Novel molecules containing structural features of NSAIDs and 1,2,3-triazole ring: Design, synthesis and evaluation as potential cytotoxic agents

Article abstract of DOI:10.1016/j.molstruc.2021.131222

For the first time the template containing structural features of more than one NSAIDs and the 1,2,3-triazole ring was explored for the identification of potential cytotoxic agents. These new and complex molecules were predicted to be effective inhibitors

Full text of DOI:10.1016/j.molstruc.2021.131222

Journal of Molecular Structure 1246 (2021) 131222
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Novel molecules containing structural features of NSAIDs and
1,2,3-triazole ring: Design, synthesis and evaluation as potential
cytotoxic agents
Jyoti Mareddya, Kazi Amirul Hossainb, N. Sudhakar Yadav c, Venkanna Banothud,
Jaya Shree Anireddye, Sarbani Pala,∗
a Department of Chemistry, MNR Degree & PG College, Kukatpally, Hyderabad 500085, India
b Department of Physical Chemistry, Gdansk University of Technology, Gdansk, Poland
c VNR Vignana Jyothi Institute of Engineering and Technology, Vignana Jyothi Nagar, Pragathi Nagar, Nizampet (S.O.), Hyderabad, Telangana 500090, India
d Department of Biotechnology, Institute of Science and Technology, Jawaharlal Nehru Technological University Hyderabad, Hyderabad 500085, India
e Center for Chemical Sciences and Technology, Institute of Science and Technology, Jawaharlal Nehru Technological University Hyderabad, Hyderabad
500085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
For the first time the template containing structural features of more than one NSAIDs and the 1,2,3-
triazole ring was explored for the identification of potential cytotoxic agents. These new and complex
molecules were predicted to be effective inhibitors of PDE4B by molecular modelling studies in sil-
ico. The multi-step synthesis of these compounds were carried out starting from the well-known drug
nimesulide and involved the use of copper-catalyzed azide-alkyne cycloaddition (CuAAC) approach as the
key step. Mainly two types of compounds e.g. 1-aryl-1H-1,2,3-triazoles and N-aryl-2-(1H-1,2,3-triazol-1-
yl)acetamide derivatives were synthesized by using this method in good yields. The in vitro screening of
these compounds against two cancer cell lines e.g. HCT-15 (human colon cancer cell line) and NCI-H226
(human lung cancer cell line) using a colorimetric MTT assay allowed identification of two preliminary
hit molecules i.e. 8a and 8f. The SAR (Structure Activity Relationship) analysis indicated that the presence
of an amide linker between the aryl ring and the 1,2,3-triazole moiety was favorable for the activities. The
compound 8a and 8f showed significant inhibition of PDE4B in vitro and good interactions with this pro-
tein in silico suggesting PDE4B as their potential target. The usefulness and concerns of these molecules
in the light of computational ADME prediction were analyzed. Overall, novel molecules were identified
as potential cytotoxic agents for further study.
Received 13 May 2021
Revised 25 July 2021
Accepted 30 July 2021
Available online 2 August 2021
Keywords:
NSAID
Triazole
CuAAC
Cytotoxicity
In silico study
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
bietic acid (DHAA)-1,2,3-triazole hybrid (A, Fig. 1) were synthe-
sized and evaluated against SK-OV-3 (ovary), PC-3 (prostate), MDA-
Assembly of two or more frameworks in a single molecu-
lar entity (molecular hybridization) has become an interesting
strategy in the identification of promising new chemical entities
(NCEs) or bioactive agents in various therapeutic areas includ-
ing cancer. Triazole being bio-isosters of amide, ester and car-
boxylic acid in addition to its ability to mimic various amino acids
has been explored widely for this purpose [1]. Till date numer-
ous polyfunctionalized or densely substituted molecules contain-
ing the 1,2,3-triazole framework has been reported for the iden-
tification of various bioactive compounds including the antiprolif-
erative agents. For example, molecules based on C-14 dehydroa-
MB-231 (breast) and MCF-7 (breast) cancer cell lines [2]. Simi-
larly, molecules based on diphenyl-1H-pyrazole-1,2,3-triazole hy-
brid linked through acrylate moiety (B, Fig. 1) were explored
as apoptosis inducing cytotoxic and anti-inflammatory agents [3].
Molecules based on benzosuberone-1,2,3-triazole hybrid (C, Fig. 1)
were evaluated for their anti-proliferative activities [4]. Notably,
besides the presence of 1,2,3-triazole ring all these molecules con-
tain either an amide or ester as a linker that allowed successful
hybridization of different frameworks. Nevertheless, the molecular
hybridization of more than two frameworks is rather uncommon in
the literature. On the other hand, due to our interest in the identi-
fication of potential anti-proliferative agents we have explored the
nimesulide-1,2,3-triazole hybrid (e.g. D, Fig. 2) previously [5]. In
further continuation of this research we also reported the synthe-
∗
Corresponding author.
E-mail address: sarbani277@yahoo.com (S. Pal).
https://doi.org/10.1016/j.molstruc.2021.131222
0022-2860/© 2021 Elsevier B.V. All rights reserved.

J. Mareddy, K.A. Hossain, N.S. Yadav et al.
Journal of Molecular Structure 1246 (2021) 131222
Fig. 1. Example of polyfunctionalized or densely substituted molecules containing
the 1,2,3-triazole framework.
Fig. 2. Design of new compounds E and F from the known agent D.
sis and biological evaluation of complex molecules [6-8] contain-
ing 1,2,3-triazole ring along with the framework of certain NSAIDs
(Nonsteroidal anti-inflammatory drugs). Indeed, the PDE4B (Phos-
phodiesterase 4B) inhibition along with cytotoxic properties of
a series of 2,2,4-trimethyl-1,2-dihydroquinolinyl substituted 1,2,3-
triazole derivatives were evaluated previously [9]. Prompted by
the earlier report on dual cytotoxic and anti-inflammatory prop-
erties [3] including the PDE4 inhibition [5, 9] of 1,2,3-triazole
based hybrid molecules we devoted our efforts on constructing
a library of similar hybrid molecules represented by E and F as
shown in Fig. 2. Indeed, the 1-aryl-1H-1,2,3-triazole based tem-
plate E was designed by modifying the C-4 substituent of the
1,2,3-triazole ring of D whereas the design of N-aryl-2-(1H-1,2,3-
triazol-1-yl)acetamide based template F involved incorporation of
a linker between the 1,2,3-triazole ring and the substituted ben-
zene moiety. The group Z was mostly designed via incorporating
the structural features of a range of known drugs mostly NSAIDs
or analgesics individually and separately. These include mefenamic
acid, naproxen, ibuprofen, tolfenamic acid, acetylsalicylic acid (as-
pirin), nimesulide (all NSAIDs) and acetaminophen (paracetamol)
(an analgesic). We anticipated that this strategy would introduce
more drug-like structural diversity into the template to afford new
molecules for pharmacological studies towards the identification of
potential cytotoxic agents that may inhibit PDE4. Notably, the inhi-
bition of PDE4 (that is widely expressed in cancer cells) provides
a new approach for targeting certain types of cancer. This is sup-
ported by the beneficial effects shown by PDE4 inhibitors in (i) in-
hibiting the brain tumor cell growth [10,11], (ii) reducing the pro-
liferation and angiogenesis of lung cancer cell lines [12] and (iii)
Fig. 3. The 2D (H-bond presented in magenta and pi-pi in green color) and 3D in-
teraction diagrams (where H-bond and pi-pi stacking are shown in orange and cyan
dashed lines, respectively) of molecule G with PDE4B (PDB ID: 4MYQ) prepared us-
ing Maestro visualizer (Schrödinger, LLC).
causing selective apoptosis of malignant cells without affecting the
normal cells [13]. Nevertheless, while molecules containing struc-
tural features of single NSAID and the 1,2,3-triazole ring have been
studied earlier however to the best of our knowledge the template
like E / F containing structural features of more than one NSAIDs
and the 1,2,3-triazole ring was not explored for the identification
of potential cytotoxic agents previously.
In order to gain some preliminary idea regarding the PDE4 in-
hibitory potential of molecules derived from F the in silico dock-
ing studies were performed using a representative molecule G. The
protein PDE4B (PDB ID: 4MYQ) was collected from the Protein Data
Bank whereas MarvinSketch [14], AutoDock tool [15] and AutoDock
Vina [16] were used for the preparation of studied ligands and per-
forming the docking study. The 2D and 3D interaction diagrams
of molecule G with PDE4B (Fig. 3, see also Fig S-1 in suppl data)
suggested that the molecule interacted well with the target pro-
tein with the docking score -10.7. Indeed, the molecule formed
a H-bond with SER614 through its amidic NH group though at
˚
a distance of 2.8 A. Additionally, it also participated in (i) a pi-
pi interaction with HIS406 and a pi-pi stacking with PHE586 and
2

J. Mareddy, K.A. Hossain, N.S. Yadav et al.
Journal of Molecular Structure 1246 (2021) 131222
Scheme 1. Synthesis of 1-aryl-1H-1,2,3-triazole derivatives 5 based on E (Fig 2).
Scheme 3. Preparation of alkyne 4.
tions. A mixture of CuSO4•5H2O and sodium ascorbate was used as
a pre-catalyst system in this coupling reaction to generate the Cu(I)
species in situ that actually catalyzed the reaction. The required
terminal alkynes (4a-i) were prepared via the reaction of propargyl
bromide with various drugs e.g. mefenamic acid, naproxen, ibupro-
fen, tolfenamic acid, acetylsalicylic acid (aspirin), nimesulide, and
acetaminophen (paracetamol) or compound 2 or a reduced product
of naproxen in DMF at 90 °C (Scheme 3). All the terminal alkynes
obtained were employed to react with the azide 3 or 7 under the
CuAAC conditions separately and individually. The duration of the
reaction was 5-15 min depending on the nature and type of ter-
minal alkynes used. The reaction proceeded well in all these cases
affording the desired product in good yield (Table 1). Thus a variety
of compound 5 and 8 were prepared using the method described
in Schemes 1 and 2.
Scheme 2. Synthesis of N-aryl-2-(1H-1,2,3-triazol-1-yl)acetamide derivatives
based on F (Fig 2).
8
(ii) several hydrophobic interactions with residues ILE582, PHE678,
˚
MET603, LEU674 etc within the distance of 4 A. All these results
prompted us to undertake a straightforward synthesis of com-
pounds based on E and F.
2. Results and discussion
The synthesis of both class of compounds i.e. compounds based
on E (or the 1-aryl-1H-1,2,3-triazole derivatives 5) and that based
on F [or N-aryl-2-(1H-1,2,3-triazol-1-yl)acetamide derivatives 8]
were involved the use of a common strategy (Schemes 1 and 2).
It is well known that the construction of a 1,2,3-triazole ring is
commonly performed by using the click chemistry approach that
involves copper (I)-catalyzed 1,3-cycloaddition reaction between
a terminal alkyne and an azide [17]. Being known as copper-
catalyzed azide-alkyne cycloaddition (CuAAC) this approach has
found enormous applications in organic synthesis and medicinal
chemistry [1-9]. This CuAAC based approach has been used as a
key step in the current synthesis of target compounds. The re-
quired azide 3 and 7 were synthesized from nimesulide (1). Thus
the aniline derivative (2) obtained from 1 via reduction of its ni-
tro group [18] was transformed into the azide 3 following the
known and traditional method (Scheme 1). In another effort the
aniline 2 was N-acylated using chloroacetyl chloride [19] to give
the compound 6 that on treatment with KI followed by NaN3 af-
forded the azide 7 (Scheme 2). These azides were separately cou-
pled with an appropriate terminal alkyne (4) under CuAAC condi-
All the synthesized compounds were characterized by spectral
(NMR, IR and MS) data. For example, 1H NMR spectra of a repre-
sentative compound 5c (Fig. 4A) showed (i) a doublet at δ 0.87
(for 2CH3) and a quintet at δ 1.81 (for CH) due to the i-propyl
group, (ii) a doublet at δ 2.41 due to the CH2 protons between the
i-propyl and phenyl group, (iii) a doublet at δ 1.48 and a quartet at
δ 3.71 due to the CH3 group attached to the benzylic carbon and
the benzylic proton, (iv) one singlet at δ 3.08 due to the -SO2CH3
protons and (v) one singlet at δ 5.24 and δ 7.01 due to the CH2
group attached to the triazole ring and the triazole ring proton. In
the 13C NMR spectra, the Me of i-propyl group and the methane-
sulfonamide moiety and that attached to the benzylic carbon ap-
peared at 22.4, 39.9 and 18.3 ppm. Further, the CH2, OCH2, and
–O-C=O group appeared at 44.9, 57.8 and 174.6 ppm, respectively.
A similar 1H and 13C NMR spectral analysis can be presented for
another compound 8c (Fig. 4B).
Next, the synthesized compounds were tested in vitro against
two cancer cell lines e.g. HCT-15 (human colon cancer cell line)
3

J. Mareddy, K.A. Hossain, N.S. Yadav et al.
Journal of Molecular Structure 1246 (2021) 131222
Table 1
List of 1-aryl-1H-1,2,3-triazole derivatives 5 and N-aryl-2-(1H-1,2,3-triazol-1-yl)acetamide derivatives 8 synthesized.
∗Figure within the bracket represents %yield obtained from the final (CuAAC) step.
and NCI-H226 (human lung cancer cell line) using a colorimet-
ric MTT assay. The well-known anticancer agent doxorubicin was
used as a reference compound in this assay. The results of active
compounds that showed moderate to good effects are presented
in Table 2. Among them the compound 8a was found to be most
active against HCT-15 whereas the compound 8f was identified as
the best active agent against NCI-H226 cell line. Notably, 8a was
not so effective against NCI-H226 whereas 8f was least effective
against HCT-15 indicating their selectivity towards the particular
cancer cell line. Among the rest of the compounds, 5d and 5e
4

J. Mareddy, K.A. Hossain, N.S. Yadav et al.
Journal of Molecular Structure 1246 (2021) 131222
Fig. 4. Partial representation of 1H and 13 C NMR spectral data of compound (A) 5c
and (B) 8c.
Table 2
The % control growth of cancer cells at
10−4 M concentration of test compounds.
Fig. 5. The 2D (H-bond presented in magenta and pi-pi in green color) and 3D in-
teraction diagrams (where H-bond and pi-pi stacking are shown in orange and cyan
dashed lines, respectively) of molecule 8f with PDE4B (PDB ID: 4MYQ) prepared us-
ing Maestro visualizer (Schrödinger, LLC).
Compound
HCT-15
NCI-H226
5c
53.6
50.7
57.7
44.1
55.2
65.2
23.1
57.9
59.0
51.6
52.3
69.1
28.3
27.6
5d
5e
8a
8b
8f
˚
drophobic contacts within the cut-off distance of 4 A among which
Doxorubicin
the contact with PHE678 (a key residue in the CR3 region) is men-
tion worthy. The other noticeable hydrophobic contacts of 8f were
observed (i) with the hydrophobic residues like ILE582, PHE586,
PHE618, MET603, LEU674, MET519 etc and (ii) with the hydropho-
bic regions of polar residues e.g. SER454, ASN455, SER520, ASN567
etc. Notably, the reference compound rolipram participated in two
Values are average of three independent
determinations
showed some effects against HCT-15 and NCI-H226, respectively.
Form the viewpoint of SAR (Structure Activity Relationship) the N-
aryl-2-(1H-1,2,3-triazol-1-yl)acetamide derivatives (8) appeared as
a better active class of compounds over 1-aryl-1H-1,2,3-triazole
derivatives (5) suggesting that the presence of amide linker be-
tween the aryl ring and the 1,2,3-triazole moiety was favorable
for the observed activities. In a preliminary assay both 8a and 8f
showed good inhibition of PDE4B e.g. 67 and 78%, respectively at
10 μM concentration when tested in vitro [20] whereas the refer-
ence compound rolipram (a well-known inhibitor of PDE4) showed
90% inhibition at 10 μM in the same assay. While interaction of
compound 8a (or compound G) with PDE4B in silico has been pre-
sented earlier (see Fig. 3) we performed docking studies using the
compound 8f (Fig. 5, see also Fig S-2 in suppl data) to understand
its interaction with this protein. The molecule 8f showed strong in-
teractions with PDE4B which is reflected by its binding affinity (i.e.
docking score -11.0 ). The molecule participated in several nonco-
valent interactions that include (i) a H-bonding with GLN456 at
˚
H-bonds with GLN615 and HIS406 at a distance of 2.9 and 3.09 A
(the second one being somewhat weaker H-bond), and two aro-
matic pi interactions with PHE618 and PHE586 (Fig. 6, see also
Fig S-3 in suppl data). Additionally, it participated in hydrophobic
˚
contacts (at a distance cut-off 4 A) mainly with residues PHE678,
TYR405, MET519, THR579, ASN567, etc.
Having identified the compound 8a and 8f as potential hits it
was necessary to conduct some initial assessment about ADME
(absorption, distribution, metabolism, and excretion) or pharma-
cokinetic properties of these compounds and compare with that of
rolipram. Thus the computational ADME prediction of these com-
pounds was carried out using Swiss ADME web-tool [21] and re-
sults are summarized in Table 3 (among the various descriptors
only notable one are listed in the table). Because of relatively
high molecular weight it was expected that unlike rolipram these
molecules would not show favorable drug likeness and high GI ab-
sorption. However, this type of concerns could be found for a num-
ber of drugs like macrolide antibiotics or anticancer drug Taxol
˚
2.68A and (ii) pi-pi interactions with TYR405, HIS406, and HIS450.
The molecule also participated in several van der Waals / hy-
5

J. Mareddy, K.A. Hossain, N.S. Yadav et al.
Journal of Molecular Structure 1246 (2021) 131222
Table 3
Computational ADME prediction of 8a, 8f and the reference compound rolipram.
Properties
Molecules
(i) Physicochemical
Molecular Weight (g/mol)
Consensus Log Pa
Log S (ESOL)b
8a
8f
rolipram
275.34
640.71
550.59
4.28
2.08
2.44
-6.75 (poorly soluble)
-4.00 (moderately soluble)
-2.90 (soluble)
(ii) Pharmacokinetics
GIc absorption
BBBd penetration
P-gpe substrate
Low
No
Low
No
High
Yes
No
Yes
Yes
(iii) Drug likeness
Lipinski rule
No; 2 violations: MWf >500, N or Og > 10
No; 2 violations: MW>500, N or O > 10
No; 2 violations: Rotorsh > 10, TPSAi > 140
No; 2 violations: Rotors > 10, TPSA > 140
No violation
No violation
Veber rule
a
Log P: Lipophilicity.
b
Log S (ESOL): water solubility, calculated by ESOL method which is a Quantitative Structure-Property Relationship (QSPR) based model.
c
d
e
f
GI: Gastrointestinal.
BBB: Blood Brain Barrier
P-gp: permeability glycoprotein.
MW: molecular weight,
g
h
i
N or O: Nitrogen/Oxygen indicates number of H-bond acceptor,
Rotors: total number of rotatable bonds,
TPSA: Total polar surface area.
3. Conclusions
In conclusion, novel molecules possessing structural features of
more than one NSAIDs and the 1,2,3-triazole ring was explored
for the identification of potential cytotoxic agents. These new and
complex molecules were predicted to be effective inhibitors of
PDE4B by molecular modelling studies in silico. The multi-step syn-
thesis of these compounds were carried out starting from the well-
known anti-inflammatory drug nimesulide and involved the use of
copper-catalyzed azide-alkyne cycloaddition (CuAAC) approach as
the key step. Mainly two types of compounds e.g. 1-aryl-1H-1,2,3-
triazoles and N-aryl-2-(1H-1,2,3-triazol-1-yl)acetamide derivatives
were synthesized by using this method in good yields. The in
vitro screening of these compounds against two cancer cell lines
e.g. HCT-15 (human colon cancer cell line) and NCI-H226 (hu-
man lung cancer cell line) using a colorimetric MTT assay al-
lowed identification of two preliminary hit molecules i.e. 8a and
8f. The SAR (Structure Activity Relationship) analysis indicated
that the presence of an amide linker between the aryl ring and
the 1,2,3-triazole moiety was favorable for the activities. The
compound 8a and 8f showed significant inhibition of PDE4B in
vitro and good interactions with this protein in silico suggest-
ing PDE4B as their potential target. The usefulness and concerns
of these molecules in the light of computational ADME predic-
tion were analysed and discussed. Overall, the current research
involving the synthesis and identification of novel molecules
as potential cytotoxic agents for further study would attract
interest.
Author statement
Jyoti Mareddy was involved in the preparation, isolation, purifi-
cation and characterization of all the target compounds presented
in the current manuscript.
Kazi Amirul Hossain, N. Sudhakar Yadav and Venkanna Banothu
were involved in performing all the in silico studies as well as in
vitro assays.
Fig. 6. 2D followed by 3D interaction diagram of reference compound rolipram
with PDE4B (PDB ID: 4MYQ).
Jaya Shree Anireddy and Sarbani Pal were responsible for con-
ceptualization, coordination and overall supervision of the entire
work presented in the submitted manuscript.
Supplementary data
that still entered into the market and are currently in patient’s use.
Moreover, both 8a and 8f were predicted to be a non-penetrant of
BBB. Finally, a non-Pgp substrate was predicted for 8a though not
for 8f.
Supplementary data associated with this article can be found,
in the on line version, at xxxxxxxxx
6

J. Mareddy, K.A. Hossain, N.S. Yadav et al.
Journal of Molecular Structure 1246 (2021) 131222
Declaration of Competing Interest
[8] S. Srinivas, P. Neeraja, V. Banothu, P.K. Dubey, K. Mukkanti,
S Pal, Syn-
thesis, biological evaluation and in silico studies of compounds based on
tryptophan-naproxen-triazole hybrids, Chem. Select
doi.org/10.1002/slct.202003786.
5 (2020) 14741–14746
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
[9] K.S.S. Praveena, S. Durgadas, N.S. Babu, S. Akkenapally, C.G. Ku-
mar, G.S. Deora, N.Y.S. Murthy, K. Mukkanti, S. Pal, Synthesis of
2,2,4-trimethyl-1,2-dihydroquinolinyl substituted 1,2,3-triazole derivatives:
their evaluation as potential PDE 4B inhibitors possessing cytotoxic properties
against cancer cells, Bioorg. Chem. 53 (2014) 8–14.
Acknowledgement
[10] P. Goldhoff, N.M. Warrington, D.D. Limbrick, J.A. Hope, B.M. Woerner, E. Jack-
son, A. Perry, D. Piwnica-Worms, J.B. Rubin, Targeted inhibition of cyclic AMP
phosphodiesterase-4 promotesbrain tumor regression, Clin. Cancer Res. 14
(2008) 7717–7725.
The authors thank the management of MNR Degree and PG Col-
lege, Hyderabad, India for continuous support and encouragement.
[11] L. Yang, E. Jackson, B.M. Woerner, A. Perry, D. Piwnica-Worms, J.B. Rubin,
Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth
in vivo, Cancer Res. 67 (2007) 651–658.
Supplementary materials
[12] S.S. Pullamsetti, G.A. Banat, M. Szibor, D. Pomagruk, J. Hänze, E. Kolosionek,
J. Wilhelm, T. Braun, F. Grimminger, W. Seeger, R.T. Schermuly, R. Savai, Phos-
phodiesterase-4 promotes proliferation and angiogenesis of lung cancer by
crosstalk with HIF, Oncogene 32 (2013) 1121–1134.
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.131222.
[13] F. Mentz, M.D. Mossalayi, F. Ouaaz, S. Baudet, F. Issaly, S. Ktorza, M. Semi-
chon, J.L. Binet, H. Merle-Beral, Theophylline synergizes with chlorambucil in
inducing apoptosis of B- chronic lymphocytic leukemia cells, Blood 88 (1996)
2172–2182.
[14] P. Csizmadia, MarvinSketch and MarvinView: molecule applets for the World
Wide Web, in: Proceedings of ECSOC-3, the Third International Electronic Con-
ference on Synthetic Organic Chemistry, 1999, pp. 367–369. September 1-30.
[15] R. Huey, G.M. Morris, AutoDock Tools, The Scripps Research Institute, La Jolla,
CA, USA, 2003.
References
[1] S. Kumar, B. Sharma, V. Mehra, V. Kumar, Recent accomplishments on the
synthetic/biological facets of pharmacologically active 1H-1,2,3-triazoles, Eur.
J. Med. Chem. 212 (2021) 113069.
[2] W. Hou, Z. Luo, G. Zhang, D. Cao, D. Li, H. Ruan, B.H. Ruan, L. Su, H. Xu,
Click chemistry-based synthesis and anticancer activity evaluation of novel
C-14 1,2,3-triazole dehydroabietic acid hybrids, Eur. J. Med. Chem. 138 (2017)
1042–1052.
[16] O. Trott, A.J. Olson, AutoDock Vina: improving the speed and accuracy of dock-
ing with a new scoring function, efficient optimization, and multithreading, J.
Comput. Chem. 31 (2010) 455–461.
[3] M.F. Khan, T. Anwer, A. Bakht, G. Verma, W. Akhtar, M.M. Alam, M.A. Rizvi,
M. Akhter, M. Shaquiquzzam, Unveiling novel diphenyl-1H-pyrazole based
acrylates tethered to 1,2,3-triazole as promising apoptosis inducing cytotoxic
and anti-inflammatory agents, Bioorg. Chem. 87 (2019) 667–678.
[17] H.C. Kolb, K.B. Sharpless, The growing impact of click chemistry on drug dis-
covery, Drug Discov. Today 8 (2003) 1128–1137.
[4] C.B.P Devi,
K
Vijay, B.H Babu,
S
Farooq Adil, M.M Alam,
M
Vijjulatha,
[18] S. Pericherla, J. Mareddy, D.P.G. Rani, P.V. Gollapudi, S. Pal, Chemical modifica-
tions of nimesulide, J. Braz. Chem. Soc. 18 (2007) 384–390.
M.B Ansari, CuSO4/sodium ascorbate catalysed synthesis of benzosuberone and
1,2,3-triazole conjugates: design, synthesis and in vitro anti-proliferative activ-
ity, J. Saudi Chem. Soc. 23 (2019) 980–991.
[19] K. Kankanala, V.R. Reddy, Y.P. Devi, L.N. Mangamoori, K. Mukkanti, S. Pal,
Nimesulide based novel glycolamide esters: their design, synthesis, and phar-
macological evaluation, J. Chem. (2013) 8 Article ID 816769pages.
[20] P. Wang, J.G. Myers, P. Wu, B. Cheewatrakoolpong, R.W. Egan, M.M. Billah, Ex-
pression, purification, and characterization of human cAMP-specific phospho-
diesterase (PDE4) subtypes A, B, C, and D, Biochem. Biophys. Res. Commun.
234 (1997) 320–324.
[5] J. Mareddy, N. Suresh, C.G. Kumar, R.K. Kapavarapu, A. Jayasree, S Pal, 1,2,3-Tri-
azole-nimesulide hybrid: their design, synthesis and evaluation as potential
anticancer agents, Bioorg. Med. Chem. Lett 27 (2017) 518–523.
[6] S. Srinivas, P. Neeraja, V. Banothu, P.K. Dubey, K. Mukkanti, S. Pal, Synthe-
sis, biological evaluation and docking study of
a series of 1,4-disubstituted
1,2,3-triazole derivatives with an indole–triazole–peptide conjugate, J. Hetero-
cycl. Chem. 57 (2020) 3126–3141 DOI: 10.1002/jhet.4020.
[21] A. Daina, O. Michielin, V. Zoete, SwissADME:
a free web tool to eval-
uate pharmacokinetics, drug-likeness and medicinal chemistry friendli-
[7] S. Srinivas, P. Neeraja, K. Naveen, V. Banothu, P.K. Dubey, K. Mukkanti, S. Pal,
Synthesis, chemotherapeutic screening and docking studies of NSAID in-
serted peptide-triazole hybrid molecules, Chem. Select 5 (2020) 6786–6791
doi.org/10.1002/slct.202000492.
ness of small molecules, Sci. Rep.
https://doi.org/10.1038/srep42717.
7 (2017) Article number: 42717.
7