Synthesis and evaluations of selective COX-2 inhibitory effects: Benzo[d]thiazol analogs

Article abstract of DOI:10.1016/j.bmcl.2020.127376

A series of benzo[d]thiazole analogs were synthesized and evaluated for their anti-inflammatory and analgesic effects. Using an ear edema model, except for compounds 2k, 2m-2q and 3a, other compounds showed the anti-inflammatory effects. Among them, compo

Full text of DOI:10.1016/j.bmcl.2020.127376

Journal Pre-proofs
Synthesis and evaluations of selective COX-2 inhibitory effects: benzo[d]thia‐
zol analogs
Li-Ya He, Shan-Shan Zhang, Ding-Xin Peng, Li-Ping Guan, Xi-Hong Wang
PII:
DOI:
Reference:
S0960-894X(20)30487-X
https://doi.org/10.1016/j.bmcl.2020.127376
BMCL 127376
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
19 April 2020
29 June 2020
29 June 2020
Please cite this article as: He, L-Y., Zhang, S-S., Peng, D-X., Guan, L-P., Wang, X-H., Synthesis and evaluations
of selective COX-2 inhibitory effects: benzo[d]thiazol analogs, Bioorganic & Medicinal Chemistry Letters
(2020), doi: https://doi.org/10.1016/j.bmcl.2020.127376
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version
will undergo additional copyediting, typesetting and review before it is published in its final form, but we are
providing this version to give early visibility of the article. Please note that, during the production process, errors
may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier Ltd.

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Synthesis and evaluations of selective COX-2 inhibitory effects: benzo[d]thiazol
analogs
Li-Ya Hea†, Shan-Shan Zhanga†, Ding-Xin Penga, Li-Ping Guana*, Xi-Hong Wang b*
a Food and Pharmacy College, Zhejiang Ocean University, Zhejiang, Zhoushan 316022, P. R. China
b Key Laboratory of Natural Resource of the Changbai Mountain and Functiaonal Molecules, Ministry of education, Yanbian University, Jilin Yanji 133000,
China
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A series of benzo[d]thiazole analogs were synthesized and evaluated for their anti-inflammatory and
analgesic effects. Using an ear edema model, except for compounds 2k, 2m-2q and 3a, other
compounds showed the anti-inflammatory effects. Among them, compounds 2c, 2d, and 2g showed
the best anti-inflammatory activity (inhibition rate: 86.8 %, 90.7 % and 82.9 %, respectively). By the
acetic acid-induced abdominal writhing test, except for compounds 2e, 2l, 2m, 2o, 2p and 3a, other
compounds showed the analgesic effects with inhibition rate values of 51.9–100 % (2a-2r) and 68.6–
100 % (3a-3g). Next, compounds 2c, 2d, 2g, 3d, 3f, 3g that displayed the excellent anti-inflammatory
and analgesic activities were evaluated for their inhibitory effect against ovine COX-1 and COX-2.
Compounds 2c, 2d, 2g, 3d, 3f, 3g were weak inhibitors of the COX-1 isozyme but exhibited the
moderate COX-2 isozyme inhibitory effects IC50 from 0.28 to 0.77 μM and COX-2 selectivity indexes
(SI: 18.6 to 7.2). This benzo[d]thiazole moiety will be proved to be of great significance for
developing more potent COX-2 inhibitors.
Keywords:
Benzo[d]thiazol
Sythesis
Anti-inflammatory
Analgesic
COX-2 inhibitors.
E-mail: glp730@163.com (L.P.Guan); shwang@ybu.edu.cn(S.-H. Wang)
Benzothiazoles are bicyclic heterocyclic aromatic
hydrocarbon compounds that possess thiazole and phenyl rings
including sulfur and nitrogen in their structures. Benzothiazole
derivatives are an interesting core responsible for numerous types
of biological effects and pharmacological properties including
anticancer, antioxidant, anti-inflammatory, antibacterial, antiviral,
a new series of benzisothiazole-2-ylimino-5-aryliden-4-thiazoli-
dinones were also found to exhibit some COX-2 inhibitory
activity (12.3-45.0 %) as shown Figure 116. Among them, two
compounds exhibited the highest potency and selectivity for
COX-2 inhibitory activity introducting of two chloro groups.
analgesic, cycloxygenase and lipoxygenase inhibitory properties.
1-8
The non-steroidal anti-inflammatory drugs are widely used
therapeutics to treat the inflammation and pain from the various
pathological disorders. The non-steroidal anti-inflammatory
drugs affect by inhibiting cyclooxygenase enzymes, which
catalyze prostaglandin biosynthesis through arachidonic acid.
Cyclooxygenase enzymes-1 (COX-1) and cyclooxygenase
enzymes-2 (COX-2) are two known cyclooxygenase isoform.
But, the use of the non-steroidal anti-inflammatory drugs might
lead to some side effect containing renal dysfunction, bleeding
N
O
F
N
S
NH2
O2N
NH
S
NO2
II
I
NO2
anti-inflammatory inhibition(78%)
Lozynskyi et al., Biopolymers and Cell. 2015, 31, 131. Venkatesh et al., Int. J. ChemTech Res. 2009, 1, 1354.
analgesic (3.70 ¡À0.60 mg)
N
Cl
S
O
and pepticulcers, mainly non-selective or selective COX-1
NH
N
9,10
O
inhibitors.
So, the interestingly selective inhibition of COX-2
N
S
S
S
N
S
NH
over COX-1 is believed to reduce gastric ulceration side effect
and identification of clinically useful non-steroidal analgesic and
anti-inflammatory and drugs via selective inhibition of COX-2 is
an ongoing goal in medicinal chemistry.11,12 Therefore, the
development and study of the efficient and new selective COX-2
inhibitory compounds is essential.
N
Cl
COX-2 inhibition (58.8%)
COX-2 inhibition (45.1%)
Eleftheriou et al., Eur. J. Med. Chem. 2012, 47, 111.
Figure 1. Benzothiazole analogs of reported anti-inflammatory, analgesic or
as COX-2 inhibitors.
In addition to benzothiazole compounds have been reported
to display the anti-inflammatory and analgesic effects, which is
an important moiety in medicinal chemistry. Such as, compounds
I displayed the anti-inflammatory activity with inhibition rate 78
%13. Compound II showed a good analgesic effect with IC50 for
3.70 mg14. In addition, Eleftheriou et al., also reported that
———
Selection of the fragments that can be used for the design of
new chemicals with the required biological activity profile is a
key stage in inhibitor of COX-2. Our research group has been
studying with the chemical and biological properties of
heterocyclic compounds. However, not many inhibition activity
reports the inhibitor of COX-2 of benzo[d]thiazole and ethoxyl-
benzo[d]thiazole analogs. Therefore the development with
† These authors contributed equally to this work.
 Corresponding author. Tel.: +86-580-2555280.+86-433-2732207

benzothiazole moiety compounds of an inhibitor of COX-2 is
essential.
Based on these results, as part of our groups search for the
potential anti-inflammatory, analgesic and selective COX-2
inhibitory compounds with the chemical and biological
properties of benzo [d]thiazol compounds, we synthesized
eighteen benzyloxybenzo [d]thiazole (2a-2r) and seven
phenoxylethoxylbenzo[d]thiazole analogs (3a–3g) (Figure 2),
and evaluated their anti-inflammatory and analgesic effects in
vivo. The COX-1 and COX-2 inhibition effects of selected
compounds were also determined in vitro.
N
S
BrCH2CH2Br
K2CO3
N
S
OH
OCH2CH2Br
R2
2
OH
K2CO3
R2
N
S
OCH2CH2O
H
N
N
3a-3g
benzyl
O
O
S
S
R2:
3a=H
3b=4-F
3f=2,4-Cl2
Scheme 1. The synthetic routes of compounds 2a–2r .and 3a-3g
3c=4-Cl
3d=4-Br
2a-2r
3e=2,4-F2
3g=2,4-Br2
phenoxylethyl
Fragment can be selected for the design, synthesis and
developing of the novel potent COX-2 inhibitors with a multiple
mechanism of action21. Based on the results of fragment library
analysis and taking into account the synthetic accessibility and
SAR analysis of the designed thiazole derivatives. 22 Twenty-five
benzo[d]thiazole derivatives and the reference drug indomethacin
were evaluated for their anti-inflammatory activities using a
xylene-induced ear edema model in vivo.23 The percentage
inhibition of the inflammation for benzo[d]thiazole derivatives
was examined after 1 h of treatment with xylene. The anti-
inflammatory activities of benzo[d]thiazole derivatives 2a-2r and
3a-3g (100 mg/kg) were comparable to indomethacin (100
mg/kg) (Table 1). 11 compounds 2a-2j and 2l displayed the anti-
inflammatory effects administered intraperitoneally before the
inflammatory agent xylene with ear inflammation values of 0.19
mg to 1.79 mg and the inhibition rate of the inflammation of 12.7
%–90.7 %. Nine compounds 2a-2d and 2f-2j exhibited good
anti-inflammatory effects with inhibition values more than 65 %,
which the part compounds was nearly equivalent to that of
indomethacin (82.4 %). Except for compound 3a, the rest
compounds 3b-3g exhibited the anti-inflammatory effect
administered intraperitoneally before the inflammatory agent
xylene with ear inflammation values from 0.11 mg to 0.90 mg
and inhibition rate of inflammation of 56.1–94.6 %. Compounds
3d, 3f, and 3g also showed the excellent anti-inflammatory
effects with inhibition rate of inflammation of 94.6 %, 85,4 %
and 87.3 %, respectively, which was nearly equivalent to that of
indomethacin (82.4 %).
N
S
OCH2CH2O
3a-3g
benzo[d]thiazol-2(3H)-one
Figure 2. The structures of benzo[d]thiazol analgesics 2a-2r and 3a-3g
Compounds 2a–2r and 3a–3g were prepared as shown in
Schemes 1. The commercially available benzo[d]thiazol-2-ol (1)
is the starting material; compounds 2a–2r is obtained through
introduction of benzyl group by a one-step nucleophilic
substitution reaction. Compounds 3a–3g are obtained through a
two-step reaction, the intermediate 2-(2-bromoethoxy) benzo[d]
thiazole (2) is synthesized and underwent a nucleophilic
substitution reaction with 1,2-dibromoethane, then the 2-(2-
bromoethoxy)benzo[d]thiazole formed is reacted with substituted
phenols.17,18 The structures of Compounds 2a–2r and 3a–3g are
determined by infrared (IR), proton nuclear magnetic resonance
(1H-NMR), carbon nuclear magnetic resonance (13C-NMR)
spectroscopy, and mass spectroscopy (MS).
The IR spectra of the synthesized derivatives 2a–2r and
3a–3g showed absorption bands at 1682–1686 cm-1 for the -C=N
stretching vibration, 1250-1255 cm-1 for the C-O-C stretching
vibration and 1050-1055 cm-1 for the C-S-C stretching vibration.
The 1H-NMR data confirmed the presence of an -CH2Ph group as
a singlet signal at 5.06-5.25 ppm. The 13C-NMR spectra showed
the appearance of a peak from 39.50–46.25 ppm for the -CH2Ph
group and 170.28–170.43 ppm for the C=N group. 19,20
Table 1. Anti-inflammatory effects of compounds 2a-2r and 3a-3g in vivo
Anti-inflammatory activity
N
N
Edema mean
±SD (mg)
Inhibition
rate %
Edema mean Inhibition
Compd
K2CO3
OH
+
CH2Br
±SD (mg)
rate %a
68.8
74.6
86.8
90.7
14,6
80.0
82.9
75.6
77.6
78.0
4.39
12.7
S
O
S
R1
3a
3b
3c
3d
3e
3f
0.64±0.23**
0.52±0.19**
0.27±0.10***
0.19±0.07***
1.75±0.64*
0.41±0.24**
0.35±0.14***
0.50±0.26**
0.46±0.21**
0.45±0.18**
1.96±0.97
1.90±0.90
2a
2b
2c
2d
2e
2f
7.31
72.7
66.3
94.6
56.1
2a-2r
1
0.56±0.32**
0.69±0.22**
0.11±0.07***
0.90±0.17*
R1:
2a=H
2e=2-Cl
2i=3-Br
2b=2-F
2f=3-Cl
2j=4-Br
2c=3-F
2g=4-Cl
2k=4-NO2
2d=4-F
2h=2-Br
2l=4-CN
0.30±0.18***
0.26±0.19***
85.4
87.3
2m=2-CF3
2q=3,5-(CH3)2
2n=4-CF3
2r=3,5-(OCH3)2
2o=4-CH3
2p=4-OCH3
3g
2g
2h
2i
2j
2k
2l
1.79±0.55*

analgesic effects. In this analysis, the order of effects for
compounds including substitutions on the phenyl ring was 3-F>4-
F>2-F and 3-Cl>4-Cl>2-Cl. The order of effects observed for
compounds containing a Br-substituent was 2-Br>4-Br>3-Br. For
compounds 3b-3d displayed the best analgesic effects was 4-
F>4-Br>4-Cl, and the order of activity for 2,4-disubstituted
2.03±0.83
1.80±0.86
2.01±0.76
2.00±0.75
2.04±0.83
1.14±0.50*
0.36±0.23***
2.05±0.40
9.75
12.2
2m
2n
2o
1.95
2.43
0.50
44.4
82.4
—
2p
2q
2r
compounds 3e-3g positions was
2,4-F2>2,4-Cl2>2,4-Br2.
0.36±0.23***
82.4
Idm
Compound 3b with a 4- fluorine substituent showed the most
analgesic effect with inhibition rate values of 99.9 %. For
compounds 2k-2n with a trifluoromethyl (-CF3), nitro (-NO2) or
cyano (-CN) groups on the phenyl ring, compounds 2k and 2n
displayed better analgesic activities with inhibition values of 97.0
% and 99.57 %. But compounds 2l and 2m did not show
analgesic activities.
control
2.05±0.40
—
Idm: Indomethacin.
a % at 1 h of anti-inflammatory activity.
*p<0.05, ** p<0.01,*** p<0.001 compared with the PEG-400 (control) group
The structure activity relationship studies for the anti-
inflammatory effects of eighteen analogs 2a-2r and seven 3a–3g
shown in table 1 illustrated. Seventeen compounds reduced the
ear inflammation and displayed the anti-inflammatory effects not
only including the electron-donating substituents but also the
electron-withdrawing substituents on the benzyloxy or phenoxyl-
ethoxyl moiety. For compounds containing the electron-donating
groups of -CH3, -OCH3, 3,5-(CH3)2 on the phenyl ring, do not
show a good anti-inflammatory effects, only compound 2r with
3,5-(OCH3)2 showed the anti-inflammatory activity. Among
compounds possessing the electro-withdrawing substituents,
fifteen compounds 2b-2j and 3b-3g with halogen atom
substitution F (2b, 2c and 2d), Cl (2e, 2f and 2g), or Br (2h, 2i
and 2j), resulted in the most anti-inflammatory effects when
substituted at the p-position of the phenyl ring as demonstrated
for compounds 2d, 2g and 2j, with the best compound being 2d
with ear inflammation values 90.7 % for benzyloxybenzo[d]
thiazole derivatives. Within 3b-3g series, the excellent anti-
inflammatory were observed when a halogen atom as electron-
withdrawing groups was present. Compound 3d exhibited the
most effect with the bromine at p-position. Therefore, the
substitution position of the halogen atom greatly influenced the
anti-inflammatory effects. The order of activity for 2b-2j
derivatives containing substitutions on the phenyl ring was 4-
F>2-F>3-F, 4-Cl>2-Cl>3-Cl, and 4-Br>2-Br> 3-Br. The order of
activities for 3b-3d compounds with substitutions on the phenyl
ring was 4-Br>4-F>4-Cl and the order of activity for 2,4-
disubstituted compounds 3e-3g positions was 2,4-Br2 2,4-Cl2>
2,4-F2. However, for compounds 2k-2n with a trifluoromethyl (-
CF3), nitro (-NO2) or cyano (-CN) groups on the phenyl ring do
not display the anti-inflammatory activity. The replacement of
less lipophilic nitro trifluoromethyl and cyano group substituent
leads to a decrease effects. It may be no clear correlation between
in vivo activity.
Notes: idm: Indomethacin
Figure 3. Analgesic effect of the designed compounds 2a-2r and 3a-3g
The analgesic effects of analogs 2a-2r and seven 3a–3g
were evaluated by the acetic acid-induced abdominal writhing
test and compared with indomethacin as the reference. Except for
compounds 2e, 2l, 2m, 2o, 2p and 3a, other compounds
displayed the analgesic effects a with activities inhibition rate
values of 51.9–99.9 % (2a-2r) and 68.6–99.9 % (3a-3g) not only
with the electron-donating substituents but also with the electron-
withdrawing substituents on the phenyl ring at a dose of 100
mg/kg administered intraperitoneally (Figure 3). For four
compounds including the electron-donor groups of -CH3, -OCH3,
3,5-(CH3)2, and 3,5-(OCH3)2 on the phenyl ring, the order of the
analgesic effects was 3,5-(OCH3)2>3,5-(CH3)2>4-OCH3>4-CH3.
Among compounds possessing electron-withdrawing substituents
2b-2j series and 3b-3g series, some with an halogen atom
substituent group, F (2b, 2c and 2d), Cl (2e, 2f and 2g), or Br
(2h, 2i and 2j), display the excellent analgesic effects specially
when in the m-position of the phenyl ring as shown for series F
(2b, 2c and 2d), Cl (2e, 2f and 2g), but at the o-position of the
phenyl ring for compounds Br (2h, 2i and 2j). Thus, the position
of the halogen atom substitution greatly also influenced the
Traditional non-steroidal anti-inflammatory drugs such as
aspirin, ibuprofen or indomethacin, mainly non-selective or
selective COX-1inhibitors, was associated with renal disorders,
gastrointestinal problems and bleeding diathesis.25-27 The
gastrointestinal irritation, bleeding, and ulceration side effects of
the classical non-steroidal anti-inflammatory drugs are attributed
to their selectivity for COX-1 versus COX-2. Therefore, the
development of novel selective COX-2 inhibitors through
medicinal chemistry approaches is essential.28,29 So, in this
present study, we select six compounds 2c, 2d, 2g, 3d, 3f, 3g that
showed the excellent anti-inflammatory and analgesic activities
were evaluated for their inhibitory effect against ovine COX-1
and COX-2 (Table 2). The results exhibited that three compounds
including a benzyloxybenzo[d]thiazole moiety were weak
inhibitors of the COX-1 isozyme but showed moderate COX-2
isozyme inhibitory effects (IC50 from 0.28 μM to 0.77 μM) and
COX-2 selectivity indexes (SI: 18.6 to 7.2). Furthermore, three
compounds containing phenoxylethoxylbenzo[d]thiazole moiety

were weak inhibitors of the COX-1 isozyme but showed
moderate COX-2 isozyme inhibitory effects (IC50: from 0.27 μM
to 0.41 μM) and COX-2 selectivity indexes (SI: 19.7 to 10.4).
Additionally, the activity of compound 2c (IC50=0.28 μM,
SI=18.6) was more similar to inhibitors of the COX-2 isozyme
than the reference drug celecoxib (IC50 =0.27 μM, SI=19.7). The
results indicated that the molecular hybridization of benzo[d]
thiazole pharmacophore of the COX-2 inhibitors was a useful
building block to produce effective hybrid scaffolds with
improved analgesic and anti-inflammatory effect potential.
1. Leleu-Chavain, N.; Baudelet, D.; Heloire, V.M.; Rocha,
D.E.; Renault, N.; Barczyk, A.; Djouina, M.; Body-Malapel,
M.; Carato, P.; Millet, R. Eur. J. Med. Chem. 2019, 165,
347.
2. Cindrić, M.; Perić, M.; Kralj, M.; Martin-Kleiner, I.;David-
Cordonnier, M.H.; Paljetak, H.Č.; Matijašić, M.; Verbanac,
D.; Karminski-Zamola, Grace.; Hranjec, M. Mol. Div. 2018,
22, 637.
3. Akhtar, T.; Hameed, S.; Al-Masoudi, N.A.; Loddo, R.; La
Colla, P. Acta Pharm. 2008, 58, 135.
4. Nagararaju, G.; Sai, K.B.; Chandana, K.; Guldipati, M.,
Suresh, P.V.; Ramarao, N. Indo. Amer. J. Pharm. Res. 2015,
5, 1288.
Table 2. COX-1/COX-2 enzyme inhibition assay in vitro
Compounds
COX-1, IC50(μM) a
COX-2, IC50(μM) COX-2, SI b
18.6
16.8
7.2
2c
5.22±0.10
6.20±0.15
0.28±0.12
0.37±0.19
2d
2g
5.55±0.20
5.32±0.26
4.28±0.18
5.08±0.14
5.33±0.11
0.77±0.29
0.50±0.08
0.41±0.26
0.36±0.03
0.27±0.07
5. Akhilesh, G.; Swati, R. J. Chem. Pharm. Res. 2010, 2, 244.
10.6
10.4
14.1
19.7
3d
3f
6. Keri, R.S.; Quintanova, C.; Marques, S.M.; Esteves, A.R.;
Cardoso, S.M.; Santos, M.A. Bioorg. Med. Chem. 2013, 21,
4559.
3g
Celecoxib
a
7. Wang, S.; Chen, Y.; Zhao, S.; Xu, X.; Liu, X.; Liu, B.F.;
IC50 value is the compound concentration required to produce 50%
inhibition of COX-1 or COX-2 for means of three determinations and
deviation from the mean is <10% of the mean value.
Zhang, G. Bioorg. Med. Chem. Lett. 2014, 24, 1766.
8. Rouf,A.; Tanyeli, C. Eur. J. Med. Chem. 2015, 97, 911.
9. Venu,T.D.; Shashikanth, S.; Khanum, S.A.; Naveen, S.;
Firdouse, A.; Sridhar, M. A.; Prasad, J.S. Bioorg. Med.Chem.
2007, 15, 3505.
10. Ottana, R.; Maccari, R.; Barreca, M.T.; Bruno, G.; Rotondo,
A.; Rossi, A.; Chiricosta, G.; Paola, R.; Sautebin, L.;
Cuzzocrea, S.; Vigorita, M.G. Bioorg. Med. Chem. 2005, 13,
4243.
11. Gouvea, D.P.; Vasconcellos, F.A.; Berwaldt, Gabriele dos A.;
Seixas Neto, A.C. P.; Fischer, G.; Sakata, R.P.; Almeida,
W.P.; Cunico, W. Eur. J. Med. Chem. 2016, 118, 259.
12. Paramashivappa, R.; Phani Kumar, P.; Subba Rao, P. V.; A
Srinivasa Rao, A. Bioorg. Med. Chem. Lett. 2003, 13, 657.
13. Lozynskyi, A. V.; Kaminskyy, D. V.; Romanchyshyn, Kh.
B.; Semenciv, N. G.; Ogurtsov, V. V.; Nektegayev, I. O.;
Lesyk, R. B. Biopolymers and Cell. 2015, 31, 131.
14. Venkatesh, P.; Pandeya, S.N. Int. J. ChemTech Res. 2009, 1,
1354.
b SI: selectivity index (COX-1 IC50/COX-2 IC50).
In conclusion, 25 benzo[d]thiazole compounds bearing a
benzyloxy or phenoxylethoxyl moiety were designed, synthesiz-
ed and evaluated for their anti-inflammatory and analgesic
activities. The results indicated that 18 compounds displayed the
anti-inflammatory effects, 20 compounds showed the analgesic.
Among them, compounds 2d and 3d exhibited the most anti-
inflammatory with inhibition of inflammation of 90.7 % and 94.6
%. Next, compounds 2c, 2d, 2g, 3d, 3f, 3g that displayed the
excellent anti-inflammatory and analgesic activities were
evaluated for their inhibitory effect against ovine COX-1 and
COX-2, compounds 2c, 2d, 2g, 3d, 3f, 3g were weak inhibitors
of the COX-1 isozyme but showed moderate COX-2 isozyme
inhibitory activities IC50 from 0.28 μM to 0.77 μM) and COX-2
selectivity indexes (SI: 18.6 to 7.2). Hence, these compounds
reported herein are promising starting points for the development
of an inhibitor of COX-2.
15. Eleftheriou, P.; Geronikaki, A.; Hadjipavlou-Litina, D.;
Vicini, P.; Filz, O.; Filimonov, D.; Poroikov, V.;
Chaudhaery, S.S.; Roy, K.K.; Saxena, A.K. Eur. J. Med.
Chem. 2012, 47, 111.
This research was funded by the National Natural Science
Foundation of China (No. 2196017).
16. Raghavendra, N.M.; Jyothsna, A.; Venkateswara Rao, A.;
Subrahmanyam, C.V.S. Bioorg. Med. Chem. Lett. 2012, 22,
820.
17. Demir Özkay, Ü.; Kaya, C.; Acar Çevik, U.; Devrim Can, Ö.
Molecules 2017, 22, 1490.
18. Haroun, M.; Tratrat, C.; Kositzi, K.; Tsolaki, E.; Petrou, A.;
Aldhubiab, B.; Attimarad, M.; Harsha, S.; Geronikaki, A.;
Venugopala, K.N.; Elsewedy, H.S.; Sokovic, M.; Glamoclija,
J.; Ciric, A. Current Topics in Med. Chem. 2018, 18, 75.
19. A stirred solution of benzothiazolone (3.0 mmol), anhydrous
K2CO3 (3.0 mmol) and 5 mL DMF were placed to round-
bottomed flask, the reaction solution was mixed for 1 hour at
60 °C, after that, 1.2 mmol 4-fluorobrominated benzyl was
placed slowly to the reaction solution. The reaction solution
was refluxed for five h, the reaction process was determined
by TLC. The filtrate was cleaned through acetone. The
removal of solution by vacuum distillation, the crude
products was purified with MeOH. The yield, melting point,
and spectral data of each compound are given as below.

2-(4-fluorobenzyloxy)benzo[d]thiazole (2d). Yield: 84.07%,
mp: 89.4-89.9°C. IR (KBr) cm-1: 2924, 1684, 1252, 1054. 1H-
NMR (CDCl3, 300 MHz): 5.11 (s, 2H, -CH2Ph), 6.94-7.21
(m, 4H, -C6H4), 7.23-7.45 (m, 4H, -C6H4). 13C-NMR (CDCl3,
75 MHz): 45.52, 111.09, 115.72, 116.01,122.67, 122.73,
164.01, 170.33. ESI-MS calcd for C14H11FNOS+([M+H]+):
260.05; found: 260.00.
123.38, 126.39, 128.93, 129.04,130.98, 136.79 ,160.74,
20. A stirred solution of benzothiazolone (3.0 mmol), anhydrous
K2CO3 (3.0 mmol) and 5 mL DMF were added a round-
bottomed flasks, the reaction solution was stirred for 1 hour
at 60 °C, and, 2-(2-bromoethoxy)benzo[d]thiazole (3.0 mmol)
was slowly added the reaction solution, after the completion
of the reaction (monitored by TLC), then added 10 mL the
mixture of NaOH and 4-bromophenols. The reaction solution
was refluxed for 5 hours. Filtered 10% HCl was washed
through water. The crude product was recrystallized with
methanol.
2-[2-(4-bromophenoxyl)ethoxyl]benzo[d]thiazole
(3d).
Yield: 40.11%, mp: 83.8-85.0°C. IR (KBr) cm−1: 2924, 1684,
1
1252, 1054. H-NMR(CDCl3, 300 MHz): 4.26 (t, 2H, -CH2),
4.34 (t, 2H, -CH2), 6.68-6.70 (m, 4H, -C6H4), 7.16-7.43 (m,
4H, -C6H4). 13C-NMR (CDCl3, 75 MHz): 42.27, 65.61,
109.85, 111.22, 113.52, 116.18, 117.25, 122.59, 122.70,
123.28, 126.29, 132.32, 137.38, 157.19, 170.34. ESI-MS
calcd for C15H13BrNO2S+ ([M+H]+): 349.98; found: 350.05.
21. Kutchukian,P.S.; Shakhnovich, E.I. Drug Discov. 2010, 5,
789.
22. Geronikaki, A.A.; Lagunin, A.A.; Hadjipavlou-Litina, D.I.;
Elefteriou, P.T.; Filimonov, D.A.; Poroikov, V.V.; Alam, I.;
Saxena, A.K. J. Med. Chem. 2008, 51, 1601.
23. Ohlsson, L. Acta Pharmacol. Toxicol. 1953, 9, 322.
24. Cordeiro, K.W.; Felipe, J.L.; Malange, K.F.; do Prado, P.R.;
de Oliveira Figueiredo, P.; Garcez, F.R.; de Cássia Freitas, K.;
Garcez, W.S.; Toffoli-Kadri, M.C. J. Ethnopharmacol. 2016,
183, 128.
25. Guan, L.P.; Xia,Y.N.; Jin, Q.H.; Liu, B.Y.; Wang, S.H.
Bioorg. Med. Chem. Lett. 2017, 27, 3378.
26. Shi, L.; Aixi, H.; X. Jiangpina, Yiping, J. Chin. J. Chem.
2012, 30, 1339.
27. Dou, J.; Shi, L.; Hu, A.; Dong, M.; Xu, J.; Liu, A.; Jiang, Y.
Arch. Pharm. Chem. Life Sci. 2014, 347, 89.
28. Eleftheriou, P.; Geronikaki, A.; Hadjipavlou-Litina, D.;
Vicini, P.; Filz, O.; Filimonov, D.; Poroikov, V.; Chaudhaery,
S.S.; Roy, K.K.; Saxena, A.K. Eur. J. Med. Chem. 2012, 47,
111.
29. El-Sayed, M.; Abdel-Aziz, N.I.; Abdel-Aziz, A.A.-M.; El-
Azab, A.S.; ElTahir, K. Bioorg. Med. Chem. 2012, 20, 3306.
Click here to remove instruction text...

Declaration of interests
☑The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
Graphical Abstract
To create your abstract, type over the instructions in the
template box below.
Fonts or abstract dimensions should not be changed or altered.
Synthesis and evaluations of selective COX-2 inhibitory
effects: benzo[d]thiazol analogs
Li-Ya Hea†, Shan-Shan Zhanga†, Ding-Xin Penga, Li-Ping Guana*, Xi-Hong Wang b*
benzyl
benzo[d]thiazol
Linker
phenoxylethyl
N
S
H
N
N
S
phenoxylethyl
O
benzyl
OCH2CH2O
O
S
3a-3g
2a-2r
benzo[d]thiazol-2(3H)-one