MEDICINAL

CHEMISTRY
RESEARCH

Med Chem Res

DOI 10.1007/s00044-017-1786-0

ORIGINAL RESEARCH

Biological activity evaluation and molecular docking study of

chromone derivatives as cyclooxygenase-2 inhibitors
Chirattikan Maicheen1 Narumol Phosrithong2 Jiraporn Ungwitayatorn1

Received: 8 July 2016 / Accepted: 10 January 2017

Springer Science+Business Media New York 2017

Abstract A series of chromone derivatives have been

evaluated as potential cyclooxygenase-2 (COX-2) inhibitors. The four most potent compounds, 48, 41, 39, and 35
displayed IC50 values of 3.30, 6.86, 7.36 and 7.46 M,
respectively. Compounds 35 and 38 showed higher selectivity for COX-2 (selectivity index, SI = 7.48 and 5.46,
respectively) than celecoxib (SI = 4.17 in the same test)
whereas compound 39 showed comparable selectivity
(SI = 4.19) to celecoxib. The molecular volumes of compounds 35 (312.84 3) and 38 (314.18 3) were similar to
celecoxib (299.28 3) but larger than ibuprofen (211.83
3). Docking results were in good agreement with the
experimental biological data in terms of evaluation of
binding energy and binding mode. Compounds 35, 38, and
39 had higher binding afnity against COX-2 (binding
energy between 9.77 and 11.42 kcal/mole) than COX-1
(binding energy between 6.28 and 7.88 kcal/mole).
These three chromone compounds also displayed active
conformation in the same orientation as that of celecoxib.
Thus, compounds in this series has the potential to be a new
class of selective COX-2 inhibitor.
Keywords Chromone series COX-2 inhibitory activity
Docking study

* Jiraporn Ungwitayatorn
jiraporn.ung@mahidol.ac.th
1

Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudhya Road,

Bangkok 10400, Thailand

Faculty of Pharmacy, Siam University, 38 Petkasem Road,

Bangkok 10160, Thailand

Introduction
Cyclooxygenases (COXs), also known as prostaglandin H2
(PGH2) synthase, catalyzes the conversion of arachidonic
acid to PGH2. There are at least two isoforms of COXs, i.e.,
COX-1 and COX-2 (Fu et al. 1990; Xie et al. 1991). COX-1
is expressed in most tissues, particularly in the gastrointestinal tract and kidneys where it is mainly responsible
for the synthesis of cytoprotective prostaglandins. COX-2 is
selectively induced in response to a variety of proinammatory stimuli such as tumor necrosis factor-
(TNF-), interleukines, and growth factors and facilitates
the release of prostaglandins involved in the inammatory
process (Crofford et al. 1994; Yucel et al. 1999; Simmons
et al. 2004). The major difference between these two isoforms rather lies in physiological function rather than in
structure. COX-1 and COX-2 are very similar in their
structures with the molecular weights of 7074 kDa (Flower
2003). They contain over 600 amino acids with an
approximately 60% homology within the same species
(Vane et al. 1998). The difference between COX-1 and
COX-2 is that the Ile at positions 434 and 523 in COX-1 is
replaced by Val in COX-2. The smaller Val side chain in
COX-2 induces a conformational change at Tyr355, thereby
forming an additional hydrophobic secondary internal
pocket protruding off the primary binding site in COX-2
which is absent in COX-1 (Kurumbail et al. 1996). Consequently, the total volume of the COX-2 primary binding
site including the secondary pocket (394 3) is about 25%
larger than that of the COX-1 binding site (316 3) (Luong
et al. 1996; Gierse et al. 1996; Guo et al. 1996). Another
essential amino acid difference between COX-1 and COX2, within the side pocket of COX-2, is Arg in place of
His513 in COX-1 which can interact with polar moieties.
These differences between the COX active sites have major

Med Chem Res

Fig. 1 Structures of selective
COX-2 inhibitors

Fig. 2 Synthesis pathway for

studied chromone derivatives

implications for selective inhibitors. The discovery of

coxib compound DuP 697, the rst diarylheterocycle,
served as the rationale for the original concept that a drug
having a greater selectivity for COX-2 than COX-1 would
reduce the gastrointestinal bleeding side effect. Subsequent
drug discovery programs led to the development of diarylheterocycles as the major class of selective COX-2
inhibitors, e.g., celecoxib, rofecoxib, valdecoxib, etc
(structures as shown in Fig. 1) (DeWitt 1999).
Beside those diarylheterocyclic compounds, a number of
selective COX-2 inhibitors with various scaffolds have
been reported, e.g., chalcone derivatives (Zarghi et al.
2006), 1,3-diarylurea derivatives (Zarghi et al. 2008),
4-benzylidene
aminoand
4-phenyliminomethylbenzenesulfonamides (Lin et al. 2008), benzofuran derivatives (Wang et al. 2010), pyridine acyl sulfonamide
derivatives (Lu et al. 2011), 1,2-diarylolenes (Uddin et al.
2004), 1,1,2-triarylethenes (Uddin et al. 2005). Flavonoids,
natural phenyl substituted chromones, display a remarkable
pharmacological actions (Havsteen 1983), some of which
suggest that certain members of this group of compounds
signicantly inhibit the function of COX-2 enzyme
(OLeary et al. 2004; Cheong et al. 2004; Suh et al. 2009;
Gacche et al. 2015). Silibinin, silymarin, hesperitin, and
myricetin were found to be potent COX-2 inhibitor

compared to other types of avonoid compounds (Gacche

et al. 2015).
In the previous study, our research group has designed,
synthesized a series of chromone compounds and evaluated
for various pharmacological activities, e.g., anti-HIV-1
protease (Ungwitayatorn et al. 2011), antioxidant (Phosrithong et al. 2012) and antimalarial activities (Lerdsirisuk
et al. 2014). In this study, chromone derivatives were
evaluated for their inhibitory activity against COX-2. The
studied compounds were also docked into the active sites of
both COX-1 and COX-2 in order to determine the probable
binding interactions in comparison with the known selective
COX-2 inhibitors.

Experimental
Synthesis
The studied chromone compounds were synthesized via
one-pot cyclization reaction. The synthesis pathway was
outlined in Fig. 2. More details of the synthesis procedures
and spectroscopic data were reported in Ungwitayatorn
et al. 2011.

Med Chem Res

Cyclooxygenase inhibition assay

The inhibitory activity of chromone compounds against
COX-2 was determined by the commercially available
COX-(human) inhibitor screening kit (Catalog No. 701080,
Cayman Chemical, Ann Arbor, MI, USA) based on the
manufacturers instructions. Briey, to reaction buffer
solution (160 L, 0.1 M Tris-HCl pH 8.0 containing 5 mM
EDTA and 2 mM phenol) with COX-2 (10 L) in the presence of heme (10 L) was added 10 L of test chromone
solution. These solution were incubated for 10 min at 37 C.
The reaction was initiated by adding 10 L of arachidonic
acid, quickly mixed and incubated for exactly two min at
37 C. PGF2 was produced by reduction of PGH2 with
stannous chloride (30 L) and was incubated for 5 min at
room temperature. The amount of PGF2 was measured by
enzyme immunoassay. The 96-well plate, previously coated
with a mouse anti-rabbit monoclonal antibody, was incubated with the COX-2 reaction for 18 h at room temperature. The plate was washed to remove unbound reagents and
then Ellmans reagent (containing the substrate to acetylcholinesterase) was added to the well. The product of this
enzymatic reaction showing a distinct yellow color was
determined by UV microplate reader at the wavelength 410
nm. The % inhibition was calculated by comparing PGF2
produced in compound-treated samples with control sample
using the following equation:
% Inhibition
fPGF2 controlPGF2 sample=PGF2 controlg  100

where [PGF2]control = PGF2 produced in untreated

sample and [PGF2]sample = PGF2 produced in
compound-treated sample.
The assay was performed in triplicate wells and celecoxib was used as a positive control. The test compounds,
dissolved in 5% DMSO, were evaluated at a concentration
of 30 M.
Selectivity index and IC50 values determinations
The ten most potent chromone compounds (i.e., compounds
25, 29, 31, 34, 35, 38, 39, 41, 48, and 49) were chosen for
selectivity index (SI) values determination. The SI values
were calculated using the following equation:
Selectivity index = % inhibition (COX-2)/% inhibition
(COX-1)
The COX-1 inhibitory activity was evaluated using the
same protocol as COX-2 inhibition assay using COX
Inhibitor Screening Assay (Catalogue no. 560131).
Those compounds found to be highly potent were tested at
additional concentrations between 30 and 0.1 M. The IC50
value (the concentration of sample required for 50%

inhibition) was determined by interpolation from the log-dose

response curve, which was generated using six concentrations.
Docking study of chromone derivatives against COX-1
and COX-2
The molecular structures of chromone compounds were
constructed using the standard parameters of the molecular
modeling software package SYBYL x2.0 (Tripos Associates, Saint Louis, MO, USA). Geometrical optimization was
performed using Powell method with a root-mean-squared
(RMS) energy gradient of 0.05 kcal/mol.. Tripos force
eld with GasteigerHckel charges was employed during
the energy minimization. These conformations of chromones
were then docked into the active sites of COX enzymes
using AutoDock version 4.2 (The Scripps Research Institute,
Molecular Graphics Laboratory, Department of Molecular
biology, CA, USA) using an empirical free energy function
and Larmarckian Genetic Algorithm.
The crystal structures of COX-1 (pdb codes 1EQG,
1EQH, 1CQE, and 1HT5) and COX-2 (pdb codes 3LN1,
1CX2, and 3NTG) complexed with inhibitors were
retrieved from the Brookhaven Protein Data Bank (http://
www.rcsb.org/pdb). The protein templates were prepared
for docking study by removing all the native ligand structures and all water molecules from the complex structures.
The polar hydrogen atoms were added and Gasteiger
charges were assigned to protein atoms. The optimized run
parameters for docking study were as follow: the maximum
number of energy evaluations was increased to 1,500,000
per run and the number of GA run was 100. All other
parameters were maintained at their default setting. One
hundred independent docking runs were carried out for each
ligand. A grid box size of 60 60 60 points, with a
spacing of 0.375 between the points was implemented
and centered on the center of mass of the ligand in the
native conformation. The docked poses were clustered
using a tolerance of 2.0 root-mean-square deviations
(RMSD). The docking results, i.e., the docked pose, binding
mode, and binding free energy were analyzed to evaluate
the interaction between the ligand and the amino acid
residues of both COX-1 and COX-2.
The target enzyme template validation was performed by
re-docking and cross-docking experiments. Each ligand was
docked into the native protein in order to determine the
ability of AutoDock program to reproduce the orientation
and position of the ligand observed in the crystal structure.
Then, cross-docking of each ligand into the non-native
protein was performed. The RMSD values were obtained
from the best cluster conformation of the re-docking and
cross-docking studies. The COX-1 template, 1EQH, and
COX-2 template, 3LN1, with the lowest RMSD values were
used for further docking study.

Med Chem Res

Table 1 The in vitro COX inhibitory activities results of the 3-unsubstitued chromone derivatives

Structure

Compd R2

COX-2

Selective index IC50 (COX-2, M) Molecular volume (3)a

% Inhibition
COX-1

Phenyl

45.06 1.80

Benzyl

49.01 4.04

Phenyl

53.18 3.96

CH3

60.90 1.65

11

3-(CF3)-Phenyl

74.69 0.65

12

4-(F)-Phenyl

74.59 2.34

13

3, 5-(diNO2)-Phenyl 49.55 2.60

14

3-(Cl)-Phenyl

64.82 1.87

15

3, 4-(diCl)-Phenyl

60.96 1.81

16

4-(t-butyl)-Phenyl

56.07 0.75

17

3-(CF3)-Phenyl

25.55 4.26

18

4-(F)-Phenyl

51.36 1.66

19

3, 4-(diF)-Phenyl

50.66 0.59

20

4-(t-butyl)-Phenyl

54.70 3.51

22

3, 5-(diNO2)-Phenyl 75.14 1.73

23

3-(Cl)-Phenyl

61.23 4.07

24

3, 4-(diCl)-Phenyl

45.75 2.14

25

4-(OCH3)-Phenyl

82.92 2.15 96.09 0.37 0.86

26

3-(OCH3)-Phenyl

47.78 1.40

27

3-(OCH3)-Phenyl

55.91 2.54

28

3-(Cl)-Phenyl

61.56 1.92

29

4-(F)-Phenyl

85.98 0.68 97.76 0.07 0.88

209.96

31

4-(t-butyl)-Phenyl

89.59 0.40 91.11 1.53 0.98

273.39

49

3-(OCH3)-Phenyl

97.51 0.28 26.27 1.12 3.71

12.97

239.56

The volumes of the molecules including celecoxib and ibuprofen were calculated using MarvinSketch program

239.59

Med Chem Res

Table 2 The in vitro COX inhibitory activities results of 3-substitued chromone derivatives
Structure

Compd

R2

% Inhibition
COX-2

32

3-(CF3)-Phenyl

76.82 0.84

Selective
index

IC50
(COX-2, M)

Molecular
volume (3)

COX-1

33

3-(Cl)-Phenyl

55.64 2.23

34

3-(OCH3)Phenyl

89.14 1.35

67.37 1.93

1.32

355.59

35

4-(F)-Phenyl

93.50 0.81

12.50 0.85

7.48

7.46

312.84

36

4-(NO2)-Phenyl

44.53 5.82

37

4-(OCH3)Phenyl

56.48 1.66

38

3, 4-(diF)Phenyl

92.75 1.88

16.99 0.67

5.46

314.18

39

3-(CF3)-Phenyl

95.47 0.75

22.80 1.09

4.19

7.36

358.68

40

3-(Cl)-Phenyl

74.96 1.06

41

3-(OCH3)Phenyl

83.00 0.82

27.22 0.98

3.05

6.86

347.00

42

4-(F)-Phenyl

54.37 2.80

43

4-(NO2)-Phenyl

59.20 0.49

44

4-(OCH3)Phenyl

70.35 0.94

45

4-(t-butyl)Phenyl

52.73 1.54

46

3-(OCH3)Phenyl

52.80 1.29

47

4-(NO2)-Phenyl

45.95 2.64

48

4-(t-butyl)Phenyl

93.52 3.16

1.44

3.30

50

3-(OCH3)Phenyl

82.70 0.63

Celecoxib
Ibuprofen

91.75 0.24

Results and discussion

In vitro COX inhibitory activity evaluation
Forty-two chromone compounds were tested in vitro to
evaluate their inhibitory activity towards COX-2. Tests
were performed using the commercially available COX

65.17 1.57

433.62

22.01 0.35

4.17

299.28

86.80 0.18

211.83

inhibitor screening assay. This assay quantied the amount

of PGF2 via an enzyme immunoassay. The inhibitory
efcacy of the chromone derivatives evaluated at concentration of 30 M and % inhibition values calculated were
the means of three determinations. Compounds found to be
highly potent were then determined the SI compared with
the standard selective COX-2 inhibitor, celecoxib. Five

Med Chem Res

Table 3 The binding energies
of chromone derivatives,
selective and non-selective
COX-2 inhibitors, docked with
COX-2 and COX-1

Compd

Binding energy (kcal/mole)

COX-2
3-Unsubstituted chromones

Compd

Binding energy (kcal/mole)

COX-1

COX-2
3-Substituted chromones

COX-1

7.81

7.61

32

10.10

6.21

8.32

7.63

33

11.35

7.58

7.69

7.70

34

10.23

7.19

6.56

6.03

35

9.77

6.28

11

8.97

8.71

36

11.90

6.66

12

8.56

8.18

37

10.02

6.62

13

9.84

9.54

38

10.37

6.90

14

9.37

8.96

39

11.42

7.88

15

9.65

8.26

40

12.11

8.58

16

8.85

7.77

41

11.07

7.63

17

9.10

8.29

42

10.47

7.63

18

8.67

7.74

43

12.74

8.31

19

8.71

7.59

44

11.02

7.21

20

8.28

7.85

45

10.96

6.12

22

10.03

9.61

46

10.97

7.06

23

9.43

8.62

47

12.40

8.29

24

9.72

8.46

48

10.91

4.87

25

8.74

7.92

50

11.14

7.08

26

9.39

8.08

27

8.50

7.71

28

8.64

7.84

29

8.07

7.39

31

9.48

8.06

49

8.92

8.26

Non-selective COX inhibitors

Selective COX-2 inhibitors

Ibuprofen

7.31

7.83

Celecoxib

10.95

6.25

Indomethacin

9.38

8.95

Etoricoxib

10.72

7.87

Diclofenac

7.89

7.13

Meloxicam

9.59

7.82

Naproxen

7.51

8.44

Parecoxib

10.52

8.21

Piroxicam

8.23

8.27

Valdecoxib

10.71

8.42

Flurbiprofen

7.57

8.94

selected compounds were further evaluated for IC50 values

against COX-2. The percentage of inhibition of COX-2, SI,
and IC50 values were summarized in Tables 1 and 2. As
shown in Tables 1 and 2, most of the chromone compounds
exhibited remarkable inhibitory activity against COX-2.
Among these compounds, compounds 35, 38, 39, 48, and
49 showed higher potency (93.50, 92.75, 95.47, 93.52, and
97.51 % inhibition, respectively) than celecoxib (91.75 %
inhibition in the same experiment). Compounds 35 and 38
also showed higher selectivity for COX-2 (SI = 7.48 and
5.46, respectively) than celecoxib (SI = 4.17) whereas
compound 39 showed selectivity (SI = 4.19) comparable to
celecoxib. Despite its highest potency against COX-2,
compound 48 (IC50 = 3.30 M) displayed lower COX-2

selectivity (SI = 1.44). In general, most of the 3-substituted

chromone compounds (compounds containing R2CO at
position 3 of the chromone nucleus) displayed > 52 %
inhibition and up to 95.47 % inhibition (except for compound 36) (Table 2). The 3-unsubstituted derivatives
showed 2589 % inhibition (except for compound 49)
(Table 1).
Due to the total volume of the COX-2 primary binding
site and its associated secondary pocket (total volume =
394 3) is larger than that of the COX-1 binding site (316
3) (Luong et al. 1996; Gierse et al. 1996; Guo et al. 1996),
the rational design of selective COX-2 inhibitors frequently
exploits the difference in the volume of the binding sites for
COX-1 and COX-2 (Habeeb et al. 2001; Zarghi et al. 2007).

Med Chem Res

Fig. 3 The selective COX-2
inhibitors, celecoxib (cyan),
etoricoxib (red), and valdecoxib
(yellow) docked into the active
sites of a COX-2 and b COX-1.
The selective COX-2,
compounds 35 (pink), 38 (blue),
39 (brown), and 41 (purple)
docked against c COX-2 and
d COX-1. The non-selective,
compounds 25 (red), 29 (cyan),
and 31 (green) docked against
e COX-2 and f COX-1. Note:
numbering of the amino acid
residues in 3LN1 is 14 units
different from the other pdb les
(as described in results and
discussion section) (for color
gures, please see the electronic
version of the article)

The drug molecular volume closer to the molecular volume

of the COX-2 binding site (394 3), the COX-2 selectivity
will be enhanced (Habeeb et al. 2001). In this study, the
molecular volumes of the higher selective COX-2 inhibitors, compounds 35 (312.84 3) and 38 (314.18 3), were

close to the volume of celecoxib (299.28 3) and larger than

that of ibuprofen (211.83 3). Compound 29 with smaller
molecular volume, 209.96 3, nearly equal to the volume of
ibuprofen, showed potent inhibitory activity against both
COX-1 and COX-2 (SI = 0.88). In this regard, differences

Med Chem Res

Fig. 4 The binding
conformations of a compound
35 (pink), b compound 38 (red),
and c compound 39 (red)
superimposed with the binding
conformation of celecoxib (blue)
(for color gures, please see the
electronic version of the article)

in molecular volume could lead to signicant changes in

both COX-1 and COX-2 selectivity.
Docking studies
Molecular docking study was performed to understand the
inhibitor-enzyme interactions and enzyme selectivity in
more detail. Towards this goal, docking study was carried
out on the active sites of COX-1 and COX-2 using AutoDock program. COX-1 (pdb code 1EQH) and COX-2 (pdb
code 3LN1) were used as templates. (Note: numbering of
the amino acid residues in pdb code 3LN1 is 14 units different from the other pdb les but the sequences are the
same, for examples, Val434, Arg513, and Val523 in other
pdb les are Val420, Arg499, and Val509, respectively, in
3LN1). All chromone derivatives as well as the known

selective and non-selective COX-2 inhibitors were docked

into the active sites of both COX-1 and COX-2. The results
were reported as binding energy (Table 3); the lower the
energy, the better the binding interaction. As shown in
Table 3, the docking results were in good agreement with
the experimental COX-2 inhibitory data. The 3-substituted
chromones exhibited higher binding energy against COX-2
(binding energy between 9.77 and 12.74 kcal/mole)
than the 3-unsubstituted compounds (binding energy
between 6.56 and 10.03 kcal/mole). Compounds 35, 38,
and 39 with high SI values had high binding afnity for
COX-2 and less afnity for the active site of COX-1. The
lower selective, compounds 25, 29, and 31, showed binding
afnity against COX-2 (binding energy between 8.07 and
9.48 kcal/mole) comparable to those against COX-1
(binding energy between 7.39 and 8.06 kcal/mole.

Med Chem Res

Fig. 5 a Superimposition of the
docked conformation of
celecoxib (cyan), etoricoxib
(red), valdecoxib (yellow), and
parecoxib (green). b
Superimposition of the docked
conformation of compounds 35
(pink), 38 (blue), 39 (brown),
and 41 (purple) (for color
gures, please see the electronic
version of the article)

Both 3-substituted and 3-unsubstituted chromones exhibited

binding energy pattern similar to those of the known
selective COX-2 and non-selective COX inhibitors.
Figure 3 depicts the binding interactions of selective
COX-2 inhibitors, i.e., celecoxib, etoricoxib and valdecoxib
and chromone compounds against COX-2 and COX-1
obtained from docking study. While the selective COX-2
inhibitors were able to t the binding pocket of COX-2
(Fig. 3a), they were too large to t into the COX-1 binding
site (Fig. 3b). Compounds 35, 38, 39, and 41 could be
positioned nicely in the COX-2 binding site (Fig. 3c) in the
same manner as the known inhibitors but they were unable
to gain the access into COX-1 pocket (Fig. 3d). Moreover,
the docking results also showed that compounds 25, 29, and
31, whose SI < 1, bound to both COX-2 (Fig. 3e) and COX1 (Fig. 3f).
Docking results of chromone compounds in COX-2
enzyme showed that they exhibited the conventional binding modes that usually adopted by reported COX-2 inhibitors. Figure 4 shows the binding mode of compounds 35,
38, and 39 compared with celecoxib. The p-methyl phenyl
group of celecoxib (colored in blue, Fig. 4ac) resided in a
close pocket surrounded by Tyr371 (or Tyr385) and Leu370
(or Leu384) whereas the benzene sulfonamide group
(pharmacophore of celecoxib) lied the side pocket of
Arg499 (or Arg513). As shown in Fig. 5a, etoricoxib, valdecoxib, and parecoxib displayed the same orientation as
celecoxib. The docked conformations of compounds 35, 38,
and 39 were in the orientations similar to that of celecoxib
(Fig. 5b). Substituent at position 3 of chromone compounds
functioned as p-methyl phenyl group of celecoxib to lie in
the hydrophobic pocket and the chromone nucleus
mimicked the benzene sulfonamide group to t in the side
pocket.

Conclusions
COX-2 plays an important role in multiple diseases through
its role in the pathogenesis of inammation. Consequently,
COX-2 remains an attractive and challenging target for
designing the new selective COX-2 inhibitor. In this study,
a series of chromone derivatives have been evaluated for
their ability to inhibit COX-2. The presence of substituent at
position 3 of the chromone nucleus led to high COX-2
inhibitory activity. Compounds 35, 38, 39, and 48 exhibited
higher activity than celecoxib. Compounds 35 and 38 also
showed higher selectivity for COX-2 than celecoxib
whereas compound 39 showed comparable selectivity to
celecoxib. Moreover, the molecular volumes of compounds
35 and 38 were similar to that of celecoxib. Docking results
showed that compounds 35, 38, and 39 had higher binding
afnity against COX-2 than COX-1 and these chromone
compounds also exhibited the conventional binding modes
that usually adopted by celecoxib.
Acknowledgements The authors thank the High Performance
Computer Center (HPCC), National Electronic and Computer Technology Center (NECTEC) of Thailand for providing SYBYL facilities.
Compliance with ethical standards
Conict of interest
peting interests.

The authors declare that they have no com-

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