1,2,3-Triazole-nimesulide hybrid: Their design, synthesis and evaluation as potential anticancer agents

Article abstract of DOI:10.1016/j.bmcl.2016.12.030

A new hybrid template has been designed by integrating the structural features of nimesulide and the 1,2,3-triazole moiety in a single molecular entity at the same time eliminating the problematic nitro group of nimesulide. The template has been used for

Full text of DOI:10.1016/j.bmcl.2016.12.030

Accepted Manuscript
1,2,3-Triazole-nimesulide hybrid: Their design, synthesis and evaluation as po-
tential anticancer agents
Jyoti Mareddy, N. Suresh, C. Ganesh Kumar, Ravikumar Kapavarapu, A.
Jayasree, Sarbani Pal
PII:
S0960-894X(16)31295-1
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.12.030
BMCL 24519
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 September 2016
16 November 2016
8 December 2016
Please cite this article as: Mareddy, J., Suresh, N., Ganesh Kumar, C., Kapavarapu, R., Jayasree, A., Pal, S., 1,2,3-
Triazole-nimesulide hybrid: Their design, synthesis and evaluation as potential anticancer agents, Bioorganic &
Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.12.030
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1,2,3-Triazole-nimesulide hybrid: Their
design, synthesis and evaluation as potential
anticancer agents
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Jyoti Mareddy, N. Suresh, C. Ganesh Kumar, Ravikumar Kapavarapu, A. Jayasree, and Sarbani Pal*
NHSO2CH3
O
Cytotoxic properties
PDE4 inhibition
NHSO2CH3
O
Compound
IC50 (μM)
A549 cells
7.1± 0.22
6.7± 0.15
6.6 ± 0.23
3f
3g
3i
N
N
NO2
N
Nimesulide
R

1
Bioorganic & Medicinal Chemistry Letters
1,2,3-Triazole-nimesulide hybrid: Their design, synthesis and evaluation as potential
anticancer agents
Jyoti Mareddy,a,b N. Suresh,b C. Ganesh Kumar,c Ravikumar Kapavarapu,d A. Jayasree,b and Sarbani Pala,*
aDepartment of Chemistry, MNR Degree & PG College, Kukatpally, Hyderabad-500085, India.
bCentre for Chemical Sciences and Technology, Institute of Science & Technology, Jawaharlal Nehru Technological University Hyderabad, Kukatpally,
Hyderabad-500085, India.
cChemical Biology Laboratory, Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India.
dDoctoral Programme in Experimental Biology and Biomedicine, Center for Neuroscience and Cell Biology, Institute for Interdisciplinary Research, University
of Coimbra (IIIUC), 3004-517 Coimbra, Portugal.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new hybrid template has been designed by integrating the structural features of nimesulide
and the 1,2,3-triazole moiety in a single molecular entity at the same time eliminating the
problematic nitro group of nimesulide. The template has been used for the generation of a library
of molecules as potential anticancer agents. A mild and greener CuAAC approach has been used
to synthesize these compounds via the reaction of 4-azido derivative of nimesulide and terminal
alkynes in water. Three of these compounds showed promising growth inhibition (IC50 ~ 6-10
µM) of A549, HepG2, HeLa and DU145 cancer cell lines but no significant effects on HEK293
cell line. They also inhibited PDE4B in vitro (60-70% at 10 µM) that was supported by the
docking studies (PLP score 87-94) in silico.
Available online
Keywords:
Nimesulide
1,2,3-Triazole
Azide
2009 Elsevier Ltd. All rights reserved.
Alkyne
Anticancer activity
Nimesulide (A, Fig.1),1 a well known non-steroidal anti-
inflammatory drug (NSAID) is an moderately selective inhibitor
of cyclooxygenase-2 (COX-2). The enzyme COX-2 is one of the
two isoforms of COX that is responsible for the formation of
prostanoids, including thromboxane and prostaglandins such as
prostacyclin. Nimesulide also exhibited impressive anticancer
properties. For example, studies have shown that it played an
important role in controlling growth, proliferation and apoptosis
of cancer cell lines and tumors.1 However, its use is associated
with an increased risk of hepatotoxicity that resulted withdrawal
of this drug from the market in many countries. Studies have
indicated that the observed hepatotoxicity of nimesulide can be
linked to its protonophoretic and NAD(P)H oxidizing properties
caused by its nitro group.2 Indeed, these effects were suppressed
when the nitro group was replaced by an amine3 or hydroxyl
moiety4 (metabolites B and C, Fig. 1). Notably, 4-cyano analog
of nimesulide (D, Fig.1) was synthesized and identified as a
potent anti-inflammatory agent when tested in rats.5 It is therefore
desirable to replace the nitro group by an appropriate unsaturated
group or substituent without affecting its pharmacological
properties and irrespective of its uses as a NSAID or anticancer
agent.
NHSO2CH3
O
played a role in hepatotoxicity
X
A;
B;
X = NO2
X = NH2
C; X = OH
D
; X = CN
Fig. 1. Nimesulide (A), its 4-amino and 4-hydroxy metabolite (B and C)
and 4-cyano analog (D).
The compounds containing 1,2,3-triazole framework on the
other hand have been reported as potential anticancer agents.6-10
Indeed, the 1,2,3-triazole-dithiocarbamate hybrids (E, Fig. 2)
have shown moderate to potent activity against human gastric
cancer MGC-803 and human breast cancer MCF-7 cell lines.10
The study has indicated that 1,2,3-triazoles show promising
pharmacological properties because of their capability of forming
H-bonds thereby improved solubility and ability to interact with
biomolecular targets.11 They are also stable to metabolic
degradation compared to the other similar compounds containing
three adjacent nitrogen atoms. All these observations and our
interest in nimesulide12 and 1,2,3-triazole derivatives13-16
prompted us to explore a series of novel 1,2,3-triazole-nimesulide
hybrids based on F (Fig. 2) as potential anticancer agents. We
----------------
* Corresponding author: Tel.: +91 40 23041488; fax: -----
E-mail address: sarbani277@yahoo.com (S. Pal)

2
NHSO2CH3
O
NHSO2CH3
O
NHSO2CH3
O
NHSO2CH3
O
(ii)
(i)
hybridization
R
NH2
NO2
NO2
A
A
1
N
N
N
CO2But
NHSO2CH3
N
N
N
NHSO2CH3
O
N
O
S
N
R
(iii)
F
S
E
Fig.2. The reported 1,2,3-triazole-dithiocarbamate hybrids (E) and the
design of 1,2,3-triazole-nimesulide hybrids (F).
N
N
N3
2
3
N
R
anticipated that integrating structural features of nimesulide (A)
and 1,2,3-triazole moiety of E in a single molecular entity at the
same time eliminating the problematic nitro group of A may
afford compounds possessing interesting pharmacological
properties. Herein we report the preliminary results of this study.
R = (time, % yield)
3a; Ph (5 min, 95%)
3b; PhOCH2 (15 min, 90%)
The paradigm of “click chemistry” begun with the seminal
discovery of the Cu(I)-catalyzed azide–alkyne cycloaddition
(CuAAC) by Meldal and Sharpless’s group independently.17-19
Soon after this most reliable, functional group tolerant and
efficient bond-forming reaction became a widespread synthetic
transformation that found applications in chemistry, biology, and
materials science. Initially the 1,3-dipolar cycloaddition reaction
of azides and alkynes was studied by Huisgen and co-workers.20
The uncatalyzed reaction required the use of high temperature
and was found to afford mixtures of 1,4- and 1,5-triazole
regioisomers. Later, the CuAAC afforded 1,4-disubstituted 1,2,3-
triazoles exclusively and was popularly termed as “click
reaction”. The reaction generally involves in situ generation of
the required Cu(I) catalyst via the reduction of a Cu(II) salt with
Na-ascorbate. A plethora of reaction conditions have been
investigated to improve the efficiency and greenness of this
process. These include the use of various Cu catalytic systems
e.g. Cu with other elements such as Cu(II) / sacrificial reducing
agent, Cu(0) / oxidizing agent or Cu(I) / auxiliary ligand, and the
use of Cu(I) species alone.21 The use of various organic solvents
and water has also been investigated and found to be effective for
click reactions. Nevertheless, maintaining the TAPE (time, atom
and pot economy) in the synthesis of library of small molecules
or new chemical entities can lead to considerable ‘greening’ of a
synthetic route over conventional synthetic methods. Hence
development of such strategies has gain considerable interest
both in academia and industrial R & Ds. We now report a
CuAAC based strategy for the rapid synthesis of our target
molecules based on F i.e. 3 (Scheme 1). This strategy involved
the use of water as a very efficient and green solvent that
accelerated the click reaction by several fold in the present case
compared to that performed in an organic solvent.
3c; C10H7OCH2 (15 min, 89%)
3d; p-CH3C6H4 (15 min, 94%)
3e; p-CH3C6H4OCH2 (10 min, 95%)
3f; p-ClC6H4OCH2 (10 min, 97%)
3g; p-Cl(m-CH3)C6H3OCH2 (15 min, 80%)
3h; o-ClC6H4OCH2 (10 min, 96%)
3i; p-NO2C6H4OCH2 (20 min, 75%)
3j; p-CHO(o-OCH3)C6H3OCH2 (5 min, 95%)
3k; m-CHO(o-OCH3)C6H3OCH2 (5 min, 79%)
3l; (C10H7O2)OCH2 (5 min, 77%)
3m; C9H6NOCH2 (5 min, 66%)
3n; p-CH2OH(o-OCH3)C6H3OCH2 (5 min, 83%)
3o; m-CH2OH(o-OCH3)C6H3OCH2 (5 min, 86%)
3p;
(10 min, 80%)
(10 min, 85%)
(10 min, 84%)
3q;
3r;
The necessary azide 2 required for the synthesis of compound 3
was prepared from nimesulide A that was reduced15 to the
corresponding amine 1 which on treatment with NaNO2 followed
by Na-azide afforded 2 (Scheme 1). The obtained 4-azido
analogue of nimesulide was then coupled with a number of
terminal alkynes13,22 in the presence of CuSO4•5H2O and Na-
ascorbate in water at room temperature to afford the desired
1,2,3-triazole-nimesulide hybrids 3. Notably, the reactions were
completed within 5-20 min affording the expected product 3a-r
in good yields. However, a significantly longer reaction time was
required to afford the product 3i that contains an electron
withdrawing NO2 group. Perhaps the reactivity of the
corresponding alkyne reactant i.e. p-NO2C6H4OCH2C≡CH was
greatly influenced by the presence of NO2 group under the
reaction condition employed. Nevertheless, we were delighted to
observe such a quick reaction rate in majority of the cases
without using any additives and/or ligands or microwave or
Scheme 1. Reagents and conditions: (i) Sn/HCl, (ii) NaNO2 /
H2O, 0 °C, NaN3, 1h, 89%; (iii) R-C≡CH, CuSO4•5H2O, Na-
ascorbate, H2O, room temp.
ultrasound.23 It is worthy to mention that the reaction progressed
well in these cases in spite of moderate to poor solubility /
miscibility of reactants in water. In order to assess the effect of
water as a solvent in the present coupling reaction we performed
a limited study on the reaction of azide 2 with phenyl acetylene
using a number of solvents (Table 1). Since PEG (polyethylene
glycol) is considered as another green solvent in organic
reactions hence we explored its use in the present reaction.
Notably, a poor yield of desired compound 3a was obtained
when the reaction was performed in PEG-400 for 5 min (entry 2
vs 1, Table 1) and the reaction did not reach to the completion

3
representative compound 3m (Fig. 3) showed (i) two singlets at
Table 1: The effect of solvents on the CuAAC of 2 with
phenyl acetylene.a
δ 5.11 and 4.39 due to two methylene protons, (ii) one singlet at δ
8.87 due to the CH proton of triazole ring, (iii) one singlet at δ
3.70 due to the -OMe protons and (iv) one singlet at δ 3.04 due to
the -SO2Me protons. In the 13C NMR spectra, the OCH2, OMe
and CH2OH appeared at 63.2, 62.2 and 55.8 ppm respectively
whereas -SO2Me group appeared at δ 41.1 ppm.
NHSO2CH3
Ph
OPh
NHSO2CH3
OPh
CuSO4 5H2O
Na-ascorbate
N
solvent
room temp (25 oC)
N
N3
Having synthesized a number of 1,2,3-triazole-nimesulide
hybrids (3) we then decided to assess their cancer cells growth
inhibitory properties against various cancer cell lines. We were
particularly encouraged by the fact that both nimesulide (A) and
the triazole derivative E (Fig. 2) showed anticancer properties.1,10
The cancer cell lines used for our study include A549 (lung
cancer), HepG2 (liver cancer), HeLa (cervical cancer) and
N
Ph
2
3a
Entry
solvent
Time (min)
Yieldb (%)
1.
2.
3.
4.
5.
H2O
5
5
180
180
180
95
12
89
93
80
PEG-400
PEG-400
DMF
MeCN
DU145 (prostate cancer).
A
colorimetric MTT [3-(4,5-
aReaction conditions: azide 2 (1 mmol), phenylacetylene (1
mmol), CuSO4•5H2O (0.25 mmol), sodium ascorbate (0.25
mmol) in a solvent (5 mL) with vigorous stirring.
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay
was used to measure the effect of test compounds along with a
standard drug doxorubicin as the reference compound. The IC50
values for the growth inhibition of cancer cells by compounds 3
and nimesulide25a,b (A) are presented in Table 2. It is evident
from Table 2 that compounds 3f and 3g showed good growth
inhibition of all the cancer cell lines tested whereas 3c and 3e
were found to be next best. However the compound 3i was found
to be effective against lung and prostate cancer cell lines. The
compound 3b and 3d also showed good effects against the
prostate cancer cell line. Overall, the compound 3g and 3i against
lung cancer, compound 3f against lung cancer, compound 3f and
3g against cervical and compound 3f and 3g against prostate
cancer cell lines were found to be most active in this series. The
compound 3h was found to be the least active in this series.
These compounds were also tested against non-cancerous human
embryonic kidney cells i.e. HEK293 when none of them showed
any significant effects indicating their selectivity towards the
growth inhibition of cancer cells. It is worthy to mention that the
newly synthesized compounds in general showed improved
growth inhibition of cancer cells tested over nimesulide. This
could be due to the combined effect of 1,2,3-trizole and the
substituent attached to it. While 1,2,3-triazole could be a
replacement for -NO2 group, the substituent attached to it could
contribute significantly towards the molecular dispersion force.
Thus, to understand their individual role in the observed anti-
cancer activities the compound N-(4'-fluoro-3-phenoxybiphenyl-
4-yl)methanesulfonamide (4) prepared via the reported method12
was tested against A549 and HepG2 cell lines and was compared
bIsolated yield.
(according to TLC test). However, the reaction was completed
when carried out for 180 min affording 3a in 89% yield (entry 3,
Table 1). A similar trend was observed when the reaction was
carried out in DMF and MeCN (entry 4 and 5, Table 1). While
performing these reactions (in PEG-400, DMF and MeCN) at an
elevated temperature (in the range of 50-70 ºC) perhaps could
decrease the reaction time without affecting the product yield
however, we carried out these reactions at room temperature (25
ºC) in order to maintain the mild nature of the reaction
conditions. Nevertheless, it appeared that all the organic solvents
tested were found to be inferior to water both in terms of product
yield and reaction time. Moreover, water is a green and
inexpensive solvent with ample availability in nature.
While the reaction rate enhancement by water was not clear in
the present CuAAC of azide 2 with the terminal alkynes however
based on the results of studies published earlier22,24 a probable
reaction mechanism is depicted in Scheme S-1 (see the
supplementary data file). Being weak base water can function as
a proton acceptor and facilitate the deprotonation of the terminal
alkyne to give a Cu-acetylide intermediate I-1 that generates a
copper-azide-acetylide complex I-2. Being a charged species the
formation and solvation / stabilization of I-2 is expected to be
facilitated by water. The complex I-2 then undergoes cyclization
via I-3 followed by protonation via I-4 in the presence of
conjugate acid of H2O. The protonation of I-4 is also expected to
be assisted by water thereby increasing in the reaction rate. This
step was much slower in case of PEG-400 thereby increasing the
reaction time.
with 3a and A. The observed activities of compound 4 [IC50
=
52± 0.41 (A549) and 38.19±0.56 (HepG2)] similar to A rather
than 3a indicated important role played by the 1,2,3-triazole
moiety in the anticancer activities of 3a. It may also be noted that
the presence of –CH2O- moiety in 3b-c and 3e-i with the
exception of 3h perhaps provided more flexible conformations
for these molecules compared to 3a and 3d for better molecular
interactions as indicated by their activities. Nevertheless, being a
new class of cytotoxic agents this series deserved further
attention and therefore we focused on elucidating the mechanism
of action (e.g. pharmacological target) of this class of
All the synthesized compounds were characterized by spectral
(NMR, IR and MS) data. For example 1H NMR spectra of a
compounds.
A
thorough literature search revealed that
nimesulide possess phosphodiesterase type 4 (PDE4) inhibiting
property25c whereas recent study indicated that PDE4 can be a
potential target for cancer.26 Thus in view of the link between
cancer and PDE4 and the reported PDE4 inhibiting properties of
nimesulide the most promising compounds i.e. 3f, 3g and 3i were
examined in vitro at 10 µM using PDE4B enzyme assay27 along
with rolipram28 as a reference compound. The cAMP specific
PDE4 that has four isoforms, e.g., PDE4A-D29a is widely
expressed in tumor cells. Since PDE4B is the major and most
important subtype29b among the four subtypes of PDE4 hence this
particular subtype was chosen as the target protein initially for in
vitro and then for docking studies. Indeed, these compounds
Fig. 3. Representation of partial 1HNMR data of compound 3n.

4
Table 2. The growth inhibition of cancer cells by compounds
Table 3. Results of docking studies
3a-i
Compounds
PLP score
H- bond interactions
GLN417
NHSO2CH3
OPh
NHSO2CH3
OPh
NHSO2CH3
OPh
3f
-87.42 kcal/mol
-92.87 kcal/mol
-94.65 kcal/mol
-58.52 kcal/mol
3g
ASP346
3i
GLN284
N
N
N
Nimesulide
SER442
N
N
N
N
N
N
PLP = Piecewise Linear Pair wise Potential
OC10H7
Ph
OPh
3a
3b
3c
NHSO2CH3
OPh
NHSO2CH3
OPh
NHSO2CH3
OPh
N
N
N
N
N
N
N
OC6H4Me-p
N
N
C6H4Me-p
OC6H4Cl-p
3e
3d
3f
NHSO2CH3
OPh
NHSO2CH3
OPh
NHSO2CH3
OPh
N
N
N
N
N
N
N
OC6H3(Me-m)Cl-p
N
N
Fig. 4. Docking of compound 3f into PDE4B (PDB ID: 1XMY).
OC6H4NO2-p
OC6H4Cl-o
3g
.
3i
3h
Entry
IC50 (μM)
3
A549
(lung)
29.9 ± 0.22
HepG2
(liver)
13.6 ± 0.21
Hela
(cervical)
21.9 ±0.25
DU145
(prostate)
14.2 ± 0.16
1
2
3a
3b
3c
3d
3e
3f
n.d.
12.3 ± 0.13
19.5 ± 0.23
18.3 ± 0.13
13.0 ± 0.11
7.5 ± 0.09
9.8 ± 0.12
25.3 ± 0.13
n.d.
n.d.
12.8 ± 0.25
n.d.
10.7 ± 0.11
9.1±0.23
11.2± 0.21
8.2±0.28
6.4±0.31
5.9±0.15
21.1±0.12
7.2±0.32
n.d.
3
8.3 ± 0.26
n.d.
4
5
8.0 ± 0.20
7.1 ± 0.22
6.7 ± 0.15
53.8 ± 0.19
6.6 ± 0.23
67.81± 0.23
15.8 ± 0.14
7.8±0.15
7.9±0.22
38.6 ± 0.19
n.d.
6
7
3g
3h
3i
8
9
10
35.21±0.72
n.d.
A
A = nimesulide; n.d. = not determined.
showed good inhibition of PDE4 e.g. 62.81 ± 1.20% by 3f, 67.50
± 2.07 by 3g and 70.24 ± 1.60% by 3i (when rolipram showed 90
± 4.13 % inhibition). Notably, nimesulide showed 52% inhibition
of PDE4 at 10 µM.
Fig. 5. Docking of nimesulide into PDE4B (PDB ID: 1XMY).
observed %inhibition shown by these compounds. Indeed, all the
test compounds showed H-bond interaction through the –NH
group of their methanesulphonamide (-NHSO2Me) moiety with
good binding modes in the active site of PDE4B on post docking
simulations (Fig 4 and 5, see also Fig S-1 and S-2 in
supplementary data file). For example, the –NH group of -
NHSO2Me moiety participated in the H-bond interaction with the
GLN417 and GLN284 residue of PDE4B, respectively in case of
3f (Fig 4) and 3i (Fig. S-2, supplementary data file). Similarly,
the –NH group formed H-bond with the ASP346 and SER442
residue of PDE4B in case of 3g (Fig. S-2, supplementary data
file) and nimesulide (Fig 5). Overall, it is evident from this study
that the cancer cells growth inhibitory properties shown by these
compounds against various cancer cell lines could be due to their
inhibition of PDE4.31
To understand the nature of interactions of these compounds
with PDE4 we performed docking studies of compound 3f, 3g,
3i, and nimesulide. A known inhibitor of PDE4 e.g. rolipram was
used as a reference compound in these studies. The molecular
docking simulations were carried out using GRIP method of
docking in Biopredicta module of Vlife MDS (Molecular Design
Suite) 4.6. The PDE4B protein in complex with rolipram was
obtained from Protein Data Bank (PDB ID: 1XMY)30 and was
used as the receptor for this study. The GRIP docking employs
PLP (Piecewise Linear Pair wise Potential) scoring function for
protein ligand interactions which includes hydrogen bonding,
steric interactions, van der Waals interactions, hydrophobic
interactions and electrostatic interactions. Accordingly,
compounds 3f, 3i and 3g showed better PLP score (docking
scores) than nimesulide (Table 3) which is in agreement with the
In conclusion, a new hybrid template has been designed by
integrating the structural features of nimesulide and the 1,2,3-

5
15. Mareddy, J.; Nallapati, S. B.; Anireddy, J.; Devi, Y. P.;
Mangamoori, L. N.; Kapavarapu, R.; Pal, S. Bioorg. Med. Chem.
Lett. 2013, 23, 6721.
16. Praveena, K. S. S.; Ramarao, E. V. V. S.; Murthy, N. Y. S.;
Akkenapally, S.; Kumar, C. G.; Kapavarapu, R.; Pal, S. Bioorg.
Med. Chem. Lett. 2015, 25, 1063.
triazole moiety in a single molecular entity at the same time
eliminating the problematic nitro group of nimesulide. The
template has been used for the generation of a library of
molecules as potential anticancer agents. A mild and greener
approach has been used to synthesize these compounds in good
yields. The methodology involved a CuAAC between 4-azido
derivative of nimesulide and readily available terminal alkynes in
the presence of precatalyst CuSO4•5H2O and sodium ascorbate.
This reaction was performed in water at ambient temperature as
the study indicated that water was not only a green solvent for
this transformation but also superior to other organic solvents in
terms of reaction time and product yields. All the synthesized
1,2,3-triazole-nimesulide hybrids were tested for their cancer
cells growth inhibitory properties against various cancer cell lines
including A549 (lung cancer), HepG2 (liver cancer), HeLa
(cervical cancer) and DU145 (prostate cancer). The compounds
3f, 3g and 3i were found to be best among all the compounds
tested. They also inhibited PDE4B in vitro that was supported by
the results of in silico docking studies. Overall, the new template
described here could be useful for the identification of novel and
potential anticancer agents. Moreover, being faster and eco
friendly the methodology described here may find wide
applications in building library of small molecules related to this
new framework.
17. Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057.
18. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed.
2001, 40, 2004.
19. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem. Int. Ed. 2002, 41, 2596.
20. (a) Huisgen, R. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.
Ed.; Wiley: New York, NY, USA, 1984, Volume 1, pp. 1–176; (b)
Padwa, A. Intermolecular 1,3-dipolar cycloaddition. In
Comprehensive Organic Synthesis; Trost, B. M. Ed.; Pergamon:
Oxford, UK, 1991, Volume 4, pp. 1069–1109.
21. Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952.
22. (a) Kant, R.; Kumar, D.; Agarwal, D.; Gupta, R. D.; Tilak, R.;
Awasthi, S. K.; Agarwal, A. Eur. J. Med. Chem. 2016, 113, 34;
(b) Mareddy, J.; Praveena, K. S. S.; Suresh, N.; Jayashree, A.;
Roy, S.; Rambabu, D.; Murthy, N. Y. S.; Pal, S. Lett. Drug Des.
Disc. 2013, 10, 343; (c) Praveena, K. S. S.; Ramarao, E. V. V. S.;
Poornachandra, Y.; Kumar, C. G.; Babu, N. S.; Murthy, N. Y. S.;
Pal, S. Lett. Drug Des. Disc. 2016, 13, 210
23. For a review, see: Barge, A.; Tagliapietra, S.; Binello, A.;
Cravotto, G. Curr. Org. Chem. 2010, 15, 189.
24. Rodionov, V. O.; Presolski, S. I.; D´ıaz, D. D.; Fokin, V. V.; Finn,
M. G. J. Am. Chem. Soc. 2007, 129, 12705
25. (a) The reported IC50 of nimesulide is 70.9 μM in A549 cell line,
see: Park, C. B.; Jeon, H. W.; Jin, U.; Cho, K. D.; Kim, C. K.;
Wang, Y. P., Korean J. Thorac. Cardiovasc. Surg. 2005, 38, 263;
(b) For anti proliferative effects of nimesulide on HepG2 cell, see:
Yang, S.; Guo, R.; Huang, L.; Yang, L.; Jiang, D. Indian J.
pharmacol. 2012, 44, 599 (c) Bevilacqua, M.; Vago, T.; Baldi, G.;
Renesto, E.; Dallegri, F.; Norbiato, G. Eur. J. Pharmacol. 1994,
268, 415.
Acknowledgements
The authors (J. M. and S. P.) thank Mr. M. N. Raju, the
chairman of MNR Educational Trust for constant support and
encouragement.
26. Pullamsetti, S. S.; Banat, G. A.; Schmall, A.; Szibor, M.;
Pomagruk, D.; Hänze, J.; Kolosionek, E.; Wilhelm, J.; Braun, T.;
Grimminger, F.; Seeger, W.; Schermuly, R. T.; Savai, R.
Oncogene 2013, 32, 1121; doi:10.1038/onc.2012.136
27. Wang, P.; Myers, J. G.; Wu, P.; Cheewatrakoolpong, B.; Egan,
R.W.; Billah, M. M. Biochem. Biophys. Res. Commun. 1997, 234,
320.
28. Demnitz, J.; LaVecchia, L.; Bacher, E.; Keller, T. H.; Muller, T.;
Schurch, F.; Weber, H. P.; Pombo-Villar, E. Molecules 1998, 3,
107.
29. (a) Jeon, Y. H.; Heo, Y. S.; Kim, C. M.; Hyun, Y. L.; Lee, T. G.;
Ro, S.; Cho, J. M. Cell. Mol. Life Sci. 2005, 62, 1198. (b)
Kodimuthali, A.; Jabaris, S. S. L.; Pal, M. J. Med. Chem. 2008,
18, 5471.
30. Card, G. L.; England, B. P.; Suzuki, Y.; Fong, D.; Powell, B.; Lee,
B.; Luu, C.; Tabrizizad, M.; Gillette, S.; Ibrahim, P. N.; Artis, D.
R.; Bollag, G.; Milburn, M. V.; Kim, S. H.; Schlessinger, J.;
Zhang, K. Y. Structure 2004, 12, 2233.
31. To assess the COX inhibitory potential of the newly synthesized
compounds, a representative compound 3f was tested in vitro at 10
µM against human COX-2 (expressed in sf9 insect cells using
baculovirus) enzyme along with nimesulide (A) [(a) Cromlish, W.
A.; Payette, P.; Culp, S. A.; Ouellet, M.; Percival, M. D.;
Kennedy, B. P. Arch. Biochem. Biophys. 1994, 314, 193; (b)
Copeland, R. A.; Williams, J. M.; Giannaras, J.; Nurnberg, S.;
Covington, M.; Pinto, D.; Pick, S.; Trzaskos, J. M. Proc. Natl.
Acad. Sci U.S.A. 1994, 91, 11202]. The observed 23% inhibition
of 3f vs 90% inhibition of nimesulide indicated that 3f is a poor
inhibitor of COX-2.
Supplementary data
Supplementary data associated with this article can be found,
in the on line version, at xxxxxxxxx
References and notes
1.
Nimesulide - Actions and Uses, By K. D. Rainsford, 2005,
Birkhauser Verlag, Basel, Switzerland.
2.
3.
Boelsterli, U. A. Drug Saf. 2002, 25, 633.
Mingatto, F. E.; Dos Santos, A. C.; Rodrigues, T.; Pigoso, A. A.;
Uyemura, S. A.; Curti, C. Br. J. Pharmacol. 2000, 131, 1154.
doi: 10.1038/sj.bjp.0703667
4.
5.
Freitas, C. S.; Dorta, D. J.; Pardo-Andreu, G. L.; Pestana, C. R.;
Tudella, V. G.; Mingatto, F. E.; Uyemura, S. A.; Santos, A. C.;
Curti, C. Eur. J. Pharmacol. 2007, 566, 43.
Yoshikawa, Y.; Ochi, Y.; Sekiuchi, K.; Saito, H.; Hatayama, K.
Japan patent application no. JP02022260A, 25 January 1990;
Chem. Abstr.113, 77922.
6.
7.
Pokhodylo, N.; Shyyka, O.; Matiychuk, V. Med. Chem. Res.
2014, 23, 2426.
Penthala, N. R.; Madhukuri, L.; Thakkar, S.; Madadi, N. R.;
Lamture, G.; Eoff, R. L.; Crooks, P. A. Med. Chem. Commun.,
2015, 6, 1535.
8.
9.
Demchuk, D. V.; Samet, A. V.; Chernysheva, N. B.; Ushkarov, V.
I.; Stashina, G. A.; Konyushkin, L. D.; Raihstat, M. M.; Firgang,
S. I.; Philchenkov, A. A.; Zavelevich, M. P.; Kuiava, L. M.;
Chekhun, V. F.; Blokhin, D. Y.; Kiselyov, A. S.; Semenova, M.
N.; Semenov, V. V. Bioorg. Med. Chem. 2014, 22, 738.
Khazir, J.; Hyder, I.; Gayatri, J. L.; Yandrati, L. P.; Nalla, N.;
Chasoo, G.; Mahajan, A.; Saxena, A. K.; Alam, M. S.; Qazi, G.
N.; Kumar, H. M. S. Eur. J. Med. Chem. 2014, 82, 255.
10. Duan, Y.-C.; Ma, Y.-C.; Zhang, E.; Shi, X.-J.; Wang, M. –M.; Ye,
X. –W.; Liu, H. –M. Eur. J. Med. Chem. 2013, 62, 11.
11. Prachayasittikul, V.; Pingaew, R.; Anuwongcharoen, N.;
Worachartcheewan, A.; Nantasenamat, C.; Prachayasittikul, S.;
Ruchirawat, S.; Prachayasittikul, V. Springer Plus 2015, 4, 571;
doi: 10.1186/s40064-015-1352-5
12. Durgadasa, S.; Chatarec, V.; Mukkanti, K.; Pal, S. Appl.
Organometal. Chem. 2010, 24, 680.
13. Kuntala, N.; Telu, J. R.; Banothu, V.; Nallapati, S. B.;
Anireddy, J. S.; Pal, S. Med. Chem. Commun., 2015, 6, 1612.
14. Praveena, K. S. S.; Durgaprasad, S.; Babu, N. S.; Akkenapally, A.;
Kumar, C. G.; Deora, G. S.; Murthy, N. Y. S.; Mukkanti, K.; Pal,
S. Bioorg. Chem. 2014, 53, 8.