New amide linked dimeric 1,2,3-triazoles bearing aryloxy scaffolds as a potent antiproliferative agents and EGFR tyrosine kinase phosphorylation inhibitors

Article abstract of DOI:10.1016/j.bmcl.2019.08.022

A search for potent antiproliferative agents has prompted to design and synthesize aryloxy bridged and amide linked dimeric 1,2,3-triazoles (7a–j) by using 1,3-dipolar cycloaddition reaction between 2-azido-N-phenylacetamides (4a–e) and bis(prop-2-yn-1-yl

Full text of DOI:10.1016/j.bmcl.2019.08.022

Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
New amide linked dimeric 1,2,3-triazoles bearing aryloxy scaffolds as a
potent antiproliferative agents and EGFR tyrosine kinase phosphorylation
inhibitors
Tejshri R. Deshmukha, Aniket P. Sarkateb, Deepak K. Lokwanic, Shailee V. Tiwarid,
⁎
Rajaram Azade, Bapurao B. Shingatea,
a Department of Chemistry, Dr. Babasaheb Ambedkar, Marathwada University, Aurangabad 431 004, Maharashtra, India
b Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, Maharashtra, India
c Department of Pharmaceutical Chemistry, R.C. Patel Institute of Pharmaceutical Education & Research, Shirpur 425 405, Maharashtra, India
d Department of Pharmaceutical Chemistry, Durgamata Institute of Pharmacy, Dharmapuri, Parbhani 431 401, Maharashtra, India
e Department of Animal Biology, University of Hyderabad, Hyderabad 500 046, India
A R T I C L E I N F O
A B S T R A C T
Keywords:
A search for potent antiproliferative agents has prompted to design and synthesize aryloxy bridged and amide
linked dimeric 1,2,3-triazoles (7a–j) by using 1,3-dipolar cycloaddition reaction between 2-azido-N-phenyla-
cetamides (4a–e) and bis(prop-2-yn-1-yloxy)benzenes (6a–b) via copper (I)-catalyzed click chemistry approach
with good to excellent yields. All the newly synthesized compounds have been screened for their in vitro anti-
proliferative activities against two human cancer cell lines. The compounds 7d, 7e, 7h, 7i and 7j have revealed
promising antiproliferative activity against human breast cancer cell line (MCF-7), whereas, the compounds 7a,
7b, 7c, 7i and 7j were observed as potent antiproliferative agents against human lung cancer cell line (A-549).
The active compounds against MCF-7 have been also analysed for their mechanism of action by the enzymatic
study, which shows that the compounds 7d, 7h and 7j were acts as active EGFR tyrosine kinase phosphorylation
inhibitors. In support to this biological study, the molecular docking as well as in silico ADME properties of all
the newly synthesized hybrids were predicted.
Antiproliferative activity
Click reaction
Dimeric 1,2,3-triazoles
EGFR tyrosine kinase phosphorylation
inhibition
Molecular docking study
Cancer is a life threatening disease that originates when there is an
imbalance in cellular signals, which generally controls the cell pro-
liferation, growth, morphogenesis and apoptosis.1 These signals were
mainly regulated by the enzymes, ‘Tyrosine Kinases’ by the phosphor-
ylation of tyrosine residue in different substrates.2 There are certain
receptors available for these kind of substrates, which plays a key role
in the genesis of many kind of cancers. ‘Epidermal Growth Factor Re-
ceptor’ (EGFR) is one of them, which activates tyrosine kinase phos-
phorylation after the binding of ligands by dimerization.3 Thus, to
control the growth of cancerous cells by balancing cellular signals, it is
necessary to inhibit those activated dimeric species of EGFR. Literature
survey reveals that, the dimeric drug can shows better binding affinity
to inhibit the activated dimeric species of EGFR rather than two sepa-
rate monomeric drugs.4 Therefore, we have synthesized the series of
dimeric compounds with hope to obtain better EGFR tyrosine kinase
phosphorylation inhibitors as well as antiproliferative agents.
azole motif in their molecular framework.5a–c Mostly, the development
of new antiproliferative agents bearing 1,4-disubstituted 1,2,3-triazole
as a pharmacophoric unit is being highlighted by many researchers.6a–d
The 1,4-disubstituted 1,2,3-triazoles are easy to synthesize by using Cu
(I)-catalyzed 1,3-dipolar cycloaddition reaction in between azide and
alkyne with the help of Sharpless and Meldal’s greener approach of
click chemistry.7 They are acts as bioisostere of amide bond, therefore,
it shows high binding affinity to many biological targets.8 Similarly,
ethereal as well as amide functionalities are also tends to interact with
various biological targets. Here, we have shown some molecular
structures of antiproliferative agents bearing amide and ethereal linked
1,2,3-triazolyl scaffolds9–12 in Fig. 1.
Considering the therapeutic significance of the above, herein, we
have planned and synthesized dimeric 1,2,3-triazoles by accumulating
amide linked substituted variant unit, dimeric 1,2,3-triazoles and ar-
yloxy moiety in a single molecular framework with hope to obtain
better antiproliferative agents with reduced side effects.
Recently, many antiproliferative agents were reported with the
⁎ Corresponding author.
E-mail address: bapushingate@gmail.com (B.B. Shingate).
https://doi.org/10.1016/j.bmcl.2019.08.022
Received 26 May 2019; Received in revised form 10 August 2019; Accepted 11 August 2019
0960-894X/©2019ElsevierLtd.Allrightsreserved.
Pleasecitethisarticleas:TejshriR.Deshmukh,etal.,Bioorganic&MedicinalChemistryLetters,https://doi.org/10.1016/j.bmcl.2019.08.022

T.R. Deshmukh, et al.
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxxx
Fig. 1. Ether and amide linked 1,2,3-triazolyl scaffolds as antiproliferative agents.
room temperature resulted into the corresponding aryloxy bridged and
amide linked dimeric 1,2,3-triazoles (7a–j) in excellent yields (Scheme
3).
The structures of all the newly designed and synthesized dimeric
1,2,3-triazole derivatives (7a–j) bearing aryloxy scaffolds are shown in
Fig. 3. All these compounds (7a–j) have been characterized by physical
data and spectral analysis.15
All the newly synthesized aryloxy bridged and amide linked sub-
stituted dimeric 1,2,3-triazoles (7a–j) were evaluated for their in vitro
antiproliferative activity against two human cancer cell lines as well as
the inhibition of EGFR tyrosine kinase phosphorylation was also studied
by comparing the results with standard antiproliferative drug, Gefitinib.
In vitro antiproliferative screening of titled compounds against the
human breast cancer cell line (MCF-7) and human lung cancer cell line
(A-549) were performed using MTT assay.16 The obtained results of in
vitro antiproliferative activities are summarized in Table 1. The detailed
study of in vitro antiproliferative with graphical representation have
been shown in Supporting Information (Table S1 and Figs. S1, S2).
From Table 1, we can conclude that among all the newly synthe-
sized compounds of the series, eight compounds have been displayed
significant antiproliferative activities against tested human cancer cell
lines MCF-7 and A-549. The compounds, 7d, 7e, 7h, 7i and 7j have
revealed promising antiproliferative activity against human breast
cancer cell line (MCF-7), whereas, the compounds, 7a, 7b, 7c, 7i and 7j
were observed as potent antiproliferative agents against human lung
cancer cell line (A-549). As most of compounds from series were shows
potency against tested human cancer cell lines, we can conclude that
the newly synthesized compounds offers an attractive lead series for the
discovery of novel antiproliferative agents in future by generating more
similar compounds and continuing further research on active com-
pounds.
Fig. 2. Molecular design strategy for the synthesis of novel dimeric 1,2,3-tria-
zole derivatives bearing aryloxy scaffolds.
The design of aryloxy bridged and amide linked substituted dimeric
1,2,3-triazoles hybrids was broadly divided into three segments as
shown in Fig. 2. The first one is the main backbone of the design
strategy, that is symmetrically situated two 1,2,3-triazolyl units. It helps
to enhance the pharmacophoric properties as they exhibits drug like
properties. The second segment is 1,2 or 1,3-diaryloxy moiety showing
etheral linkages with triazolyl units as a source of hydrogen bond ac-
ceptor. Lastly, the substituted 1,2,3-triazolyl acetamide fragment with
substitutional variant unit, which was generally used to control the li-
pophilicity as well as it contributes as the most active pharmacophoric
unit due to presence of amide linkage.
The synthesis of new aryloxy bridged and amide linked substituted
dimeric 1,2,3-triazoles (7a–j) were carried out via multi-step synthetic
pathway as illustrated in Schemes 1–3. The desired compounds (7a–j)
were synthesized by using copper(I)-catalyzed click reaction as de-
scribed in Scheme 3. The required starting material, 2-azido-N-pheny-
lacetamide derivatives (4a–e) were prepared from corresponding ani-
lines (1a–e) via chloro acylation reaction followed by treatment with
sodium azide as depicted in Scheme 1.13
In this study, the compounds 7b and 7c were observed as the most
potent antiproliferative agents from the series against A-549 as they
exhibited antiproliferative activities with IC50 values 2.22 µM and
2.34 µM, respectively. The compounds 7i and 7j were having good
antiproliferative activities against both the cancer cell lines, MCF-7 and
A-549. The compound 7i was displayed IC50 values 6.70 and 5.56 µM
whereas; the compound 7j has shown IC50 values 2.80 µM and 5.61 µM,
respectively against MCF-7 and A-549. Therefore, it was observed that
the compound 7j shows better antiproliferative activity against MCF-7
among the newly synthesized compounds of the series. In addition to
this, some other compounds like 7d, 7e and 7h were also display po-
tency against MCF-7 with IC50 values 6.01 µM, 6.13 µM and 4.18 µM,
respectively. Furthermore, the compound 7a was also found to be ac-
tive against A-549 with IC50 value 7.05 µM.
The another precursors, 1,3-bis(prop-2-yn-1-yloxy)benzene (6a)
and 1,2-bis(prop-2-yn-1-yloxy)benzene (6b) were synthesized from re-
sorcinol (5a) and catechol (5b), respectively. The compounds (5a) and
(5b) were separately allowed to react with propargyl bromide in pre-
sence of K2CO3 as a base in N,N-dimethylformamide (DMF) at room
temperature14 resulted in good to excellent yields of dialkynes (6a) and
(6b), respectively (Scheme 2).
The desired aryloxy bridged and amide linked dimeric 1,2,3-tria-
zoles (7a–j) were synthesized by 1,3-dipolar cycloaddition reaction of
freshly synthesized 2-azido-N-phenylacetamide derivatives (4a–e) with
bis(prop-2-yn-1-yloxy)benzene (6a–b) as a source of dialkyne. This
click reaction was carried out in presence of catalytic amount of
CuSO4·5H2O and sodium ascorbate in PEG-400:H2O (3:1) for 8 h at
As we found that the compounds 7h and 7j were act as the most
potent antiproliferative agents against MCF-7 cancer cell line, they are
2

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Scheme 1. Synthesis of 2-azido-N-phenylacetamides (4a–e) via 2-chloro-N-phenylacetamides (3a–m) from respective aromatic amines (1a–e).
Scheme 2. Synthesis of bis(prop-2-yn-1-yloxy)
benzene (6a–b) from commercially available
resorcinol (5a) and catechol (5b), respectively.
Scheme 3. Synthesis of aryloxy and amide linked substituted dimeric 1,2,3-triazoles (7a–j).
also evaluated for study their cytotoxic nature against MCF-10A
(normal breast epithelial cell line). This study helps to know the se-
lectivity of these active compounds towards cancerous cells. If the
compound is more selective towards cancerous cells then it must be less
toxic to the normal cells. From the Table 1, it was observed that the
compound 7h shows IC50 value 33.44 μM against MCF-10A, which
means that it shows eight times more selectivity towards MCF-7. Si-
milarly, the compound 7j shows 5 times more selectivity towards MCF-
7 cancer cell line as it displays IC50 value 14 μM against MCF-10A. After
this comparative study, we can conclude that the potent compounds
from the newly synthesized series were more selective towards can-
cerous cells, whereas, they were very less toxic towards the normal
breast epithelial cells.
bioactivity, whereas, the compounds with no substituents observed as
inactive. Specifically, the most potent compounds from series, 7j and
7b bearing -Cl and –NO2 groups on the phenyl rings with catechol and
resorcinol moieties, respectively as a source of aryloxy scaffolds may
responsible for their highly potent biological activities.
In addition to this, to explicate the inhibition of cancer cells pro-
liferation were associated with EGFR, the inhibition of EGFR tyrosine
kinase phosphorylation was studied. ‘Epidermal Growth Factor
Receptor’ (EGFR) is one of the receptor, that used to activates tyrosine
kinase phosphorylation after the binding of ligands by dimerization.3
Thus, to control the growth of cancerous cells, it is necessary to inhibit
these activated dimeric species of EGFR. Literature survey reveals that,
the dimeric drug can show better binding affinity to inhibit the acti-
vated dimeric species of EGFR rather than two separate monomeric
drugs.4 Therefore, we have evaluated only the potent antiproliferative
agents of the newly synthesized series against MCF-7 using Western blot
analysis.17 Here, Gefitinib was used as a standard drug, as it was al-
ready a good inhibitor of EGFR tyrosine kinase phosphorylation. It
shows the complete inhibition of the EGFR tyrosine kinase
From the above results, it was observed that most of the compounds
from the series displays moderate to good antiproliferative activities.
But the careful examination leads to the establishment of a significantly
regular structure activity relationship (SAR), which indicates that, the
presence of different substituents such as –NO2, –OCH3, –CH3 and –Cl
on the phenyl rings of compounds may responsible to enhance the
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Fig. 3. Structures of newly synthesized aryloxy bridged and amide linked dimeric 1,2,3-triazoles (7a–j).
phosphorylation with ∼100% inhibition against MCF-7 cell line. The
results of inhibition of EGFR tyrosine kinase phosphorylation by newly
synthesized compounds were summarized in Table 2.
inhibition, respectively against MCF-7. The immunoblot analysis of the
EGFR against MCF-7 cancer cell line for potent compounds were shown
in Fig. 4.
From Table 2, the compound 7h was displayed most potent activity
among all the synthesized compounds with 88.34% inhibition of EGFR
tyrosine kinase phosphorylation. The compounds 7d and 7j also acts as
good inhibitors of EGFR-TK Phosphorylation with 76.87% and 72.68%
Fig. 4 reveals that, the inhibition of EGFR tyrosine kinase phos-
phorylation after exposure to compounds 7j (Lane 1), 7d (Lane 2), 7h
(Lane 3) and Gefitinib (Lane 4) for 48 h. From all these results, we can
conclude that, the compound 7h was found as a good inhibitor of EGFR-
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Table 1
hydrogen bond acceptor (Fig. 6). These compounds also showed H-
bonding with amino acid residues Phe723 Lys745, Arg841, Thr854, and
Asp855 which support ligand-enzyme complex. It is also visualized that
one of the traizole ring and phenyl ring strengthen the stability of
complex by making π-cation interaction with amino acid residue
Lys745 and/or Arg841.
In vitro antiproliferative activity of the synthesized derivatives (7a–j).
Entry
IC50Value (µM)
MCF-7
A549
MCF-10A
7a
NA
NA
NA
7.05
2.22
2.34
NA
3.93
0.07
0.74
NT
A drug can be said as successful if it having good efficacy as well as
an acceptable ADME profile. ADME properties prediction is one of the
important as well as widely known pharmacokinetic parameter for the
prediction of the oral bioavailability of any drug. A compound is also
considered to be an orally active drug as well as obeys the Lipinski’s
rule of five if there is only one violation is observed out of the following
four criteria’s: miLog P (octanol–water partition coefficient) ≤ 5, mo-
lecular weight ≤ 500, number of hydrogen bond acceptors ≤ 10 and
number of hydrogen bond donors ≤ 5. Therefore, to know the oral
bioavailability, Lipinski violations and drug likeness properties of all
the newly synthesized aryloxy bridged and amide linked substituted
dimeric 1,2,3-triazolyl compounds (7a–j), herein, we have predicted
and studied the in silico ADME properties, % of absorption and drugli-
keness model score. The results of in silico ADME prediction studies
including Lipinski violations, % of absorption and druglikeness model
score were summarized in Table S2 (Supporting Information). Ac-
cording to obtained results, most of the predictions were found to be
within the acceptable range. All the synthesized compounds exhibited
moderate to good % ABS ranging from 29.74 to 61.36%. Drug likeness
score was also calculated in order to achieve biological activity of
compound. Most of the compounds from the synthesized series shows
positive drug likeness score. All the results shows that the compounds
possess average to good potential for the development as orally active
drug molecule.
7b
NT
7c
NT
7d
6.01
6.13
NA
3.09
3.81
NT
7e
NA
NT
7f
NA
NT
7g
NA
NA
NT
7h
4.18
6.70
2.80
2.97
3.18
4.13
2.47
1.09
NA
33.44
NT
7i
5.56
5.61
2.11
2.05
3.35
0.88
7j
14.00
NT
Gefitinib
NA: Not Applicable; NT: Not Tested.
Table 2
The percentage EGFR-TK inhibitory activity of the active anti-
proliferative agents against MCF-7 cell line.
Compound
% EGFR-TK Inhibition of MCF-7a
7d
76.87
32.62
88.34
28.22
72.68
∼100*
0.68
0.10
0.09
0.42
0.18
7e
7h
7i
7j
bGefitinib
* Absence of immunoblot in Lane 4 of MCF-7 showed complete
inhibition of EGFR phosphorylation.
a
The data were means from at least three independent experiments
In conclusion, the aryloxy bridged and amide linked substituted
dimeric 1,2,3-triazole hybrids (7a–j) were synthesized and evaluated
for antiproliferative activity against two human cancer cell lines (MCF-
7 and A549). Eight compounds of the series were displayed good to
excellent antiproliferative activities against tested human cancer cell
lines. The compounds, 7d, 7e, 7h, 7i and 7j were observed as potent
antiproliferative agents against human breast cancer cell line (MCF-7),
whereas, the compounds, 7a, 7b, 7c, 7i and 7j have been revealed
promising antiproliferative activity against human lung cancer cell line
(A-549). Furthermore, the study of EGFR tyrosine kinase phosphor-
ylation inhibition also carried out with active antiproliferative agents
against MCF-7 cell line. The results of this study shows that, the com-
pounds, 7d, 7h and 7j were acts as active EGFR tyrosine kinase phos-
phorylation inhibitors. In support to this study, the newly synthesized
compounds have been also shows good results of molecular docking as
well as ADME properties were observed in acceptable range. From the
above observations it can be conclude that newly synthesized aryloxy
bridged and amide linked substituted dimeric 1,2,3-triazole hybrids
(7a–j) offers an attractive lead series for the discovery of novel anti-
proliferative agents as well as EGFR tyrosine kinase phosphorylation
inhibitors.
at a single dose of 10 μM concentration.
b
Gefitinib was used as a standard antiproliferative drug at 10 µM
concentration.
Fig. 4. Immunoblot analysis of the EGFR in MCF-7 cancer cell line.
TK Phosphorylation as it displays 88% inhibition of EGFR-TK Phos-
phorylation against MCF-7 cancer cell line, which is found to be close to
the standard drug Gefitinib. Therefore, the compound 7h was acts as a
potent antiproliferative agent due to its ability to inhibit EGFR tyrosine
kinase phosphorylation.
Furthermore, in support to biological activities, the molecular
docking was also performed in Maestro 9.1 using the Induced Fit
Docking (IFD) protocol (Schrodinger LLC)18 for newly synthesized
compounds against EGFR kinase domain (PDB entry: 3W33). The IFD
combines the Glide docking program for ligand flexibility and the Prime
program for receptor flexibility. In the refinement module of Prime for
protein, the side chain degrees of freedom are mainly sampled, while
minor backbone movements are allowed through minimization. The
docking results indicated that the compounds were held in the active
pocket by combination of various hydrogen and hydrophobic interac-
tions with EGFR enzyme. The compounds 7d, 7h and 7j showed
binding affinity and pose similar to that of standard drug Gefitinib
(Figs. 5a and 5b).
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
It was found from literature that all EGFR inhibitors make a weak
interaction with amino acids residue Met793. Thus the constraints was
defined during IFD studies that all compounds must forms the H-bond
with Met793 and it is surprised that ether linkage of most of the
compounds shows the H-bond with Met793. This interaction also con-
firms our compound design strategy for ether linkage, which act as
Acknowledgments
Authors are also thankful to the Head, Department of Chemistry, Dr.
Babasaheb Ambedkar Marathwada University, Aurangabad-431 004,
India for providing laboratory facility.
5

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Fig. 5a. The superimposition of docking pose of compound 7d (green coloured), 7h (light blue coloured) and 7j (magenta coloured) into the active site of EGFR
enzyme.
Fig. 5b. The superimposition of docking pose of standard Gefitinib (gray coloured) and compound 7h (light blue coloured) into the active site of EGFR enzyme.
6

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Fig. 6. The docking pose of compounds (a) 7d, (b) 7h and (c) 7j into the active site of EGFR enzyme. The yellow coloured dotted line indicate H-bond and green
coloured dotted line indicate π-cation interaction. The magenta coloured numerical indicates the distance of H-bonds. The amino acids are coloured according to
their property like hydrophobicity, charged and polar (Gray colour: Cysteine, green colour: hydrophobic, cyan colour: polar uncharged, blue colour: positives, and
red colour: negatives).
Appendix A. Supplementary data
(b) Kumar S, Kumar SV, Gupta GK, et al. Antibacterial, tyrosinase and DNA photo-
cleavage studies of some triazolylnucleosides. Nucleos Nucleot Nucl.
2017;36:543–551
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bmcl.2019.08.022.
(c) Huang RZ, Liang GB, Li MS, et al. Synthesis and discovery of asiatic acid based
1,2,3-triazole derivatives as antitumor agents blocking NF-kB activation and cell
migration. Med Chem Commun. 2019;10:584–597
(d) Bebenek E, Tomanek MK, Chrobak E, Latocha M, Boryczka S. Novel triazoles of
3-acetylbetulin and betulone as anticancer agents. Med Chem Res.
2018;27:2051–2061.
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7.43 (d, 4H, Ar-H), 7.65 (d, 4H, Ar-H), 8.30 (s, 2H, triazolyl-H), 10.66 (s, 2H, amido-H);
13C NMR (125 MHz, DMSO‑d6, δC ppm) 52.7, 61.5, 102.0, 107.8, 121.3, 126.8, 127.8,
129.3, 134.6, 137.8, 142.9, 159.8, 164.9; HRMS (ESI) calcd. For C28H25Cl2N8O4 [M
+H]+: 607.1376; found: 607.1372. Compound 7f: Creamish white solid; Yield: 90%;
Mp: 190–192 °C; IR (ѵmax cm−1) 3267 (NeH, amide), 1669 (C]O, amide); 1H NMR
(400 MHz, DMSO‑d6, δH ppm) 5.20 (s, 4H, O-CH2), 5.37 (s, 4H, N-CH2), 6.96 (dd, 2H, Ar-
H), 7.11 (t, 2H, Ar-H), 7.23 (dd, 2H, Ar-H), 7.36 (t, 4H, Ar-H), 7.60 (d, 4H, Ar-H), 8.27 (s,
2H, triazolyl-H), 10.50 (s, 2H, amido-H); 13C NMR (100 MHz, DMSO‑d6, δC ppm) 52.7,
62.1, 114.8, 119.7, 121.8, 124.3, 126.9, 129.4, 138.9, 143.1, 148.4, 164.7; HRMS (ESI)
calcd. For C28H27N8O4 [M+H]+: 539.2155; found: 539.2143. Compound 7g: Blackish
green solid; Yield: 92%; Mp: > 270 °C; IR (ѵmax cm−1) 3244 (NeH, amide), 1673 (C]O,
amide); 1H NMR (400 MHz, DMSO‑d6, δH ppm) 5.20 (s, 4H, O-CH2), 5.45 (s, 4H, N-CH2),
6.96 (d, 2H, Ar-H), 7.21 (d, 2H, Ar-H), 7.82 (d, 4H, Ar-H), 7.97 (d, 4H, Ar-H), 8.25 (s, 2H,
triazolyl-H), 11.09 (s, 2H, amido-H); 13C NMR (100 MHz, DMSO‑d6, δC ppm) 62.4, 70.4,
116.7, 119.8, 122.1, 125.7, 131.0, 143.2, 145.1, 148.6, 151.6, 163.0; HRMS (ESI) calcd.
For C28H25N10O8 [M+H]+: 629.1857; found: 629.1850. Compound 7h: Creamish white
solid; Yield: 89%; Mp: 213–215 °C; IR (ѵmax cm−1) 3267 (NeH, amide), 1670 (C]O,
amide); 1H NMR (400 MHz, DMSO‑d6, δH ppm) 3.71 (s, 6H, OCH3), 5.16 (s, 4H, O-CH2),
5.29 (s, 4H, N-CH2), 6.89 (d, 4H, Ar-H), 6.92 (dd, 2H, Ar-H), 7.19 (dd, 2H, Ar-H), 7.48 (d,
4H, Ar-H), 8.22 (s, 2H, triazolyl-H), 10.33 (s, 2H, amido-H); 13C NMR (100 MHz,
DMSO‑d6, δC ppm) 52.6, 55.8, 62.1, 114.4, 114.6, 121.2, 121.4, 127.0, 132.0, 143.1,
148.4, 156.1, 164.2; HRMS (ESI) calcd. For C30H31N8O6 [M+H]+: 599.2367; found:
13. Tiew KC, Dou D, Teramoto T, et al. Inhibition of Dengue virus and West Nile virus
proteases by click chemistry-derived benz[d]isothiazol-3(2H)-one derivatives. Bioorg
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14. (a) Anand A, Naik RJ, Revankar HM, Kulkarni MV, Dixit SR, Joshi SD. A click
chemistry approach for the synthesis of mono and bis aryloxy linked coumarinyl
triazoles as anti-tubercular agents. Eur J Med Chem. 2015;105:194–207
(b) Kant R, Kumar D, Agarwal D, et al. Synthesis of newer 1,2,3-triazole linked
chalcone and flavone hybrid compounds and evaluation of their antimicrobial and
cytotoxic activities. Eur J Med Chem. 2016;113:34–49.
15.. Compound 7a: White solid; Yield: 92%; Mp: 228–230 °C; IR (ѵmax cm−1) 3268
(NeH, amide), 1677 (C]O, amide); 1H NMR (400 MHz, DMSO‑d6, δH ppm) 5.17 (s, 4H,
O-CH2), 5.36 (s, 4H, N-CH2), 6.68 (dd, 2H, Ar-H), 6.77 (s, 1H, Ar-H), 7.08 (t, 2H, Ar-H),
7.20 (t, 1H, Ar-H), 7.32 (d, 4H, Ar-H), 7.57 (d, 4H, Ar-H), 8.27 (s, 2H, triazolyl-H), 10.48
(s, 2H, amido-H); 13C NMR (100 MHz, CDCl3, δC ppm) 57.5, 66.3, 106.8, 112.6, 124.5,
129.1, 131.6, 134.2, 135.3, 143.7, 147.7, 164.6, 169.4; HRMS (ESI) calcd. For
C
28H27N8O4 [M+H]+: 539.2155; found: 539.2160. Compound 7b: Dark creamish solid;
Yield: 94%; Mp: 128–130 °C; IR (ѵmax cm−1) 3254 (NeH, amide), 1679 (C]O, amide);
1H NMR (500 MHz, DMSO‑d6, δH ppm) 5.19 (s, 4H, O-CH2), 5.46 (s, 4H, N-CH2), 6.68 (dd,
2H, Ar-H), 6.78 (s, 1H, Ar-H), 7.23 (t, 1H, Ar-H), 7.84 (d, 4H, Ar-H), 8.26 (d, 4H, Ar-H),
8.29 (s,2H, triazolyl-H), 11.09 (s, 2H, amido-H); 13C NMR (100 MHz, DMSO‑d6, δC ppm)
52.8, 61.6, 102.1, 107.9, 119.6, 125.6, 126.9, 130.6, 143.1, 143.2, 145.0, 159.8, 165.9;
LCMS (ESI) calcd. For C28H25N10O8 [M+H]+: 629.1857; found: 629.1. Compound 7c:
Dark yellowish solid; Yield: 91%; Mp: 197–198 °C; IR (ѵmax cm−1) 3267 (NeH, amide),
1667 (C]O, amide); 1H NMR (400 MHz, DMSO‑d6, δH ppm) 3.91 (s, 6H, OCH3), 5.34 (s,
4H, O-CH2), 5.50 (s, 4H, N-CH2), 6.85 (dd, 2H, Ar-H), 6.95 (s, 1H, Ar-H), 7.09 (d, 4H, Ar-
H), 7.40 (t, 1H, Ar-H), 7.68 (d, 4H, Ar-H), 8.44 (s, 2H, triazolyl-H), 10.53 (s, 2H, amido-
H); 13C NMR (100 MHz, DMSO‑d6, δC ppm) 52.6, 55.6, 61.5, 102.0, 107.8, 114.5, 121.3,
126.7, 130.5, 131.9, 142.9, 156.0, 159.8, 164.1; HRMS (ESI) calcd. For C30H31N8O6 [M
+H]+: 599.2367; found: 599.2363. Compound 7d: Pale yellow solid; Yield: 93%; Mp:
206–208 °C; IR (ѵmax cm−1) 3267 (NeH, amide), 1661 (C]O, amide); 1H NMR
(400 MHz, DMSO‑d6, δH ppm) 2.26 (s, 6H, CH3), 5.17 (s, 4H, O-CH2), 5.33 (s, 4H, N-CH2),
6.67 (dd, 2H, Ar-H), 6.77 (s, 1H, Ar-H), 7.14 (d, 4H, Ar-H), 7.22 (t, 1H, Ar-H), 7.47 (s, 4H,
Ar-H), 8.26 (s, 2H, triazolyl-H), 10.39 (s, 2H, amido-H); 13C NMR (100 MHz, DMSO‑d6, δC
ppm) 20.9, 52.7, 61.5, 102.0, 107.8, 119.7, 126.8, 129.8, 130.5, 133.3, 136.4, 143.0,
159.8, 164.4; HRMS (ESI) calcd. For C30H31N8O4 [M+H]+: 567.2468; found: 567.2469.
Compound 7e: Light yellowish solid; Yield: 89%; Mp: 250–253 °C; IR (ѵmax cm−1) 3275
(NeH, amide), 1685 (C]O, amide); 1H NMR (400 MHz, DMSO‑d6, δH ppm) 5.20 (s, 4H,
O-CH2), 5.40 (s, 4H, N-CH2), 6.70 (dd, 2H, Ar-H), 6.80 (s, 1H, Ar-H), 7.25 (t, 1H, Ar-H),
599.2366. Compound 7i: Light yellow solid; Yield: 91%; Mp: 232–235 °C; IR (ѵmax cm−1
)
3265 (NeH, amide), 1660 (C]O, amide); 1H NMR (400 MHz, DMSO‑d6, δH ppm) 2.26 (s,
6H, CH3), 5.17 (s, 4H, O-CH2), 5.32 (s, 4H, N-CH2), 6.94 (d, 2H, Ar-H), 7.14 (d, 4H, Ar-H),
7.21 (d, 2H, Ar-H), 7.46 (d, 4H, Ar-H), 8.23 (s, 2H, triazolyl-H), 10.39 (s, 2H, amido-H);
13C NMR (125 MHz, DMSO‑d6, δC ppm) 20.9, 52.6, 62.1, 114.8, 119.7, 121.8, 126.8,
129.7, 133.2, 136.4, 143.1, 148.4, 164.4; HRMS (ESI) calcd. For C30H31N8O4 [M+H]+
:
567.2468; found: 567.2471. Compound 7j: Yellowish solid; Yield: 85%; Mp: 253-255°C;
IR (ѵmax cm−1) 3255 (NeH, amide), 1680 (C]O, amide); 1H NMR (400 MHz, DMSO‑d6,
δH ppm) 5.17 (s, 4H, O-CH2), 5.37 (s, 4H, N-CH2), 6.66 (dd, 2H, Ar-H), 7.23 (dd, 2H, Ar-
H), 7.39 (d, 4H, Ar-H), 7.62 (d, 4H, Ar-H), 8.27 (s, 2H, triazolyl-H), 10.63 (s, 2H, amido
NeH); 13C NMR (100 MHz, DMSO‑d6, δC ppm) 52.7, 61.6, 121.3, 121.4, 127.0, 127.9,
129.3, 129.5, 130.7, 137.9, 143.0, 164.9; HRMS (ESI) calcd. For C28H25Cl2N8O4 [M
+H]+: 607.1376; found: 607.1377.
16. Dofe VS, Sarkate AP, Azad R, Gill CH. Novel quinoline-based oxadiazole derivatives
induce G2/M arrest and apoptosis in human breast cancer MCF-7 cell line. Res Chem
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17. Johnson AC, Murphy BA, Matelis CM, et al. Activator protein-1 mediates induced but
not basal epidermal growth factor receptor gene expression. Mol Med. 2000;6:17–27.
18. Scherman W, Day T, Jacobson MP, Friesner RA, Farid R. Novel procedure for mod-
elling ligand/receptor induced fit effects. J Med Chem. 2006;49:534–553.
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