Novel 2,4-dichlorophenoxy acetic acid substituted thiazolidin-4-ones as anti-inflammatory agents: Design, synthesis and biological screening

Article abstract of DOI:10.1016/j.bmcl.2016.12.069

A library of fourteen 2-imino-4-thiazolidinone derivatives (1a-1n) has been synthesized and evaluated for in vivo anti-inflammatory activity and effect on ex-vivo COX-2 and TNF–α expression. Compounds 1k (5-(2,4-dichloro-phenooxy)-acetic acid (3-benzyl-4-oxo-thiazolidin-2-ylidene)-hydrazide) and 1m (5-(2,4-dichloro-phenooxy)-acetic acid (3-cyclohexyl-4-oxo-thiazolidin-2-ylidene)-hydrazide) exhibited in vivo inhibition of 81.14% and 78.80% respectively after 5 h in comparison to indomethacin which showed 76.36% inhibition of inflammation without causing any damage to the stomach. Compound 1k showed a reduction of 68.32% in the level of COX-2 as compared to the indomethacin which exhibited 66.23% inhibition of COX-2. The selectivity index of compound 1k was found to be 29.00 in comparison to indomethacin showing selectivity index of 0.476. Compounds 1k and 1m were also found to significantly suppress TNF-α concentration to 70.10% and 68.43% in comparison to indomethacin which exhibited 66.45% suppression.

Full text of DOI:10.1016/j.bmcl.2016.12.069

Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel 2,4-dichlorophenoxy acetic acid substituted thiazolidin-4-ones as
anti-inflammatory agents: Design, synthesis and biological screening
a,
b
c
a
Yakub Ali a, Mohammad Sarwar Alam a, , Hinna Hamid , Asif Husain , Abhijeet Dhulap , Sameena Bano ,
⇑
⇑
Chetna Kharbanda a
a Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi 110 062, India
b Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi 110 062, India
c CSIR Unit for Research and Development of Information Products, Pune 411038, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A library of fourteen 2-imino-4-thiazolidinone derivatives (1a-1n) has been synthesized and evaluated
Received 21 June 2016
Revised 9 December 2016
Accepted 28 December 2016
Available online xxxx
for in vivo anti-inflammatory activity and effect on ex-vivo COX-2 and TNF–
a expression. Compounds
1k (5-(2,4-dichloro-phenooxy)-acetic acid (3-benzyl-4-oxo-thiazolidin-2-ylidene)-hydrazide) and 1m
(5-(2,4-dichloro-phenooxy)-acetic acid (3-cyclohexyl-4-oxo-thiazolidin-2-ylidene)-hydrazide) exhibited
in vivo inhibition of 81.14% and 78.80% respectively after 5 h in comparison to indomethacin which
showed 76.36% inhibition of inflammation without causing any damage to the stomach. Compound 1k
showed a reduction of 68.32% in the level of COX-2 as compared to the indomethacin which exhibited
66.23% inhibition of COX-2. The selectivity index of compound 1k was found to be 29.00 in comparison
to indomethacin showing selectivity index of 0.476. Compounds 1k and 1m were also found to signifi-
Keywords:
2-Imino-4-thiazolidinone
Anti-inflammatory
COX-2
cantly suppress TNF-
a concentration to 70.10% and 68.43% in comparison to indomethacin which exhib-
TNF-a
ited 66.45% suppression.
Anti-nociceptive
Ulcerogenic
Ó 2016 Published by Elsevier Ltd.
Introduction
containing compounds.17 Sharma et al.18 reported a series of thia-
zolidinone derivatives and found 2-hydroxyphenyl thiazolidinones
as a potential anti-inflammatory and analgesic agent. Ali et al.6 also
reported a series of 4-thiazolidinone derivatives and found 2-
imino-4-thiazolidinons as a potent anti-inflammatory as well as
Inflammation is a part of the complex biological response of
vascular tissues to harmful stimuli, such as pathogens, damaged
cells, or irritants.1 It is a protective attempt by the organism to
remove the injurious stimuli there by initiating the healing pro-
cess. Non-Steroidal anti-Inflammatory drugs (NSAIDs) such as
indomethacin, ibuprofen, naproxen, and fenbufen are most com-
monly used for the treatment of inflammation, pain, fever and
arthritis.2 However NSAIDs are associated with adverse effects
such as gastrointestinal disorders, ulceration and kidney damage.3
Therefore the development of new drugs with potent anti-inflam-
matory activity and reduced side effects is still a great challenge.
4-Thiazolidinones are an important class of compounds which
have been found to exhibit, anti-inflammatory,4–8 analgesic,9
anti-HIV,10 anticancer,11 anti-bacterial,12 anti-fungal,13 anti-tuber-
cular,14 anti-histaminic activities15 and have also been found out to
TNF-a antagonists. In addition, thiazolidinone has been considered
as an effective lead scaffold for anti-inflammatory COX-2 inhibi-
tors. Ottana et al.19 evaluated 3,3-(1,2-ethanediyl) bis[2-(4-meth-
oxyphenyl)-thiazolidin-4-one] as
a new COX-2 inhibitor and
showed its ability to attenuate the carrageenan-induced lung
injury in experimental models. Considering the biological impor-
tance of 4-thiazolidinones as anti-inflammatory agents, we herein
report the synthesis of novel 2,4-dichlorophenoxy acetic acid
based 4-thiazolidinone derivatives. The synthesized molecules
have been subjected to in vivo anti-inflammatory evaluation. In
order to explore the mechanistic aspects of activity, the synthe-
sized molecules were subjected to in silico molecular docking stud-
act as tumor necrosis factor-
importance in the anti-inflammatory potential of thiazolidinones
a
antagonists.16 Of particular
ies with respect to COX-2 as well as TNF-
synthesized compounds were also evaluated for their ex-vivo
COX-2 and TNF- inhibition. The synthesized compounds have
a target. All the
a
been further screened for their anti-nociceptive potential and also
evaluated for lipid peroxidation and gastric risk.
⇑
Corresponding authors.
E-mail addresses: msalam@jamiahamdard.ac.in, msalam5555@gmail.com
(M.S. Alam), hhamid@jamiahamdard.ac.in (H. Hamid).
http://dx.doi.org/10.1016/j.bmcl.2016.12.069
0960-894X/Ó 2016 Published by Elsevier Ltd.
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2
Y. Ali et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
In the present study, the library of 5-(2,4-dichloro-phenoxy)-
3LN1). All docking runs were carried out using Maestro (Schrodin-
ger). However, only nine molecules (1a, 1c, 1d, 1e, 1g, 1h, 1k, 1l
and 1n) could be docked against the target protein. The docking
scores of ligands 1h and 1k were found to be À7.5 and À8.4 respec-
tively. The molecular binding and interactions of ligands 1h and 1k
in 3D and 2D space are shown in Fig. 1. Molecule 1h interacted
through H-bonding with the ARG-499 residue, whereas molecule
acetic acid 3-(4-substituted-phenyl-4-oxo-thiazolidin-2-ylidene)-
hydrazides were prepared by the condensation of substituted
thiosemicarbazides with ethyl chloroacetate in the presence of
sodium acetate (Scheme 1).
The formation of the synthesized compounds (1a-1n) was con-
firmed by IR, 1H, 13C NMR and mass spectrometry studies (Supple-
mentary data). The 1H NMR data showed the appearance of NH
protons as singlets in the range of d 8.72–10.65 along with CH2
(thiazolidinone ring) protons appearing as singlets at d 3.88–4.25
in the 1H NMR spectra. In the 13C NMR spectra, CH2 carbon of thi-
azolidinone ring appeared at d 31.89–32.98. Other peaks were
observed at appropriate values. Further confirmatory evidence
was obtained from their mass spectra.
All the synthesized compounds (1a-1n) were evaluated for their
in vivo anti-inflammatory activity by carrageenan induced rat paw
edema model. The results of anti-inflammatory activity are shown
in Table 1. Standard drugs indomethacin and celecoxib are well
known anti-inflammatory drugs which are already available in
the market, so we used these two drugs as standard drugs for com-
paring anti-inflammatory activities of synthesized compounds. The
compounds 1k and 1m showed 81.14% and 78.80% inhibition,
respectively which was better than the standard drugs indometha-
cin and celecoxib (76.31% inhibition and 77.67%, respectively) after
5 h. The compounds 1d (72.22%), 1h (68.12%), 1j (68.02%) and 1c
(64.00%) showed anti-inflammatory activity comparable to the
standard drug indomethacin.
1k was found to exhibit hydrophobic interactions and p-p stacking
with TYR-341 and ARG-106 residues. The docking score of refer-
ence ligands indomethacin and celecoxib were found to be À7.06
and À11.57 respectively. Reference drug celecoxib binds into the
binding pocket with specific interactions including H-bond forma-
tion with residues like LEU-338, PHE-504 and ARG-499, whereas
indomethacin exhibits hydrophobic interactions with target pro-
tein as shown in Fig. 1. The glide score and binding energy of all
the nine docked molecules have been summarized in Table 2.
Although compound 1 m exhibited significant in vivo inhibition
of inflammation but it could not be docked against COX-2 target.
In 1 m molecule, cylcohexyl ring is directly attached to oxo-thiazo-
lidin-ylidene ring, resulting in a rigid bulky structure having
restricted rotation. All these factors hinder docking of the molecule
into the binding pocket of COX-2 target.
Intrigued by the docking results, ex-vivo COX-2 activity of the
nine compounds (1a, 1c, 1d, 1e, 1g, 1h, 1k, 1l and 1n) was deter-
mined. Compound 1k was found to show a higher suppression
68.32% of COX-2 enzyme as compared to the standard drug indo-
methacin which exhibited 66.23% inhibition but the suppression
was slightly less than the other reference drug viz celecoxib which
showed 72.96% COX-2 suppression. Other compounds showed
In order to determine their mode of action, all the synthesized
compounds (1a-1n) were docked against COX-2 target (PDB No.
Cl
Cl
I
OH
OC2H5
O
O
90%
Cl
O
Cl
O
I
88 %
II
Cl
Cl
NHNH2
III
NHNH
C
S
NH R
O
O
82-85%
Cl
O
Cl
O
III
II
75-83%
IV
Cl
O
O
Cl
NH N
S
N
R
O
IV
Reagents and Conditions: (I) Absolute alcohol, sulphuric acid refluxes; (II) Hydrazine hydrate,
absolute alcohol, refluxes; (III) Absolute alcohol, isothiaocyanates, reflux; (IV) ethyl
chloroacetate, absolute alcohol, sodium acetate, reflux.
Scheme 1. Protocol for synthesis of title compounds.
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Y. Ali et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
3
Cl
O
O
Cl
O
O
Cl
O
O
Cl
NH N
N
Cl
Cl
NH N
N
Cl
NH N
N
S
S
S
F
O
O
O
1c
1a
1b
Cl
O
O
Cl
O
O
Cl
O
O
Cl
NH N
Cl
NH N
N
Cl
NH N
N
S
S
S
N
Br
H3CO
O
O
OCH3
1f
O
1d
1e
Cl
O
O
Cl
O
O
Cl
O
O
Cl
NH N
N
Cl
NH N
N
Cl
NH N
N
S
S
S
C2H5O
H3C
C2H5
O
O
O
1g
1i
1h
O
Cl
O
O
Cl
O
Cl
O
O
Cl
NH N
N
Cl
NH N
N
Cl
NH N
N
S
S
S
O2N
O
O
O
Cl
1j
1l
1k
Cl
O
O
Cl
O
O
Cl
NH N
N
Cl
NH N
N
S
S
O
O
1m
1n
Structure of the synthesized compounds (1a-1n)
Scheme 1 (continued)
Table 1
Anti-inflammatory activity of synthesized compounds.
Compounds
R
Dose (mg/kg po)
Change in paw volume (ml)
mean (SEM)
% inhibition
3h
3h
5h
5h
Control
Standard (indomethacin)
Standard (celecoxib)
1a
1b
1c
1d
1e
1f
–
–
–
2 ml/kg
1.550 0.020
0.557 0.017**
0.555 0.020**
0.984 0.013*
0.801 0.018*
0.720 0.014**
0.603 0.015**
0.904 0.020*
0.841 0.014*
0.950 0.017*
0.672 0.019**
1.590 0.011
0.528 0.013**
0.524 0.017**
0.966 0.015*
0.860 0.026*
0.702 0.015**
0.581 0.017**
0.870 0.023*
0.801 0.024*
0.920 0.017*
0.654 0.017**
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
73.57
74.56
43.48
55.40
62.00
69.96
48.94
55.40
45.94
66.06
76.31
77.67
46.63
59.06
64.00
72.22
51.90
59.60
50.00
68.12
Phenyl
p-Fluro phenyl
p-chloro phenyl
p-bromo phenyl
p-methoxy phenyl
O-methoxy phenyl
p-ethoxy phenyl
p-C2H5 phenyl
1g
1h
(continued on next page)
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Y. Ali et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Table 1 (continued)
Compounds
R
Dose (mg/kg po)
Change in paw volume (ml)
mean (SEM)
% inhibition
3h
3h
5h
5h
1i
1j
1k
1L
1m
1n
p-methyl phenyl
O-methyl phenyl
Benzyl
p-nitro phenyl
Cyclohexyl
Butyl
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
0.788 0.023*
0.636 0.019**
0.510 0.015**
0.920 0.020*
0.516 0.021**
1.040 0.016*
0.822 0.016*
0.670 0.021**
0.491 0.021**
0.964 0.022**
0.490 0.010**
1.080 0.011*
57.20
64.71
74.45
47.47
76.57
37.23
55.90
68.02
81.14
45.90
78.80
35.96
Data is analyzed by one way ANOVA followed by Dunnett’s ‘t’ test and expressed as mean SEM from five observations.
*
p < 0.05.
p < 0.01.
**
Fig. 1. Docking images of active compounds (1h, 1k) and standard drugs indomethacin and celecoxib with respect to COX-2 target.
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Y. Ali et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
5
Table 2
Docking results of synthesized compounds with respect to COX-2 target.
Table 3
Selectivity index of active compounds.
Ligands
Glide score
Glide energy
Compounds
COX-1
(IC 50 lM)
COX-2
(IC 50 lM)
Selectivity index (SI)
COX-1/COX-2
1a
1c
1d
1e
1g
1h
1k
1L
À4.968
À4.088
À4.94
À9.655
À0.638
Indomethacin
Celecoxib
1d
1h
1k
3.87
8.13
0.64
9.58
6.93
3.29
0.476
39.67
14.06
16.32
29.00
À13.084
À14.584
À15.34
25.39
134.78
113.12
95.44
À3.977
À5.623
À7.525
À8.402
À4.828
À6.549
À7.06
À12.868
À19.939
À11.697
À7.832
1n
Standard (indomethacin)
Celecoxib
À26.165
À61.768
Compounds 1k and 1m (Fig. 3) were found to form hydrogen
bonds with GLY-121 residue of the target protein and stacking
À11.574
p-p
with TRY-119, TRY-59 respectively. The glide score and
binding energy of all the synthesized compounds are shown in
Table 4.
COX-2 suppression comparable to indomethacin (Fig. 2). The safer
gastric profile of the compounds (1d, 1h and 1k) and may be
related to their COX-2 selectivity (Table 3). Compound 1k (COX-1
All the synthesized compounds were then screened for ex-vivo
TNF-
TNF-
a
a
activity (Fig. 4). Compounds 1k and 1m suppressed the
concentration by 70.20% and 68.43%, respectively in com-
Ic50 = 95.44
Ic50 = 113.12
1 Ic50 = 134.78
potent selective COX-2 inhibition as compared to indomethacin
(COX-1 Ic50 = 3.87 M, COX-2 Ic50 = 8.13 m; SI = 0.476). The
l
l
M; COX-2 Ic50 = 3.29
M; COX-2 Ic50 = 6.93
M; COX-2 Ic50 = 9.58
l
l
M; SI = 29.00), 1h (COX-1
M; SI = 16.32) and 1d (COX-
M; SI = 14.06) exhibited
parison to indomethacin which suppressed the concentration by
66.45%. Whereas the compounds 1h, 1d and 1f showed significant
l
l
decrease in TNF-
compared to the standard drug. Other compounds showed moder-
ate decrease in TNF- level. Thus of all the compounds, 1k and 1m
showed better in vivo anti-inflammatory activity with significant
a concentration of 61.92%, 60.38% and 59.60% as
l
l
COX-1/COX-2 Selective Index (SI value) of the compounds 1d, 1h
and 1k shows the selective nature of these compounds towards
COX-2 inhibition as compared to indomethacin.
a
ex-vivo suppression in the levels of TNF-a. This result was also sup-
The synthesized molecules (1a-1n) were also subjected to in sil-
ported by docking studies.
ico molecular docking against the TNF-a target. Molecular docking
Compounds showing significant in vivo anti-inflammatory
activity were further tested for the anti-nociceptive activity by
acetic acid induced writing test (Table 5). The compounds 1k and
1m showed 51.57% and 49.26% inhibition respectively in compar-
ison to standard drug indomethacin which showed 54.37%
inhibition.
Compounds 1k, 1m, 1d and 1h showing the most potent anti-
inflammatory activity were further checked for ulcerogenic effect.
The compounds 1k, 1m and 1d did not cause any gastric ulceration
(Fig. 5) and epithelial tissue damage as compared to indomethacin
which caused some epithelial layer damage and gastric ulceration
in the stomach wall of rats. Although the compound 1h caused
mild epithelial damage, it was found to be lesser than
indomethacin.
studies were done to provide an insight into the molecular binding
modes of the molecules inside the large pocket of TNF alpha. Crys-
tallized structure of 2AZ5 was chosen from protein data bank and
was used for molecular docking studies with the specific ligand
indomethacin20–22 which inhibits it. In order to determine the
binding pattern and the energies of new ligands; they were docked
individually against the generated grid. All the ligands docked
against the grid showed good glide score as well as binding ener-
gies. The compounds 1k, 1m, 1j, 1f, 1d and 1a, exhibited better
glide score of À6.18, À5.98, À5.77, À5.32, À5.28, and À5.24 respec-
tively in comparison to indomethacin whose glide score was found
to be À5.02. The standard drug indomethacin was found to align
perfectly with the hydrophobic pocket of the TNF-
a protein.
Fig. 2. Effect of synthesized compounds on carrageenan induced COX-2 cytokine level in the rat paw tissue. Data is analyzed by one way ANOVA followed by Dunnett’s ‘t’ test
and expressed as mean SEM from five observations where ⁄p < 0.05, ⁄⁄p < 0.01.
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Y. Ali et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Fig. 3. Docking images of active compounds (1k, 1m) and standard drug indomethacin with respect to TNF-a target.
Table 4
Docking results of synthesized compounds with respect to TNF-
a
target.
Glide energy
Compounds 1k, 1m, 1d and 1h were also evaluated for their
lipid peroxidation activity which is measured as nmol of MDA
per 100 mg of gastric mucosa tissue. Gastric ulceration is also asso-
ciated with cellular membrane disruption and destabilizing via
lipid peroxidation. It has already been reported that the process
of lipid peroxidation proceeds by free radical chain reaction which
is scavenged through enzymatic and non enzymatic antioxidants.
It has been observed that carrageenan increases the level of LPO in
animals. The level of lipid peroxidation in the carrageenan induced
animals was found to be significantly increased. However the level
of LPO was found to decrease significantly in the presence of stan-
dard drug and the test compounds, 1k, 1m, 1d and 1h. The active
compounds 1k, 1m, 1d, caused better reduction in lipid peroxidation
as compared to the standard drug (Fig. 6) whereas the compound
1h caused lesser reduction as compared to the standard drug.
Ligands
Glide score
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1L
1m
1n
À5.24
À4.68
À5.13
À5.28
À4.85
À5.32
À4.31
À4.71
À4.78
À5.77
À6.18
À5.67
À5.98
À4.80
À5.02
À40.06
À37.63
À42.41
À41.12
À42.50
À41.00
À38.18
À39.88
À39.21
À40.40
À39.58
À37.46
À37.50
À34.24
À33.09
Standard (indomethacin)
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Y. Ali et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
7
Fig. 4. Effect of synthesized compounds on carrageenan en induced TNF-a cytokine level in the rat paw tissue. Data is analyzed by one way ANOVA followed by Dunnett’s ‘t’
test and expressed as mean SEM from five observations where ⁄p < 0.05, ⁄⁄p < 0.01.
Table 5
Analgesic activity of active compounds.
Groups
Dose (mg/kg po)
Number of writhes in 10 min
% Protection
Control
Indomethacin
2 ml/kg
95 1.51
–
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
43 1.84**
55.2 1.85**
57.6 1.60*
51.6 1.24*
46.0 1.64**
51.2 1.24**
54.37
41.81
39.36
46.10
51.57
49.26
1d
1h
1j
1k
1m
Data is analyzed by one way ANOVA followed by Dunnett’s ‘t’ test and expressed as mean SEM from five observations.
*
p < 0.05.
p < 0.01.
**
Fig. 5. Histopathology of rat stomach in Albino Wistar rats. Low power (10x) and high power photomicrographs (40x) of stomach wall of the animal groups administered
with control group 1k, 1m, 1d, 1h, (90 mg/kg b.w) and standard drug, indomethacin, respectively.
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Y. Ali et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Fig. 6. Lipid peroxidation assay of active compounds.
acetic acid (3-benzyl-4-oxo-thiazolidin-2-ylidene)-hydrazide) and
Structure activity relationship
1m (5-(2,4-dichloro-phenooxy)-acetic acid (3-cyclohexyl-4-oxo-
thiazolidin-2-ylidene)-hydrazide) exhibited significant anti-
inflammatory and analgesic activities. Compound 1k reduced
COX-2 level significantly and showed potent COX-2 selectivity.
The structure activity relationship of the synthesized com-
pounds has been analyzed as follows.
The level of TNF-
a was also significantly reduced by compounds
1k and 1m. Furthermore these two compounds caused reduction
in LPO concentration and did not cause any damage to the stomach
lining. Compounds 1k and 1m may thus be considered as promis-
ing candidates for development of new and safer anti-inflamma-
tory agents.
Cl
O
O
Cl
NHN
N
S
R
O
Acknowledgements
Ring A
The authors wish to express their thanks to Dr G N Qazi, Vice
Chancellor, Jamia Hamdard for providing necessary research facil-
ities. One of the authors, YA is also thankful to Hamdard National
Foundation for providing financial assistance.
Bullet Compounds having halogen atom on ring (A) showed bet-
ter anti-inflammatory activity in the increasing order of
the size of halogen atoms i.e. the order of anti-inflamma-
tory activity was found to be 1b < 1c < 1d.
Bullet The presence of para ethyl group at ring (A) showed better
activity as compared to methyl being present at para posi-
tion i.e. the compound 1h showed better activity than the
compound 1i. While no significant difference in activity
was seen for p-methoxy and p-ethoxy group substitution
at ring A.
Supplementary material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.12.
069.
References
1. Buer JK. Inflammopharmacology. 2014;22:263–267.
2. Warden SJ. Phys Sportsmed. 2010;38:132–138.
Bullet Compound having benzyl substitution (1k) in place of ring
A showed maximum in vivo anti-inflammatory activity and
3. Hasnain H, Ali H, Tariq A, Zafar F, Naveed S. J Bioequiv Availab. 2016;8:84–88.
4. Sharad KS, Varun J, Sandeep L, et al. Eur J Med Chem. 2013;63:589–602.
5. Hua J, Wang Yi, Xiaoyan W, et al. Eur J Med Chem. 2013;64:292–301.
6. Ali Y, Alam MS, Hamid H, et al. New J Chem. 2016;40:711–723.
7. Abdellatif KRA, Abdelgawadp MA, Helshemy HA, Alsayed SSR. Bio Org Chem.
2016;64:1–12.
8. Maccari R, Vitale RM, Ottanà R, Rocchiccioli M, Marrazzo A, Cardile V. Eur J Med
Chem. 2014;81:1–14.
9. Sandeep J, Prabodh CS, Priyanka P, Manav M. Med Chem Res.
2012;21:1652–1659.
suppression in COX-2 and TNF-a level.
Bullet Cyclohexyl substitution (1m) in place of ring A showed sig-
nificant activity as compared to any other substitution on
ring A.
Bullet Replacing ring A with butyl group (1n) significantly low-
ered in vivo as well as ex-vivo activity.
Bullet Ortho substitution was found to be more active than para
substitution when comparison of same substitution at dif-
ferent position on ring A was made.
10. Küçükgüzel I, Satılmıs, Gurukumar GKR, et al. Eur
J
Med Chem.
2013;69:931–941.
11. Rashid M, Husain A, Shaharyar M, Mishra R, Hussain A, Afzal O. Eur J Med Chem.
2014;83:630–645.
12. Desai NC, Dodiya AM. Arabian J Chem. 2014;7:906–913.
13. Marques GH, Kanzuler A, Bareno VD, et al. Med Chem. 2014;10:355–360.
In summary, a library of fourteen compounds has been synthe-
14. Samadhiya P, Sharma R, Srivastava SK, Srivastava SD. Arabian
J Chem.
sized out of which two compounds 1k (5-(2,4-dichloro-phenooxy)-
2014;7:657–665.
Please cite this article in press as: Ali Y., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2016.12.069

Y. Ali et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
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15. Diurno MV, Mazzoni O, Correale G, Monterry IG. Farmaco. 2011;54:579–583.
16. Voss ME, Carter PH, Tebben AJ, et al. Bioorg Med Chem Lett. 2003;13:533–538.
20. Slomiany BL, Piotrowaski J, Slomiany A, Scand J. Gastroenterology.
1997;32:638–642.
17. Geronikaki AA, Lagunin AA, Hadjipavlou-Litina DI, et al.
2008;511:601–1609.
J
Med Chem.
21. Jung CL, Jeng SD, Chuan SC, et al. Complementary Altern Cardiovasc Med.
2012;1–12.
18. Kumar AV, Jain S, Sharma PC. J Enzyme Inhib Med Chem. 2011;26:546–552.
19. Ottana R, Maccari R, Barreca ML, et al. Bioorg Med Chem. 2005;13:4243–4252.
22. Saqlain H, Alam MS, Hinna H, et al. Med Chem Res. 2014;23:4250–4268.
Please cite this article in press as: Ali Y., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2016.12.069