
itors (coxibs) have fulfilled the hope of possessing reduced risk in
gastrointestinal events, but unfortunately cardiovascular concerns
regarding the use of these agents have emerged that led to the
withdrawal of rofecoxib (Vioxx) and valdecoxib (Bextra) from the
market in 2004 and 2005, respectively.5 Ongoing safety concerns
pertaining to the use of non-selective NSAIDs have spurred devel-
opment of coxibs with improved safety profile.
Coumarin and its derivatives have engrossed substantial atten-
tion from organic and medicinal chemists over the last few years as
they exhibit multiple biological activities6–9 especially anti-inflam-
matory and antioxidant activities.10,11 Naturally occurring couma-
rins like esculetin, fraxetin, daphnetin and other related coumarin
derivatives have gained recognition as inhibitors of not only
lipoxygenase and cyclooxygenase enzymes, but also of the neutro-
phil-dependent superoxide anion generation.9 Pyrazole is a nitrog-
enous five-membered heterocyclic component of the drugs and
has been well explored as anti-inflammatory,12,13 antiviral,14 anti-
malarial,15 HIV-reverse transcriptase inhibitors,16 and antitumor
agent.17 A perusal of literature has presented pyrazole derivatives
as selective COX-2 and COX-1 inhibitors and their clinical
applications as NSAIDs. Among the highly marketed COX-2 inhibi-
tors, celecoxib that comprises pyrazole nucleus is the only COX-2
inhibitor available in the USA. Some other examples of pyrazole
derivatives as NSAIDs are mefobutazone, ramifenazone, fampro-
fazone.18,19 Therefore, both coumarins and pyrazoles possess
worthy and imperative bioactivities, which render them useful
lead molecules for development of COX inhibitors. Moreover, many
reports have witnessed excellent anti-inflammatory activity of
coumarin derivatives containing pyrazole as heterocyclic ring.20–22
In view of these observations and in continuation of our research
programme to discover new COX inhibitors,23,24 we report herein
⇑
Corresponding author. Tel.: +91 172 2214683; fax: +91 172 2214692.
E-mail addresses: sanjayjachak@niper.ac.in, sjachak11@gmail.com (S.M. Jachak).
http://dx.doi.org/10.1016/j.bmcl.2014.08.050
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
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J. Grover et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Table 1
Compounds and their yield
the synthesis and biological evaluation of new 3-methyl-1-phenyl-
chromeno[4,3-c]pyrazol-4(1H)-ones as potential COX-2 inhibitors.
The methodology used to synthesize the target compounds
(3a–s) is outlined in Scheme 1. In general, classical Knoevenagel
condensation of commercially available salicylaldehydes and ethyl
acetoacetate was followed to prepare 3-acetylcoumarins (1a–d).
They were then treated with various substituted phenylhydrazines
to prepare 3-[1-(phenylhydrazono)-ethyl]-chromen-2-ones (2a–s),
followed by our recently reported strategy of potassium carbonate
mediated cyclization25 of 2 to furnish final compounds (3a–s) in
excellent yields (Table 1).
Compound
R1
R2
Ar
Yielda
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
H
H
H
H
H
H
H
H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Br
C6H5
95
90
93
95
90
89
91
92
98
92
96
95
96
90
88
85
88
82
83
4-CF3-C6H4
4-Cl-C6H4
4-Br-C6H4
2,4-(Cl)2-C6H3
2,5-(CH3)2C6H3
2-CF3-C6H4
4-F-C6H4
C6H5
2-CF3-C6H4
4-CF3-C6H4
4-Cl-C6H4
4-Br-C6H4
4-F-C6H4
2,5-(CH3)2C6H3
C6H5
4-CF3-C6H4
2,5-(CH3)2C6H3
C6H5
All the prepared chromenopyrazoles (3a–s) were evaluated23
for their ability to inhibit COX-1 and COX-2 using an ovine
COX-1/COX-2 assay kit (Catalog No. 560101, Cayman Chemicals
Inc., Ann Arbor, MI, USA) and results obtained are presented in
Table 2. Of the tested compounds, seven compounds (3a–d, 3h,
3k and 3q) displayed selective inhibition of COX-2. The study
was further extended to determine IC50 values of these com-
H
H
H
pounds. Celecoxib exhibited IC50 value of >30 and 0.15 lM against
COX-1 and COX-2, respectively, indicating that celecoxib is selec-
tive COX-2 inhibitor. Compound 3b demonstrated highest COX-2
a
Isolated yields.
inhibition (IC50 = 1.79
lM), followed by 3h (IC50 = 2.36 lM) and
3c (IC50 = 2.43 M). From structure activity relationship (SAR), it
l
Table 2
COX-1 and COX-2 enzyme inhibitory activity of chromenopyrazole derivatives
was observed that substitution of N-phenyl ring with electron
withdrawing groups (3b–d, 3h, 3k and 3q) increased COX-2 selec-
tivity, whereas electron donating groups (3f, 3o and 3r) had a
reverse effect (Fig. 1). Within halogens, relative profile for selective
inhibition of COX-2 was found to be p-CF3 (3b) > p-F (3h) > p-Cl
(3c) > p-Br (3d). This observation highlighted the significance of
CF3 group as a pharmacophoric feature for selective COX-2 inhibi-
tion, which is also evidenced from literature.26–28 It was also
noticed that methoxy group at C-7 (3k and 3n) led to dramatic
decrease in COX-2 activity, whereas chloro substitution at C-8
(3q) had a little effect.
Seven compounds (3a–d, 3h, 3k and 3q) that displayed potent
COX-2 inhibition in vitro were further evaluated for anti-inflam-
matory activity in carrageenan-induced rat paw edema assay,
described by Winter et al.29 Carrageenan-induced edema is a
non-specific inflammation resulting from a complex of diverse
mediators. This assay has been used for investigating new anti-
inflammatory agents, since it reliably predicts the anti-inflamma-
tory efficacy of the NSAIDs.23 Compounds were tested at a dose
Compound
COX inhibition at 30
l
Ma
(IC50
COX-1
,
l
M)
SIb
COX-1
COX-2
COX-2
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
48.07 0.78
34.26 0.27
43.74 0.37
47.51 2.11
30.54 0.87
21.33 1.24
34.58 2.19
28.28 1.13
43.23 0.48
38.25 0.14
33.22 1.09
34.81 0.53
27.3 0.73
87.44 1.29
94.29 0.78
92.73 1.21
88.57 0.21
61.34 1.78
60.31 0.46
51.98 2.10
93.83 0.60
78.34 0.23
53.84 0.40
87.76 1.49
69.14 2.43
74.72 1.21
61.21 0.98
53.2 1.35
>30
>30
>30
>30
ND
ND
ND
>30
ND
ND
>30
ND
ND
ND
ND
ND
>30
ND
ND
0.18
ND
2.63
1.79
2.43
3.65
ND
ND
ND
2.36
ND
ND
4.35
ND
ND
ND
ND
ND
2.58
ND
ND
ND
>11.4
>16.7
>12.3
>8.2
ND
ND
ND
>12.7
ND
ND
>6.8
ND
ND
ND
ND
ND
>11.6
ND
ND
ND
34.82 2.47
39.5 1.17
43.75 0.79
33.17 1.62
39.25 1.45
54.23 0.52
98.23 0.33
13.01 0.63
78.51 1.08
90.17 0.68
56.5 1.33
65.12 0.94
50.99 0.34
95.57 0.48
3q
3r
3s
of 150 lmol/kg and results obtained are summarized in Table 3.
Indomethacinc
Celecoxibc
Of the seven compounds, four (3b, 3c, 3h and 3q) were found to
possess potent anti-inflammatory activity with percentage inhibi-
tion of edema ranging from 49.43 to 59.86 at 5 h, while the refer-
ence drug, celecoxib at the same dose demonstrated 51.44%
inhibition at 5 h. Considering the fact that carrageenan-induced
paw edema assay is a biphasic event and during the second phase
(between 2 h and 5 h), it detects compounds that are anti-inflam-
matory agents as a result of inhibition of prostaglandin amplifica-
tion.30 It was observed that all the examined compounds inhibited
development of second phase of edema. This could be attributed to
their ability to bind cyclooxygenase (COX), an enzyme responsible
for the biosynthesis of prostaglandins.
0.15
ND
ND—not determined.
a
Values are expressed as mean SEM (n = 3).
Selectivity index (COX-1 IC50/COX-2 IC50).
Positive control used.
b
c
To gain insight into the plausible mode of interaction of com-
pounds within COX-1 and COX-2 enzyme, molecular docking study
was performed using GOLD program. All compounds docked
successfully into the active sites of COX-1 and COX-2 enzyme. In
general, the compounds displayed higher gold fitness score against
Scheme 1. Reagent and conditions: (a) Piperidine, rt, 20 min; (b) ArNHNH2, EtOH, reflux, 5 h; (c) K2CO3, acetone, reflux, 24 h.
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J. Grover et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
Figure 1. Structure activity relationship of chromenopyrazole derivatives.
Table 3
In vivo anti-inflammatory activity of chromenopyrazole derivatives in carrageenan-induced rat paw edema assay at dose 150
l
mol/kg
Compound
Anti-inflammatory activity
% Inhibition after 3 h SEM
% Inhibition after 1 h SEM
% Inhibition after 5 h SEM
3a
3b
3c
3d
3h
3k
3q
Celecoxib
19.33 3.06**
27.63 4.78***
21.34 1.84***
14.22 2.10*
30.09 4.42***
40.36 2.84***
35.18 2.10***
27.76 3.44***
39.75 1.02***
32.23 3.03***
36.09 3.40***
38.82 2.92***
38.23 2.86***
59.86 2.26***
49.43 1.13***
36.96 4.10***
55.60 1.22***
43.71 2.51***
57.81 2.72***
51.44 2.68***
24.57 1.80***
21.70 2.40***
23.33 4.47***
24.38 2.29***
The results are expressed as mean SEM (n = 5). Significance was calculated by using one-way ANOVA with Dunnet’s t-test. The difference in results were considered
significant when p <0.05 versus control.
*
p < 0.05.
p < 0.01.
p < 0.001.
**
***
COX-2 in comparison to COX-1, which suggested favorable binding
interactions of chromenopyrazoles in the COX-2 active site
(Table 4). The most potent compound 3b was found to dock into
the active site of COX-2, wherein oxygen atom of C@O and,
hydrophobic interactions with the trifluoromethyl group, with a
maximum distance cutoff of 4.00 Å. It was observed that insertion
of trifluoromethyl group into the side-pocket of COX-2 is assisted
by one carbon chain which might be a reason for observed high
COX-2 selectivity with this group, as compared to other halogens.
In contrast, the docked pose of compound 3b was found to be in
inverse conformation in the COX-1 active site, wherein C@O
formed a hydrogen bond with Ser530 (C@O. . .HO = 2.4 Å). The
trifluoromethyl group was surrounded by residues Arg120 and
Tyr355 (Fig. 2A1). The docking analysis of celecoxib was also
a-pyrone ring showed H-bond interactions with Tyr355
(C@O. . .HO = 2.04 Å, O. . .HO = 2.20 Å). In addition, the C@O group
of 3b was positioned towards the side-pocket lined by the residues
Ser353, Arg513 and Tyr355. The trifluoromethyl group occupied
hydrophobic side-pocket surrounded by the residues Phe381,
Leu384, Tyr385 and Trp387 (Fig. 2A2). These residues displayed
Table 4
Gold fitness scores of chromenopyrazoles and HBs formed with amino acid residues of COX-1 and COX-2
Compound
Gold fitness score COX-1
Residue involved in H-bond interaction
with COX-1
Gold fitness score COX-2
Residue involved in H-bond interaction
with COX-2
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
40.96
36.17
39.70
42.60
36.17
19.82
20.20
36.45
36.51
26.48
28.13
31.33
27.11
37.83
37.39
35.37
34.70
39.21
38.59
32.21
Ser530
Ser530
Ser530
Ser530
Tyr355
Tyr355
Tyr385, Ser530
Ser530
Ser530
Ser530
Tyr355
Tyr355
Tyr355
Ser530
Tyr355
Ser530
Ser530
Ser530
Ser530
Ser530, Tyr385
48.55
48.83
48.81
48.63
40.57
42.76
33.46
49.44
44.21
30.22
44.76
43.52
47.54
40.51
40.91
43.23
49.27
41.73
40.31
56.86
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
3s
Celecoxib
His90, Gln192, Leu352, Tyr355
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J. Grover et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Figure 2. Docking pose of compound 3b at the active site of COX-1 (A1) and COX-2 (A2), respectively.
Figure 3. Docking pose of Celecoxib at the active site of COX-1 (A1) and COX-2 (A2), respectively.
performed for comparison. The compound 3b occupy the same
binding sites as that of celecoxib in COX-1 and COX-2 structure.
In COX-1 active site, NH2 of sulfonamide group in celecoxib was
involved in hydrogen bonding with Tyr385 (O. . .HN = 2.0 Å) and
Ser530 (O. . .HN = 2.0 Å, Fig. 3A1). In COX-2 structure, the
oxygen atom and NH2 of sulfonamide group in celecoxib forms
three hydrogen bond with His90 (S@O. . .HN = 3.0 Å), Gln192
(C@O. . .HN = 2.4 Å) and Leu352 (C@O. . .HN = 2.1 Å), respectively.
The nitrogen atom of pyrazole forms hydrogen bond with Tyr355
(N. . .HO = 3.0 Å, Fig. 3A2), same residue was also involved in
hydrogen bonding with compound 3b. Overall, docking analysis
significantly indicated that the interaction of ligands with residue
Tyr355 is important for directing COX-2 selectivity, which is also
in agreement with our recent study.23
substantiated the observed COX-2 inhibition in vitro. The SAR study
showed that appropriately substituted chromenopyrazoles have
the necessary structural features to provide potent and selective
inhibition of the COX-2 isozyme, and to exhibit excellent anti-
inflammatory activity.
Acknowledgment
Authors thank the Director, NIPER for providing financial
support and necessary facilities to carry out present work.
Supplementary data
Supplementary data (Full experimental details, mp, 1H, 13C
NMR and HRMS data have been incorporated in the supporting
information.) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.bmcl.2014.08.050.
In conclusion nineteen 3-methyl-1-phenylchromeno[4,3-c]pyr-
azol-4(1H)-one derivatives were synthesized and evaluated for
COX-1 and COX-2 inhibition. Compound 3b exhibited potent
COX-2 inhibition (IC50 = 1.79 lM) and selectivity (SI >16.7). Seven
References and notes
compounds (3a–d, 3h, 3k and 3q) that displayed significant
COX-2 inhibition, were tested for anti-inflammatory activity. Com-
pound 3b was identified as the most potent anti-inflammatory
agent. Molecular docking studies further helped in understanding
the binding orientation of ligands at the active site of enzyme and
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J. Grover et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
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Please cite this article in press as: Grover, J.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.08.050