Design and synthesis of novel (Z)-5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-3-((1-substituted phenyl-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-diones: a potential cytotoxic scaffolds and their molecular modeling studies

Article abstract of DOI:10.1007/s11030-020-10093-3

In an effort to discover potential cytotoxic agents, a series of novel (Z)-5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-3-((1-substituted phenyl-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-dione derivatives (8a–n) were designed and synthesized in various

Full text of DOI:10.1007/s11030-020-10093-3

Molecular Diversity
https://doi.org/10.1007/s11030-020-10093-3
ORIGINAL ARTICLE
Design and synthesis of novel (Z)‑5‑((1,3‑diphenyl‑1H‑pyrazol‑4‑yl)
methylene)‑3‑((1‑substituted phenyl‑1H‑1,2,3‑triazol‑4‑yl)methyl)
thiazolidine‑2,4‑diones: a potential cytotoxic scafolds and their
molecular modeling studies
N. J. P. Subhashini1 · Kolluri Prashanth Kumar1 · Edigi Praveen Kumar1 · Putta Shravani2 ·
Surya Sathyanarayana Singh2 · Tamalapakula Vani3 · Manga Vijjulatha3
Received: 7 February 2020 / Accepted: 21 April 2020
© Springer Nature Switzerland AG 2020
Abstract
In an efort to discover potential cytotoxic agents, a series of novel (Z)-5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-3-((1-
substituted phenyl-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-dione derivatives (8a–n) were designed and synthesized
in various steps with acceptable reaction procedures with quantitative yields and characterized by 1H NMR, 13C NMR, IR,
HRMS and ESI–MS spectra. These newly synthesized novel derivatives were screened for their in vitro cell viability/cytotoxic
studies against human breast cancer cell line (MCF-7) with various concentrations of 0.625 µM, 1.25 µM, 2.5 µM, 5 µM
and 10 µM, respectively. The biological interpretation assay outcome was demonstrated in terms of cell viability percentage
reduction and IC50 values against standard reference drug cisplatin. Based on these results, most of the derivatives exhibited
promising cytotoxic activity. Among them, particularly compounds 8j (R1 =OMe and R3 =NO2) and 8e (R3 =CF3) demon-
strate remarkable cytotoxic activity with IC50 values 0.426 µM 0.455 and 0.608 µM 0.408, which are even better than
the standard drug cisplatin 0.636 µM 0.458 and compounds 8m (R2 =OMe and R3 =OMe) and 8c (R3 =OMe) exhibited
closely equivalent IC50 values to the standard drug with IC50 values 0.95 µM 0.32 and 0.976 µM 0.313 and rest of the
compounds exhibits moderate cytotoxic activity. Moreover, molecular modeling studies and ADME calculations of the novel
synthesized derivatives are in adequate consent with the pharmacological screening results.
Keywords Pyrazole · 2,4-Thiazolidinedione (TZD) · 1,2,3-Triazoles · Cytotoxic activity · Molecular modeling studies
Introduction
Cancer is a lethal disease. The term cancer encompasses
more than 100 diseases afecting almost every part of the
body, and all are presumably life-threatening. Cancer is a
disease in which incongruous cell proliferation and expan-
Electronic supplementary material The online version of this
sion of anomalous cells beyond their conventional outer
limits that can impinge on contiguous parts of the body
and destroy body tissue afect other organs. The global
cancer burden is evaluated to have risen to 18.1 million
new cases and 9.6 million deaths in 2018 [1]. Breast can-
cer is most frequently diagnosed cancer in women (24%,
i.e., about one in four of all new cancer cases diagnosed
in women worldwide are breast cancer), and it is the most
common cancer and also the leading cause of cancer death
in women followed by lung cancer and colorectal can-
cer, approximately 2.1 million diagnoses are estimated in
article (https://doi.org/10.1007/s11030-020-10093-3) contains
supplementary material, which is available to authorized users.
* N. J. P. Subhashini
njsubhashini@yahoo.co.in
1
Department of Chemistry, University College of Science,
Osmania University, Hyderabad, Telangana 500007, India
2
Department of Biochemistry, University College of Science,
Osmania University, Hyderabad, Telangana 500 007, India
3
Molecular Modeling and Medicinal Chemistry Laboratory,
Department of Chemistry, University College of Science,
Osmania University, Hyderabad, Telangana 500 007, India
Vol.:(0123456789)
1 3

Molecular Diversity
2018 [2]. Although the causes of cancer are not completely
understood, there was signifcant progress to decrease can-
cer percentage in the world. The present cancer therapies,
face various limitations and current cancer medicine are
not always persuasive, efcient and may often engender
hostile efects. Therefore, there is a necessity for the explo-
ration and development of new anticancer drugs with enor-
mous efciency and low in adverse efects is a major and
signifcant need of research across the world [3–5].
Nitrogen consisting of heterocyclic moieties has always
played an extensive role in modern medicinal and agro-
chemical felds because of their outstanding biological
properties which have emanated in various applications.
Among them, pyrazole embedded pharmacophores are
prominent structural fragments and the essential backbone
of various synthetic and natural existing pharmacological
active moieties. In recent years, exploration on condensed
pyrazole-4-carbaldehyde compounds has gained consider-
able scientifc signifcance and proven advantageous for
cancer treatment. Many pyrazole-containing molecules are
in the advancement phase as promising new drugs acting
against distinct biological targets. Derivatives of pyrazole
compounds have been described for excellent drug-like
properties and exhibit a wide range of biological activities
which comprise antimalarial [6], antimycobacterial [7],
antiviral [8], antitubercular [9], antioxidant [10], antican-
cer [11, 12], antileishmanial [13] and anti-infammatory
activities [14].
Moreover, triazoles are an essential heterocyclic structural
moieties that are associated with numerous pharmacological
activities and privileged motifs in medicinal and agrochem-
ical felds. Among them, 1,2,3-triazole motif is a unique
structure and this compound is an impressive option to use it
is a fundamental component in the drug design of new mol-
ecules because they are exceedingly stable under any con-
ditions (acidic/basic) and exhibit high dipole moment and
they have capable of forming hydrogen bonds with various
biological targets [27]. 1,2,3-Triazoles have been the sub-
ject of considerable research because of their involvement
in the regulation of distinctive biological processes, and it
is embedded in a number of clinically used medicines such
as tazobactam, carboxyamidotriazole, cefatrizine, etc., and
exhibit broad-spectrum of pharmacological activities which
include antioxidant [28], antitubercular [29], antibacterial
[30], antiviral [31], anticancer [32], antimicrobial [33] and
anti-infammatory [34] activities. Some of the proclaimed
natural and synthetically developed cytotoxic compounds
bearing 2,4-thiazolidinedione, 1,2,3-triazole and pyrazole
pharmacophores are displayed in Fig. 1.
Pharmacophore hybridization is a powerful tool to design
and development of potentially high active new chemical
compounds by covalently incorporating two and more bio-
logical active compounds into a novel scafold. In the view
of the above exploration and pharmacological signifcance
of these pharmacophores (pyrazole, 2,4-thiazolidinedione
and 1,2,3-triazole), we have made in an attempt to design,
develop and synthesize of excellent tumor growth inhibitors
with potent cytotoxic activity, high ability and less toxic
drugs for the treatment of cancer and designed prototype
scafold based on cytotoxic active compounds which are
demonstrated in Fig. 2. Based on these investigations and
our ongoing signifcance on these moieties in the explora-
tion of new pharmacophores with potent cytotoxic activity,
we developed and synthesized a series of novel (Z)-5-((1,3-
diphenyl-1H-pyrazol-4-yl)methylene)-3-((1-substituted
phenyl-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-dione
analogues (8a–n) and these derivatives were screened for
their cell viability/cytotoxic activity against human breast
cancer cell line (MCF-7).
On the other hand, thiazolidinediones are generally called
as glitazones after the prototypical medicine ciglitazone
used in the treatment of type-2 diabetes that were introduced
in the late 1990s and the thiazolidinediones are a broad class
of heterocyclic pharmacophores with many extensive phar-
macological properties [15]. Among them, 2,4-thiazolidin-
edione (TZD) was essential and privileged moiety consists
of a fve-membered C3NS ring with two carbonyl groups at
second and fourth positions, sulfur at the frst position, and
variable substitution reactions take place on third and ffth
positions and possess low molecular weight. Various hetero-
cyclic compounds embedded TZD scafold were exhibited
signifcant biological activities, and it is bearing a number
of clinically used medicines which include rosiglitazone,
lobeglitazone, pioglitazone, englitazone, netoglitazone and
revoglitazone and a fewer TZD containing drugs; in par-
ticular, ciglitazone and troglitazone have shown cytotoxic
activity. In recent years, experimental investigation on TZD
moiety was attracted extensive scientifc attention due to
their adaptable, diverse and fexible nature and has shown a
wide range of biological activities, which include antiviral
[16], antimicrobial [17], anticancer [18, 19], aldose reduc-
tase inhibitors [20], antihyperglycemic [21], cytotoxic [22],
antioxidant [23], anti-infammatory [24], antidiabetic [25]
and peptide deformylase inhibitors [26].
Results and discussion
Chemistry
The synthetic approach of desired compounds (Z)-5-((1,3-
diphenyl-1H-pyrazol-4-yl)methylene)-3-((1-substituted
phenyl-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-dione
(8a–n) was accomplished as demonstrated in Scheme 1.
The vital intermediate pharmacophore (Z)-5-((1,3-diphe-
nyl-1H-pyrazol-4-yl)methylene)-3-(prop-2-yn-1-yl)
1 3

Molecular Diversity
Cl
O
O
NH2
Cl
N
O
N
N
NH
O
S
O
O
N
N
Cl
Cl
H2N
O
H2N
F
Cl
HO
HN
Carboxyamidotriazole
Troglitazone
Crizotinib
O
O
O
NH2
N
N
N
H
N
S
H
N
N
S
NH
NH
S
N
N
O
F
O
HO
O
O
HN
Cl
O
S
O
Cefatrizine
Encorafenib
Ciglitazone
Fig. 1 Pyrazole, 2,4-thiazolidinedione and 1,2,3-triazole based inhibitors reported as cytotoxic agents
Fig. 2 Designed prototype scafold based on cytotoxic active pharmacophores
1 3

Molecular Diversity
Scheme 1 Synthesis of novel (Z)-5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-3-((1-substituted phenyl-1H-1,2,3-triazol-4-yl)methyl)thiazoli-
dine-2,4-dione analogues (8a–n)
thiazolidine-2,4-dione (6) was synthesized in four steps.
First, we have synthesized 1,3-diphenyl-1H-pyrazole-4-car-
baldehyde, as reported by previously published literature,
concisely, condensation reaction of acetophenone (1) and
phenyl hydrazine (2) gives corresponding phenyl hydra-
zone (3). Subsequently, these compounds (3) underwent
Vilsmeier–Haack cyclization reaction using DMF/POCl3
as a solvent/reagent to produce corresponding compound
(4) [39]. In the third step, the desired compound (5) was
achieved from 1,3-diphenyl-1H-pyrazole-4-carbaldehyde
with 2,4-thiazolidinedione involving Knoevenagel conden-
sation using a few drops of glacial acetic acid and a catalytic
amount of piperidine in toluene yielded required compound
(5) [40] that upon treating with propargyl bromide in the
presence of DMF using K2CO3 as a base to aford intermedi-
ate (6). Finally, the desired fnal derivatives were acquired
by employing click reaction of compound (6) with various
substituted phenyl azides (7a–n) in DMF by using 10 mol%
of sodium ascorbate and 10 mol% copper sulfate provided
fnal derivatives (8a–n) in reasonable to signifcant yields
and entire physical data of fnal derivatives are depicted in
Table 1.
as expected from Z-form, comparatively to the shielded
proton of E-from (6.22–6.46 ppm) thus proving that all the
synthesized derivatives were obtained exclusively in Z-form
and Z-isomer was thermodynamically more stable due to
intramolecular hydrogen bond that can be formed between
the hydrogen bond of arylidene proton and oxygen atom
of carbonyl group in 2,4-thiazolidinedione [41–43] and the
nitrogen attached methylene protons (N–CH2) was appeared
as a singlet at 5.07–5.15 ppm. In 13C NMR spectra, the two
carbonyl carbons of 2,4-thiazolidine ring were appeared at
165.2–164.2 ppm and 166.6–165.3 ppm region. The nitro-
gen attached methylene carbon (N–CH2) was appeared at
37.3–36.3 ppm, and remaining all protons and carbons were
resonating at expected region. Additionally, it is also con-
frmed by HRMS and ESI–MS spectra of the analogues.
Cell viability assay/cytotoxic activity
All these newly synthesized (Z)-5-((1,3-diphenyl-1H-pyra-
zol-4-yl)methylene)-3-((1-substituted phenyl-1H-1,2,3-tri-
azol-4-yl)methyl)thiazolidine-2,4-dione (8a–n) analogues
were screened for their in vitro cell viability/cytotoxic activ-
ity against MCF-7 cell line (Source: National Centre for Cell
Science-Pune). The standard MTT assay was employed for
cytotoxic activity, and the standard drug used was cisplatin
[44, 45]. Cell viability analysis of fnal derivatives was con-
ducted with MCF-7 cell line at fve distinct concentrations
of 0.625; 1.25; 2.5; 5; and 10 µM, respectively, and fnal
cell viability assay summary is demonstrated in Table 2 and
All these newly synthesized moieties (8a–n) were con-
1
frmed by H NMR, 13C NMR, IR, HRMS and ESI–MS
spectra. In 1H NMR, the characteristic pyrazole proton was
appeared as a singlet at 8.42–8.16 ppm region, the triazole
proton was appeared at 8.04–7.98 ppm as a singlet and char-
acteristic arylidene proton was appeared in preferably either
as singlet or multiplet at deshielded region of 7.96–7.81 ppm
1 3

Molecular Diversity
Table 1 Physical data of fnal
derivatives (8a–n)
S. no. R1
R2
R3
R4 M.F (M.Wt)
M.P (°C) Time (h) Yield (%)
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
H
H
H
H
H
H
H
H
H
OCH3
H
H
H
H
H
H
H
H
H
OH
H
Cl
H
F
Br
OCH3
COCH3
CF3
NO2
H
Cl
H
NO2
H
I
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C28H19FN6O2S (522.1)
C28H19BrN6O2S (582.1) 240–242 12
C29H22N6O3S (534.2)
C30H22N6O3S (546.2)
C29H19F3N6O2S (572.2) 212–214 12
C28H19N7O4S (549.2)
C28H20N6O3S (520.2)
C28H19ClN6O2S (538.2) 238–240 12
208–210 12
68
71
73
65
63
62
66
72
74
61
75
69
61
70
244–246 12
252–254 12
228–230 12
232–234 12
C28H19ClN6O2S (538.2) 248–250 12
C29H21N7O5S (579.2)
C28H20N6O2S (504.2)
C28H19IN6O2S (630.1)
C30H24N6O4S (564.2)
C29H22N6O2S (518.1)
218–220 12
242–244 12
220–222 12
210–212 12
256–258 12
H
H
OCH3 OCH3
CH3
H
H
M.F, molecular formula; M.Wt, molecular weight; M.P (°C), melting points in degrees centigrade
Isolated yield
Table 2 Cell viability
evaluation of novel synthesized
derivatives (8a–n)
S. no. Compound Concentrations
0.625 µM
1.25 µM
2.5 µM
5 µM
10 µM
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
Cisplatin
33% 4.866 45.25% 0.64 38.09% 2.58 35.43% 3.77 32.18% 5.23
235.01% 3.4
24.66% 1.22 25.81% 0.76 31.89% 2.02 19.62% 3.47
33.67% 2.33 39.96% 5.17 30.46% 0.93 19.01% 4.19 18.82% 4.27
51.93% 0.527 48.09% 2.24 47.95% 2.3
38.67% 2.3 32.9% 4.88 42.58% 0.59
45.61% 3.58 31.57% 2.69 28.4% 4.1
51.14% 0.877 66.45% 5.96
58.2% 6.42 46.84% 1.36
45.18% 3.39 37.23% 0.16
26.15% 3.134 33.07% 1.38 36.13% 1.32 34.88% 0.79
46.85% 2.88 34.51% 2.63 43.82% 1.59 35.42% 2.22 41.42% 0.46
21.79% 2.18 22.92% 1.66 34.53% 3.51 31.59% 2.2 22.56% 2.28
47.26% 5.48 39.2% 1.878 25.95% 4.04 45.19% 4.55 38.43% 1.53
44.41% 2.56 40.46% 0.85 34.47% 1.88 42.96% 1.91 31.05% 3.40
40.31% 2.46 37.85% 1.37 31.98% 1.25 24.87% 4.43 38.9% 1.84
45.33% 3.25 40.88% 1.26 47.05% 4.04 34.54% 1.56 22.46% 6.97
23.54% 2.64 26.2% 1.45 26.71% 1.22 32.52% 1.36 38.37% 3.98
51.45% 7.56 40.27% 2.56 34.30% 0.1
35.6% 1.09
9
10
11
12
13
14
15
28.17% 2.85 18.53% 7.16
Fig. 3. The cell viability percentage was calculated by using
for concentrations and growth inhibition percentages were
needed for switching to Table 3. The x–y graph was plotted
for determination of IC50 values. From formula y = ax + b,
the plot x–y with a linear regression was studied. Then,
IC50 values of synthesized derivatives were evaluated
employing formula IC50 = 0.5 − b/a, which are depicted in
Table 3. The standard deviation for Table 2 was calculated
from values of percentage of cell viability of every sample
of various concentrations and for Table 3 was calculated
from IC50 values.
the following formula:
Cell viability percentage
= Absorbance of treated cells/
Absorbance of untreated cells × 100
The percentage of cell viability of synthesized deriva-
tives (8a–n) subjected to the MCF-7 cell line was evalu-
ated, and from Table 2, a standard clustered column graph
was plotted between the concentration of synthesized com-
pounds on x-axis and percentage of cell viability was sub-
jected to compounds on y-axis. A series of response data
A close investigation of results from Table 3 and Fig. 4
clearly illustrated that all the synthesized derivatives exhib-
ited in vitro cytotoxic efciency with IC50 values ranging
1 3

Molecular Diversity
CYTOTOXICITY ASSAY OF SYNTHESIZED COMPOUNDS WITH MCF -7 CELL LINE
80%
70%
60%
50%
40%
30%
20%
10%
0%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CONCENTRATION OF SYNTHESIZED COMPOUNDS
0.625µM
1.25µM
2.5µM
5µM
10µM
Fig. 3 Cell viability evaluation of novel synthesized derivatives (8a–n) measured by MTT assay
Table 3 Cytotoxic assay of novel synthesized derivatives (8a–n) in
terms of aIC50 values
8m and 8c exhibited approximately comparable IC50 values
compared to standard reference drug and derivatives 8n, 8d
and 8f showed promising activity and the remaining deriva-
tives have shown reasonable cytotoxic activity.
S. no.
IC50 values (µM)
MCF-7
The structure activity relationship (SAR) of these (Z)-
5-((1, 3-diphenyl-1H-pyrazol-4-yl) methylene)-3-((1-phe-
nyl-1H-1, 2, 3-triazol-4-yl) methyl) thiazolidine-2, 4-dione
derivatives (8a–n) was explored. These synthesized deriva-
tives consist of pyrazole moiety embedded two phenyl
rings and one triazole phenyl ring system, all the synthe-
sized compounds have a same pyrazole system, and SAR
of these fnal derivatives was examined by difering the
substitutions attached to the triazole phenyl ring; we have
synthesized various fnal derivatives by placing an electron-
withdrawing and electron-donating groups. The SAR study
reveals that the derivatives embedded electron-donating and
electron-withdrawing groups (R1 =OMe and R3 =NO2; 8j)
and electron-withdrawing group (R3 = CF3; 8e) exhibited
more potential cytotoxic activity compared to standard with
IC50 values 0.426 µM 0.455 and 0.608 µM 0.408. When
cell viability percentage is observed in Table 2 and Fig. 3
for compounds 8j and 8e, the cell viability percentage is
independent of its concentration and most of the triazole
precursors bearing electron-donating groups increased the
cytotoxic activity; among them, particularly 3,4-dimethoxy
compound (R2 = OMe and R3 = OMe; 8m) showed excel-
lent activity with IC50 value 0.95 µM 0.32; when moving
to Table 2 and Fig. 3, the cell viability of 8m compound is
concentration dependent from 0.625 to 2.5 µM, and then,
decreasing in concentration is seen from with increasing
in concentration from 2.5 µM, 5 µM and 10 µM. Removal
of one methoxy group at R2 position of triazole phenyl
1
2
3
4
5
6
7
8
8a
2.056 µM 0.034
2.284 µM 0.0212
0.976 µM 0.313
1.54 µM 0.167
0.608 µM 0.408
1.589 µM 0.157
2.38 µM 0.049
4.943 µM 0.71
4.827 µM 0.68
0.426 µM 0.455
2.043 µM 0.037
3.126 µM 0.241
0.95 µM 0.32
8b
8c
8d
8e
8f
8g
8h
9
8i
10
11
12
13
14
15
8j
8k
8l
8m
8n
1.366 µM 0.212
0.636 µM 0.458
Cisplatinb
aIC50 values are the concentration that cause 50% inhibition of cancer
cell growth. Data represent as mean values standard deviation and
are displayed in micromolar concentrations (µM)
bPositive control
from 0.426 to 4.943 μM, respectively; among them, most
of the derivatives have shown excellent cytotoxic activity
compared to that of standard reference drug and some of
the derivatives exhibited reasonable activity. Based on these
conclusions, some of the representative analogues excep-
tionally derivatives 8j and 8e exhibited greater capability
compared to that of standard reference drug and derivatives
1 3

Molecular Diversity
Fig. 4 IC50 values of novel syn-
thesized derivatives (8a–n)
IC50 VALUES
6
5
4
3
2
1
0
4.943
4.827
3.126
2.38
2.284
2.056
2.043
1.589
1.54
1.366
0.976
0.95
0.636
0.608
0.426
COMPOUNDS
ring system from compound 8m resulted in compound 8c
(R3 = OMe; 8c) which exhibited slightly lower cytotoxic
activity with IC50 0.976 µM 0.313, and in Table 2 and
Fig. 3, it has been observed that the cell viability percent-
ages are increasing from 33.67% at concentration 0.625 µM
to 39.96% at concentration 1.25 µM, and after 1.25 µM
concentration, gradually the cell viability percentage is
decreasing with increasing in concentration. Further, com-
pound consists of methyl group (R3 = Me; 8n) and acetyl
group (R3 =COCH3; 8d) at fourth position exhibited prom-
ising cytotoxic activity with IC50 values 1.366 µM 0.212
and 1.54 µM 0.167. On observing data in Table 2 and
Fig. 3 due to the presence of methyl group in compound
8n, the cell viability percentage is increasing with increase
in concentration, and for compound 8d, the cell viability
percentage is concentration dependant due to adding of
acetyl group. Moreover, the compounds bearing diferent
halo substituents at diferent positions on the triazole phenyl
ring (8a, 8b, 8l, 8i and 8h) exhibit lesser cytotoxic activ-
ity compared to other substituted compounds. So, fnally, it
was determined that compounds bearing electron-donating
groups on the triazole phenyl ring enhanced the cytotoxic
activity and some of the analogues with their IC50 values are
displayed in Fig. 5.
Molecular modeling studies
Cisplatin, the positive control in the current work, acts by
interfering with DNA replication by aquation process [47].
In this process, water molecule in cisplatin gets displaced by
nucleotide bases of DNA preferentially Guanine [48, 49].
To assess the formation of cisplatin–DNA adducts along
Fig. 5 IC50 values of some of the representative compounds
1 3

Molecular Diversity
with the binding mode of the newly synthesized deriva-
tives, docking studies have been carried out in Schrodinger.
Two homologous DNA sequences with PDB ID/3LPV [50]
and 1A2E [51] have been retrieved from protein data bank,
respectively. The cisplatin-induced apoptosis was associ-
ated with the formation of intra in addition to interchain
cross-links with nucleotides principally DG-5, DC-6, DT-7
from A-chain and DG-15, DC-16, DG-17 and DA-18 from
B-chain (54). The newly synthesized derivatives along with
positive control have been docked into the active site and
found that cisplatin has formed intramolecular adduct with
DG-6 and DG-7 of A-Chain in 3LPV protein, while inter-
molecular adduct with DG-5, DT-7 of A-Chain and DG-15
of B-Chain in 1A2E protein is depicted in Fig. 6 (A) and (B).
Hence, docking has been carried out on both proteins for the
above synthesized compounds initially.
the higher electronegativity of fuorine (8a) and trifuoro-
methyl (8e) groups which requires more dissociation energy
to displace with nucleotide of DNA which has been clearly
confrmed with the binding energies that are tabulated in
Table 4. The binding energies of lowest active 8h are found
to be −30.88 which is far greater than positive control cis-
platin binding energy −8.381, respectively. This demon-
strates that those compounds possessing high ∆G could form
molecular adduct with DNA and hence shows less activity.
Dock scores along with the ∆G are tabulated in Table 4.
ADME properties
It is always preferable to analyze the ADME profle of newly
synthesized derivatives, which have signifcant impact on
a good drug. The fundamental ADME properties were
determined by using QikProp module version 3.4 [52] and
scrutinized for drug-likeness by applying Lipinski rule of
fve. QikProp module aids in enumerating pharmacodynam-
ics (study of the biochemical and physiological efects of
drugs) and pharmacokinetics (study of how the organism
afects the drug) of the molecules by accessing drug-like
properties. Notably, all these novel synthesized derivatives
have shown signifcant percentage of human oral absorption
exclude compound 8n, QPPMDCK cell permeability in nm/s
values appeared as agreeable limits, some of the derivatives
have shown excellent values, and remaining compounds
have shown moderate values. Blood–brain barrier perme-
ability values (QPlogBB) appeared as acceptable limits,
The docking studies reveal that highest active compound
8j has displayed similar intermolecular adduct formation
with DG-5 of A-Chain and DG-18 of B-Chain as that of
positive control in 1A2E protein as illustrated in Fig. 7,
while 3LPV has not succeeded in displaying neither intra-
nor intermolecular adduct, thereby further docking has been
carried out exclusively on 1A2E itself. The compounds 8c,
8g, 8i and 8k are forming single hydrogen-bonding interac-
tions with DG-13 (green) of the B-Chain, while compounds
8f, 8l, 8m are forming two hydrogen-bonding interactions
with DG-5 (blue) of A-Chain as shown in Fig. 8. The lowest
active compound 8h along with 8a, 8b, 8d, 8e and 8n has
not shown any interactions with DNA. This might be due to
Fig. 6 Dock poses of positive control drug cisplatin demonstrating intramolecular cross-linking with DG-6 and DG-7 of A-Chain in 3LPV pro-
tein (a), and intermolecular cross-linking with DG-5, DT-7 of A-Chain and DG-15 of B-Chain in the protein 1A2E (b)
1 3

Molecular Diversity
Fig. 7 Dock pose of highest
active compound (8j) display-
ing intermolecular hydrogen
bond interactions with DG-5 of
A-Chain and DG-18 of B-Chain
in the protein 1A2E
and all remaining properties are in an acceptable ranges as
displayed in Table 5. All these novel synthesized analogues
exhibit drug-likeness properties and can be further opti-
mized for better cytotoxic activity.
Chemical shift values are presented in ppm, and spin mul-
tiplicities are described as s (singlet); d (doublet); dd (dou-
blet of doublet); td (triplet of doublet); t (triplet); and m
(multiplets), and coupling constants are presented in hertz.
Mass spectra were recorded on GCMS-QP 1000 EX mass
spectrometer.
Experimental
Materials and methods
General procedure for the synthesis
of (Z)‑5‑((1,3‑diphenyl‑1H‑pyrazol‑4‑yl)
methylene)‑3‑(prop‑2‑yn‑1‑yl)
thiazolidine‑2,4‑dione (6)
All the reagents, chemicals and solvents were acquired
from Sigma-Aldrich, Merck and Avra and were used
without further purifcation. Reactions were monitored
by thin-layer chromatography on silica gel plate (60 f254
.
A mixture of (Z)-5-((1,3-diphenyl-1H-pyrazol-4-yl)meth-
ylene)thiazolidine-2,4-dione (5) (1 mmol) and anhydrous
K2CO3 (2 mmol) in dry DMF solution was stirred under
N2 atmosphere at rt for 10–15 min. Then, to the above
reaction mixture, propargyl bromide (1 mmol) was added
and the reaction was stirred for 3 h. After completion of
the reaction (TLC analyses), the resulting reaction mix-
ture was poured into a beaker contained crushed ice. The
resultant solid product was fltered and collected under
suction pump.
0.2 mm), visualization was done by exposing UV light,
and column chromatography was done by using silica gel
(60–120 mesh) and eluting with distilled petroleum ether/
ethyl acetate. Melting points were recorded on melting
point apparatus and are uncorrected. The IR spectra were
determined in the Shimadzu FTIR-8400S spectrometer.
1H NMR and 13C NMR were recorded on Bruker Avance
II 400 MHz spectrometer using TMS (Tetramethylsilane)
as standard and using CDCl3 and DMSO-d6 as solvents.
1 3

Molecular Diversity
Fig. 8 Dock poses of intramolecular hydrogen-bonding interaction in A-chain (a, 8f) as well as B-Chain (b, 8i) (c, 8c) and (d, 8k)
(Z)‑5‑((1,3‑diphenyl‑1H‑pyrazol‑4‑yl)
General procedure for the synthesis of compound (8a–n)
methylene)‑3‑(prop‑2‑yn‑1‑yl)thiazolidine‑2,4‑dione (6)
Compound (Z)-5-((1,3-diphenyl-1H-pyrazol-4-yl)
methylene)-3-(prop-2-yn-1-yl)thiazolidine-2,4-dione (6)
(1 mmol) was dissolved in dimethylformamide (DMF) to
this a solution of 10 mol% sodium ascorbate, and 10 mol%
copper sulfate was added. Then, to the above reaction mix-
ture, various substituted phenyl azides (1 mmol) in DMF
were added slowly to the reaction mixture and stirred for
12 h at rt under nitrogen atmosphere. After the completion
of the reaction by using TLC, the resulting crude was diluted
with ice-cold water and was extracted with DCM (20 ml×3
times) and the combined organic layer was washed with
brine, dried over Na2SO4 and concentrated under reduced
pressure. The crude product was purifed by using column
chromatography on silica gel eluting with petroleum ether/
Light yellow colored solid; M.F: C22H15N3O2S; Yield:
81%; M.P: 216–218 °C; IR (KBr cm−1):2312, 1739,
1
1687, 1531, 1367, 1215; H NMR (400 MHz, CDCl3) δ
(ppm): 8.20 (s, 1H, Pyrazole-H), 7.98 (s, 1H, Arylidene-
H), 7.83–7.79 (m, 2H, Ar–H), 7.69–7.65 (m, 2H, Ar–H),
7.56–7.50 (m, 6H, Ar–H), 4.53 (d, J = 3.022 Hz, 2H,
Propinyl-CH2), 2.30 (t, J = 3.022 Hz, 1H, Propynyl-
CH); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 166.0,
164.2, 153.7, 138.6, 131.1, 129.5, 129.0, 128.9, 128.7,
128.3, 127.5, 124.0, 119.5, 119.4, 115.2, 77.2, 74.5, 30.5;
MS (ESI mass) m/z [M + H]+: 386.1; Anal. Calcd for
C22H15N3O2S: C-68.56, H-3.92, N-10.90; Found: C-68.58,
H-3.94, N-10.86.
1 3

Molecular Diversity
Table 4 Binding energies (∆G),
dock scores and PIC50 values of
newly synthesized derivatives
(8a–n)
S. no.
Compound
IC50 values (μM)
PIC50 (μM)
Dock scores
Binding
energies
(∆G)
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
Cisplatin
2.056 µM 0.034
2.284 µM 0.0212
0.976 µM 0.313
1.54 µM 0.167
0.608 µM 0.408
1.589 µM 0.157
2.38 µM 0.049
4.943 µM 0.71
4.827 µM 0.68
0.426 µM 0.455
2.043 µM 0.037
3.126 µM 0.241
0.95 µM 0.32
5.686
5.641
6.010
5.812
6.216
5.798
5.623
5.305
5.316
6.370
5.689
5.505
6.022
5.864
6.196
−6.420
−6.266
−6.105
−6.240
−6.313
−5.457
−6.668
−6.921
−6.126
−6.799
−5.964
−7.021
−6.331
−6.014
−7.008
−28.30
−27.09
−26.13
−17.60
−24.24
−27.40
−22.93
−30.88
−28.76
−19.37
−21.01
−18.98
−14.99
−20.68
−8.381
9
10
11
12
13
14
15
1.366 µM 0.212
0.636 µM 0.458
More negative indicates higher binding energies
Table 5 ADME properties of the novel synthesized derivatives (8a–n)
S. no.
Compound
M.Wt
QPlogPo/wa
QPlogSb
QPPCacoc
QPlogBBd
QPPMDCKe
% of
human oral
absorptionf
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
630.462
539.01
7.016
6.886
5.542
5.673
6.539
6.421
7.303
6.883
5.683
6.784
6.37
−9.62
−9.568
−8.421
−8.861
−9.184
−8.852
−10.172
−9.622
−8.685
−9.463
−8.884
−9.261
−8.652
−8.779
641.023
596.749
74.067
−0.878
−0.962
−2.398
−1.944
−1.118
−1.269
−0.888
−0.989
−1.873
−1.011
−1.222
−1.136
−1.101
−2.507
1365.754
1085.666
38.886
92.346
91.029
53.984
73.455
87.599
88.393
93.29
90.622
75.175
89.754
87.848
89.547
87.657
51.864
579.589
520.564
522.555
564.617
572.563
583.461
546.602
539.01
534.591
518.592
504.565
549.563
155.084
498.384
603.417
582.819
567.736
192.036
546.851
584.601
603.123
603.97
99.542
634.197
432.226
1833.096
1071.833
124.997
956.458
417.278
431.424
431.73
9
10
11
12
13
14
6.619
6.294
5.511
57.718
34.37
aForeseened octanol/water partition coefcient log p (agreeable range 2.0–6.5)
bForeseened aqueous solubility in mol/L (agreeable range 6.5–0.5)
cForeseened caco cell permeability in nm/s (agreeable range <25 is poor and >500 is excellent)
dForeseened blood–brain barrier permeability (agreeable range 3–1.2)
eForeseened apparent MDCK cell permeability in nm/s (agreeable range <25 is poor and >500 is excellent)
fPercentage of human oral absorption (agreeable range <25% is poor and >80% is excellent)
1 3

Molecular Diversity
ethyl acetate to aford desired fnal derivatives (8a–n) with
Anal. Calcd for C29H22N6O3S: C-65.16, H-4.15, N-15.72;
excellent yields.
Found: C-65.18, H-4.17, N-15.68.
(Z)‑5‑((1,3‑diphenyl‑1H‑pyrazol‑4‑yl)methylene)‑3‑((1‑(4‑fu
orophenyl)‑1H‑1,2,3‑triazol‑4‑yl)methyl)thiazolidine‑2,4‑di‑
one (8a) Light yellow colored solid; M.F: C28H19FN6O2S;
M.P: 208–210 °C; Yield: 68%; IR (KBr cm−1): 2310, 1737,
(Z)‑3‑((1‑(4‑acetylphenyl)‑1H‑1, 2, 3‑triazol‑4‑yl)
methyl)‑5‑((1,3‑diphenyl‑1H‑pyrazol‑4‑yl)methylene)thia‑
zolidine‑2,4‑dione (8d) Light yellow colored solid; M.F:
C30H22N6O3S; M.P: 252–254 °C; Yield: 65%; IR (KBr
cm−1): 2308, 1739, 1689, 1527, 1369, 1215; H NMR
1
1
1691, 1531, 1367, 1222; H NMR (400 MHz, CDCl3) δ
(ppm): 8.19 (s, 1H, Pyrazole-H), 8.02 (s, 1H, Triazole-H),
7.96 (s, 1H, Arylidene-H), 7.80 (t, J=1.6 Hz, 1H, Ar–H),
7.79–7.78 (m, 1H, Ar–H), 7.71–7.68 (m, 2H, Ar–H), 7.67–
7.66 (m, 1H, Ar–H), 7.65–7.64 (m, 1H, Ar–H), 7.51 (m,
5H, Ar–H), 7.42–7.37 (m, 1H, Ar–H), 7.24–7.19 (m, 2H,
Ar–H), 5.12 (s, 2H, N–CH2); 13C NMR (100 MHz, CDCl3)
δ (ppm): 166.4, 165.2, 142.4, 139.1, 131.5, 131.3, 129.7,
129.1, 128.9, 127.7, 127.3, 125.5, 122.7, 122.6, 121.8,
119.6, 119.3, 116.8, 116.6, 116.1, 36.5; MS (ESI mass) m/z
[M+H]+: 523.1; Anal. Calcd for C28H19FN6O2S: C-64.36,
H-3.67, N-16.08; Found: C-64.33, H-3.69, N-16.09.
(400 MHz, CDCl3) δ (ppm): 8.18 (s, 1H, Pyrazole-H), 8.15
(s, 1H, Triazole-H), 8.12 (d, J = 8.8 Hz, 2H, Ar–H), 7.97
(s, 1H, Arylidene-H), 7.88 (d, J=2.1 Hz, 1H, Ar–H), 7.86
(d, J=2.1 Hz, 1H, Ar–H), 7.82–7.78 (m, 2H, Ar–H), 7.66
(dd, J=8.0, 1.5 Hz, 2H, Ar–H), 7.54–7.49 (m, 5H, Ar–H),
7.39 (m, 1H, Ar–H), 5.14 (s, 2H, N–CH2), 2.65 (s, 3H,
Acetyl-H); 13C NMR (100 MHz, CDCl3) δ (ppm): 196.4,
165.2, 164.6, 155.0, 142.7, 139.8, 139.1, 136.9, 131.3,
130.1, 129.7, 129.5, 129.4, 129.1, 128.9, 128.8, 127.8,
127.3, 125.6, 121.4, 120.1, 119.7, 119.6, 119.2, 116.1, 36.6,
26.7; MS (ESI mass) m/z [M+H]+: 547.2; Anal. Calcd for
C30H22N6O3S: C-65.92, H-4.06, N-15.38; Found: C-65.90,
H-4.04, N-15.42.
(Z)‑3‑((1‑(4‑bromophenyl)‑1H‑1,2,3‑triazol‑4‑yl)
methyl)‑5‑((1,3‑diphenyl‑1H‑pyrazol‑4‑yl)methylene)thia‑
zolidine‑2,4‑dione (8b) Light yellow colored solid; M.F:
C28H19BrN6O2S; M.P: 240–242 °C; Yield: 71%; IR (KBr
cm−1): 2312, 1737, 1683, 1531, 1234; 1H NMR (400 MHz,
CDCl3) δ (ppm): 8.19 (s, 1H, Pyrazole-H), 8.05 (s, 1H, Tri-
azole-H), 7.96 (s, 1H, Arylidene-H), 7.80 (t, J=1.6 Hz, 1H,
Ar–H), 7.78 (d, J=0.9 Hz, 1H, Ar–H), 7.67–7.62 (m, 6H,
Ar–H), 7.53–7.48 (m, 5H, Ar–H), 7.39 (dd, J=9.2, 5.7 Hz,
1H, Ar–H), 5.12 (s, 2H, N–CH2); 13C NMR (100 MHz,
CDCl3) δ (ppm): 166.4, 165.2, 155.0, 142.5, 139.1, 135.8,
132.9, 131.3, 129.7, 129.1, 128.9, 127.8, 127.3, 125.6,
122.6, 122.0, 121.4, 119.6, 119.3, 116.1, 36.5; HRMS (ESI)+
calcd for C28H20BrN6O2S [M+H]+: 583.05492 and found:
583.05463; Anal. Calcd for C28H19BrN6O2S: C-57.64,
H-3.28, N-14.40; Found: C-57.68, H-3.26, N-14.38.
(Z)‑5‑((1,3‑diphenyl‑1H‑pyrazol‑4‑yl)methylene)‑3‑((1‑(
4‑(trifluoromethyl)phenyl)‑1H‑1,2,3‑triazol‑4‑yl)methyl)
thiazolidine‑2,4‑dione (8e) Light yellow colored solid;
M.F: C29H19F3N6O2S; M.P: 212–214 °C; Yield: 63%; IR
(KBr cm−1): 2310, 1739, 1691, 1531, 1371, 1215; 1H NMR
(400 MHz, CDCl3) δ (ppm): 8.19 (s, 1H, Pyrazole-H), 8.14
(s, 1H, Triazole-H), 7.97 (s, 1H, Arylidene-H), 7.82–7.78
(m, 3H, Ar–H), 7.69–7.64 (m, 4H, Ar–H), 7.53–7.48 (m,
6H, Ar–H), 7.42–7.38 (m, 1H, Ar–H), 5.14 (s, 2H, N–
CH2); 13C NMR (100 MHz, CDCl3) δ (ppm): 166.5, 165.2,
155.0, 142.8, 139.1, 131.3, 130.6, 130.2, 130.1, 129.7,
129.1, 129.0, 128.9, 127.8, 127.7, 127.3, 125.6, 125.6,
123.7, 121.6, 119.6, 119.2, 116.1, 36.5; MS (ESI mass) m/z
[M+H]+: 573.2; Anal. Calcd for C29H19F3N6O2S: C-60.83,
H-3.34, N-14.68; Found: C-60.81, H-3.32, N-14.72.
(Z)‑5‑((1,3‑diphenyl‑1H‑pyrazol‑4‑yl)methylene)‑3‑((1‑(
4‑methoxyphenyl)‑1H‑1,2,3‑triazol‑4‑yl)methyl)thiazo‑
lidine‑2,4‑dione (8c) Light yellow colored solid; M.F:
C29H22N6O3S; M.P: 244–246 °C; Yield: 73%; IR (KBr
(Z)‑5‑((1,3‑diphenyl‑1H‑pyrazol‑4‑yl)methylene)‑3‑((1‑(4‑nitr
ophenyl)‑1H‑1,2,3‑triazol‑4‑yl)methyl)thiazolidine‑2,4‑dione
(8f) Light yellow colored solid; M.F: C28H19N7O4S; M.P:
228–230 °C; Yield: 62%; IR (KBr cm−1): 2312, 1739,
1
cm−1): 2312, 1685, 1598, 1521, 1303, 1246; H NMR
1
(400 MHz, CDCl3) δ (ppm): 8.20–8.17 (s, 1H, Pyrazole-H),
7.98 (s, 1H, Triazole-H), 7.96 (s, 1H, Arylidene-H), 7.81–
7.78 (m, 2H, Ar–H), 7.67–7.64 (m, 2H, Ar–H), 7.62–7.59
(m, 2H, Ar–H), 7.53–7.49 (m, 5H, Ar–H), 7.39 (m, 1H,
Ar–H), 7.01 (m, 1H, Ar–H), 7.00–6.98 (m, 1H, Ar–H), 5.12
(s, 2H, N–CH2), 3.86 (s, 3H, O–CH3); 13C NMR (100 MHz,
CDCl3) δ (ppm): 166.4, 165.3, 159.9, 155.0, 142.1, 139.2,
131.4, 130.3, 130.2, 129.8, 129.7, 129.6, 129.0, 128.9,
127.7, 127.5, 127.3, 125.4, 122.3, 121.7, 119.6, 119.5,
119.5, 116.1, 114.7, 55.6, 36.6; HRMS (ESI)+ calcd for
C29H23N6O3S [M+H]+: 535.15452 and found: 535.15469;
1689, 1531, 1317; H NMR (400 MHz, CDCl3) δ (ppm):
8.42 (s, 1H, Pyrazole-H), 8.40 (s, 1H, Triazole-H), 8.19
(d, J=2.1 Hz, 2H, Ar–H), 7.98–7.96 (m, 2H, Ar–H), 7.80
(m, 1H, Ar–H), 7.79 (m, 1H, Ar–H), 7.67–7.66 (m, 1H,
Ar–H), 7.65 (d, J=1.4 Hz, 1H, Ar–H), 7.55–7.49 (m, 6H,
Ar–H), 7.39 (m, 1H, Ar–H), 5.15 (s, 2H, N–CH2); 13C NMR
(100 MHz, CDCl3) δ (ppm): 165.7, 165.2, 143.2, 129.7,
129.7, 129.1, 128.97, 128.96, 127.8, 127.3, 126.8, 125.8,
125.5, 125.5, 121.5, 120.6, 119.69, 119.67, 116.0, 36.4;
HRMS (ESI)+ calcd for C28H20N7O4S [M+H]+: 550.13015
and found: 550.12920; Anal. Calcd for C28H19N7O4S:
1 3

Molecular Diversity
C-61.20, H-3.18, N-17.84; Found: C-61.27, H-3.14,
N-17.81.
(Z)‑5‑((1,3‑diphenyl‑1H‑pyrazol‑4‑yl)methylene)‑3‑((1‑(2‑
methoxy‑4‑nitrophenyl)‑1H‑1,2,3‑triazol‑4‑yl)methyl)thi‑
azolidine‑2,4‑dione (8j) Light yellow colored solid; M.F:
C29H21N7O5S; M.P: 218–220 °C; Yield: 61%; IR (KBr
cm−1): 2316, 1685, 1523, 1309, 1247; 1H NMR (400 MHz,
CDCl3) δ (ppm): 8.38 (s, 1H, Pyrazole-H), 8.20–8.17 (s,
1H, Triazole-H), 8.10 (d, J=8.8 Hz, 1H, Ar–H), 8.02–7.98
(m, 1H, Ar–H), 7.96 (d, J=2.5 Hz, 2H, Ar–H), 7.81–7.76
(m, 2H, Ar–H), 7.67–7.63 (m, 2H, Ar–H), 7.51 (m, 5H,
Ar–H), 7.39 (m, 1H, Ar–H), 5.14 (s, 2H, N–CH2), 4.06 (s,
3H, O-CH3); 13C NMR (100 MHz, CDCl3) δ (ppm): 166.4,
165.2, 154.9, 150.6, 148.1, 139.1, 131.3, 130.7, 129.7,
129.5, 129.4, 129.1, 128.9, 127.8, 127.3, 125.5, 125.4,
125.2, 119.6, 119.4, 116.7, 116.1, 107.7, 56.8, 36.4; HRMS
(ESI)+ calcd for C29H22N7O5S [M + H]+: 580.14066 and
found: 580.13976; Anal. Calcd for C29H21N7O5S: C-60.10,
H-3.65, N-16.92; Found: C-60.15, H-3.62, N-16.89.
(Z)‑5‑((1,3‑diphenyl‑1H‑pyrazol‑4‑yl)methylene)‑3‑((1‑(3‑hyd
roxyphenyl)‑1H‑1,2,3‑triazol‑4‑yl)methyl)thiazolidine‑2,4‑di‑
one (8g) Light yellow colored solid; M.F: C28H20N6O3S;
M.P: 232–234 °C; Yield: 66%; IR (KBr cm−1): 3024, 2310,
1
1737, 1531, 1367, 1222; H NMR (400 MHz, DMSO) δ
(ppm): 10.04 (s, 1H, Ar–OH), 8.81 (s, 1H, Pyrazole-H),
8.77 (s, 1H, Triazole-H), 8.05 (d, J = 7.7 Hz, 2H, Ar–H),
7.74 (s, 1H, Ar–H), 7.66 (dd, J = 8.1, 1.4 Hz, 2H, Ar–H),
7.61–7.52 (m, 6H, Ar–H), 7.43 (m, 1H, Ar–H), 7.39–7.34
(m, 1H, Ar–H), 7.30–7.26 (m, 2H, Ar–H), 4.97 (s, 2H, N–
CH2); 13C NMR (100 MHz, DMSO) δ (ppm): 166.6, 164.9,
153.7, 142.0, 138.7, 137.39, 137.37, 131.2, 130.7, 129.6,
129.0, 128.9, 128.7, 128.2, 127.5, 123.5, 121.6, 120.1,
119.4, 115.6, 115.3, 110.3, 106.9, 36.4; MS (ESI mass) m/z
[M + H]+: 521.2; Anal. Calcd for C28H20N6O3S: C-64.60,
H-3.87, N-16.14; Found: C-64.58, H-3.85, N-16.19.
(Z)‑5‑((1,3‑diphenyl‑1H‑pyrazol‑4‑yl)methylene)‑3‑((1‑ph
enyl‑1H‑1,2,3‑triazol‑4‑yl)methyl)thiazolidine‑2,4‑dione
(8k) Light yellow colored solid; M.F: C28H20N6O2S; M.P:
242–244 °C; Yield: 75%; IR (KBr cm−1): 2312, 1739, 1691,
(Z)‑3‑((1‑(4‑ chlorophenyl)‑1H‑1,2,3‑triazol‑4‑yl)
methyl)‑5‑((1,3‑diphenyl‑1H‑pyrazol‑4‑yl)methylene)thia‑
zolidine‑2,4‑dione (8h) Light yellow colored solid; M.F:
C28H19ClN6O2S; M.P: 238–240 °C; Yield: 72%; IR (KBr
cm−1): 2310, 1739, 1531, 1367, 1220; 1H NMR (400 MHz,
CDCl3) δ (ppm): 8.21–8.20 (s, 1H, Pyrazole-H), 8.07 (s, 1H,
Triazole-H), 7.98 (s, 1H, Arylidene-H), 7.82 (m, 2H, Ar–H),
7.71 (d, J=2.1 Hz, 1H, Ar–H), 7.68 (m, 3H, Ar–H), 7.52
(m, 7H, Ar–H), 7.42 (m, 1H, Ar–H), 5.14 (s, 2H, N–CH2);
13C NMR (100 MHz, CDCl3) δ (ppm): 166.4, 165.2, 155.0,
142.5, 139.1, 135.3, 134.7, 131.3, 129.9, 129.7, 129.7,
129.6, 129.1, 128.9, 127.7, 127.3, 121.7, 121.5, 119.6,
119.3, 116.1, 36.4; HRMS (ESI)+ calcd for C28H20ClN6O2S
[M + H]+: 539.10593 and found: 539.10515; Anal. Calcd
for C28H19ClN6O2S: C-62.39, H-3.55, N-15.59; Found:
C-62.35, H-3.60, N-15.58.
1
1531, 1373, 1219; H NMR (400 MHz, CDCl3) δ (ppm):
8.19 (s, 1H, Pyrazole-H), 8.05 (s, 1H, Triazole-H), 7.96
(s, 1H, Arylidene-H), 7.79 (d, J=7.8 Hz, 2H, Ar–H), 7.67
(t, J=8.0 Hz, 4H, Ar–H), 7.55–7.47 (m, 8H, Ar–H), 7.39
(m, 1H, Ar–H), 5.12 (s, 2H, N–CH2); 13C NMR (101 MHz,
CDCl3) δ (ppm): 166.4, 165.2, 142.5, 139.1, 139.0, 138.3,
135.3, 129.9, 129.7, 129.1, 128.9, 127.8, 127.3, 125.6, 121.7,
121.5, 119.8, 119.6, 119.3, 116.1, 36.4; MS (ESI mass) m/z
[M + H]+: 505.2; Anal. Calcd for C28H20N6O2S: C-66.65,
H-4.00, N-16.66; Found: C-66.61, H-4.05, N-16.65.
(Z)‑5‑((1,3‑diphenyl‑1H‑pyrazol‑4‑yl)methylene)‑3‑((1‑(4‑io
dophenyl)‑1H‑1,2,3‑triazol‑4‑yl)methyl)thiazolidine‑2,4‑di‑
one (8l) Light yellow colored solid; M.F: C28H19IN6O2S;
M.P: 220–222 °C; Yield: 69%; IR (KBr cm−1): 2310, 1739,
1
(Z)‑3‑((1‑(3‑ chlorophenyl)‑1H‑1,2,3‑triazol‑4‑yl)
methyl)‑5‑((1,3‑diphenyl‑1H‑pyrazol‑4‑yl)methylene)thi‑
azolidine‑2,4‑dione (8i) Light yellow colored solid; M.F:
C28H19ClN6O2S; M.P: 248–250 °C; Yield: 74%; IR (KBr
cm−1): 2312, 1687, 1527, 1244; 1H NMR (400 MHz, CDCl3)
δ (ppm): 8.19 (s, 1H, Pyrazole-H), 8.07 (s, 1H, Triazole-
H), 7.97 (s, 1H, Arylidene-H), 7.82–7.76 (m, 3H, Ar–H),
7.65 (m, 3H, Ar–H), 7.56–7.47 (m, 6H, Ar–H), 7.41 (m, 2H,
Ar–H), 5.13 (s, 2H, N–CH2); 13C NMR (100 MHz, CDCl3)
δ (ppm): 166.4, 165.2, 155.0, 142.5, 139.1, 137.6, 135.6,
131.3, 130.8, 129.7, 129.1, 129.0, 128.9, 127.8, 127.3, 125.6,
120.8, 119.6, 119.3, 118.6, 116.1, 36.5; MS (ESI mass) m/z
[M+H]+: 539.2; Anal. Calcd for C28H19ClN6O2S: C-62.39,
H-3.55, N-15.59; Found: C-62.35, H-3.58, N-15.60.
1689, 1531, 1367, 1220; H NMR (400 MHz, CDCl3) δ
(ppm): 8.20–8.17 (s, 1H, Pyrazole-H), 8.16 (s, 1H, Tria-
zole-H), 7.97–7.94 (s, 1H, Arylidene-H), 7.93–7.89 (m,
2H, Ar–H), 7.86–7.84 (m, 1H, Ar–H), 7.83–7.78 (m, 3H,
Ar–H), 7.67–7.63 (m, 2H, Ar–H), 7.54–7.49 (m, 5H, Ar–H),
7.42–7.37 (m, 1H, Ar–H), 5.14 (s, 2H, N–CH2); 13C NMR
(100 MHz, CDCl3) δ (ppm): 165.8, 164.6, 142.5, 139.19,
139.18, 138.8, 131.3, 129.7, 129.1, 129.1, 128.9, 127.8,
127.38, 127.36, 125.7, 125.6, 124.7, 124.6, 122.1, 119.6,
36.6; MS (ESI mass) m/z [M+H]+: 631.1; Anal. Calcd for
C28H19IN6O2S: C-53.34, H-3.04, N-13.33; Found: C-53.37,
H-3.06, N-13.28.
1 3

Molecular Diversity
(Z)‑3‑((1‑(3,4‑dimethoxyphenyl)‑1H‑1,2,3‑triazol‑4‑yl)
methyl)‑5‑((1,3‑diphenyl‑1H‑pyrazol‑4‑yl)methylene)thia‑
zolidine‑2,4‑dione (8m) Light yellow colored solid; M.F:
C30H24N6O4S; M.P: 210–212 °C; Yield: 61%; IR (KBr
cm−1): 2312, 1739, 1685, 1527, 1244; 1H NMR (400 MHz,
CDCl3) δ (ppm): 8.21 (s, 1H, Pyrazole-H), 7.98 (s,1H, Tri-
azole-H), 7.81 (dd, J=8.6, 1.1 Hz, 2H, Ar–H), 7.68–7.65
(m, 2H, Ar–H), 7.55–7.48 (m, 6H, Ar–H), 7.42–7.38 (m, 1H,
Ar–H), 7.08–7.04 (m, 1H, Ar–H), 6.98 (m, 2H, Ar–H), 5.07
(s, 2H, N–CH2), 3.96 (s, 3H, O-CH3), 3.91 (s, 3H, O-CH3);
13C NMR (100 MHz, CDCl3) δ (ppm): 166.5, 165.3, 155.0,
150.4, 149.2, 145.5, 139.2, 131.4, 129.7, 129.5, 129.5,
129.4, 129.3, 129.2, 129.1, 129.0, 128.9, 128.9, 127.7,
127.3, 125.4, 119.7, 119.5, 118.7, 116.2, 110.7, 109.7,
56.2, 56.1, 37.3; MS (ESI mass) m/z [M+H]+: 565.2; Anal.
Calcd for C30H24N6O4S: C-63.82, H-4.28, N-14.88; Found:
C-63.80, H-4.32, N-14.86.
growth inhibition of synthesized compounds. The 10 mM
stocks were prepared initially by diluting the synthesized
compounds and standard cisplatin in DMSO. The diferent
concentrations of 25 µM, 50 µM, 100 µM, 200 µM, 500 µM
were prepared from 10 mM stocks diluted in DMSO. After
seeding of cells for 24 h in 96-well plate, 5 µl of given
synthesized compounds and standard cisplatin of respec-
tive concentrations 25 µM, 50 µM, 100 µM and 200 µM,
500 µM were added to each well in duplicates having MCF 7
cells to reach the fnal concentration of 0.625 µM, 1.25 µM,
2.5 µM, 5 µM and 10 µM, respectively. The culture medium
(DMEM) was added to wells containing only MCF 7 cells
for control, and also culture medium (DMEM) was added
to each well without cells for blank prepared in duplicates.
After treatment, the plates were incubated in humidifed 5%
CO2 incubator for 24 h at 37 °C. Upon completion of 24 h,
20 µl stock MTT dye solution (5 mg/ml) was added to each
well and incubated at 37 °C in humidifed 5% CO2 incubator
for 4 h. After incubation of 4 h, an MTT dye solution was
aspirated and 100 µl of DMSO was added to solubilize the
MTT formazan crystals. This formazan is directly propor-
tional to the number of viable cells and inversely propor-
tional to the degree of cytotoxicity. After 1 h, the absorbance
of each well at 490 nm was measured on microplate spec-
trophotometer. IC50 values were calculated by plotting the
graph between the concentration of synthesized compounds
at which 50% of cells remain viable to the control on x-axis
(0.625 µM, 1.25 µM, 2.5 µM, 5 µM and 10 µM) and percent-
age of cell viability on y-axis. The cell viability percentage
can be calculated from the following formula:
(Z)‑5‑((1,3‑diphenyl‑1H‑pyrazol‑4‑yl)methylene)‑3‑((1‑(p‑
tolyl)‑1H‑1,2,3‑triazol‑4‑yl)methyl)thiazolidine‑2,4‑dione
(8n) Light yellow colored solid; M.F: C29H22N6O2S; M.P:
256–258 °C; Yield: 70%; IR (KBr cm−1): 2308, 1739, 1689,
1
1531, 1369, 1217; H NMR (400 MHz, CDCl3) δ (ppm):
8.19 (s, 1H, Pyrazole-H), 8.03 (s, 1H, Triazole-H), 7.96 (s,
1H, Arylidene-H), 7.80 (t, J=1.6 Hz, 1H, Ar–H), 7.80–7.78
(m, 1H, Ar–H), 7.67–7.64 (m, 2H, Ar–H), 7.60–7.57 (m,
2H, Ar–H), 7.54–7.48 (m, 5H, Ar–H), 7.42–7.37 (m, 1H,
Ar–H), 7.30 (d, J = 8.1 Hz, 2H, Ar–H), 5.12 (s, 2H, N–
CH2), 2.41 (s, 3H, Tolyl-H); 13C NMR (100 MHz, CDCl3)
δ (ppm): 166.4, 165.3, 155.0, 142.1, 139.1, 139.0, 134.6,
131.5, 131.4, 130.2, 129.7, 129.0, 128.9, 127.7, 127.7,
127.3, 125.4, 121.6, 120.5, 119.6, 119.5, 119.5, 116.1, 36.6,
21.1; MS (ESI mass) m/z [M+H]+: 519.2; Anal. Calcd for
C29H22N6O2S: C-67.17, H-4.28, N-16.21; Found: C-67.20,
H-4.31, N-16.11.
Cell viability percentage
= Absorbance of treated cells/
Absorbance of untreated cells × 100.
Cell viability assay/cytotoxic activity of newly
synthesized derivatives toward MCF‑7 cell line
Conclusion
Materials and method
In summary, we have designed and synthesized a series of
novel (Z)-5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-
3-((1-substituted phenyl-1H-1,2,3-triazol-4-yl)methyl)
thiazolidine-2,4-dione hybrids (8a-n). These synthesized
MTT (3-(4, 5-dimethyl thiazol-2yl)-2, 5-di phenyl tetrazo-
lium bromide) assay was carried out as a standard assay
for determining in vitro cytotoxicity assay of the MCF-7
tumor cell line subjected to synthesized compounds. Under
sterile conditions, the MCF-7 tumor cells were seeded in
96-well microassay, culture plate at a density of 3×103 cells
per well in 200 µl in Dulbecco’s modifed eagles medium
(DMEM) (Gibco NY, USA) supplemented with 10% Fetal
bovine serum (FBS) (Bio cell, CA, USA) and 1 × antibi-
otic–antimycotic solution(contains Penicillin, Streptomy-
cin, Amphotericin-D) and were grown exponentially for
24 h in a humidifed 5% CO2 incubator at 37 °C to test the
1
derivatives were confrmed by H NMR, 13C NMR, IR,
HRMS and ESI–MS spectra and screened for their in vitro
cell viability assay/cytotoxic activity. Overall, this biological
assay outcome clearly illustrated that most of the synthe-
sized derivatives showed moderate-to-excellent cytotoxic
activity. These fndings described that derivatives embedded
electron-donating groups have shown remarkable cytotoxic
activity. Among the series, lead analogues 8j (R1 = OMe
and R3 = NO2) and 8e (R3 = CF3) have shown excellent
1 3

Molecular Diversity
Synthesis, in silico experiments and biological evaluation of
1,3,4-trisubstituted pyrazole derivatives as antimalarial agents.
Eur J Med Chem 163:353–366. https://doi.org/10.1016/j.ejmec
h.2018.11.067
cytotoxic activity with IC50 values 0.426 µM 0.455 and
0.608 µM 0.408, which are even better than the standard
drug cisplatin 0.636 µM 0.458. Noticeably, compounds
bearing diferent halo substituents at diferent positions on
the triazole phenyl ring (8a, 8b, 8l, 8i and 8h) showed lesser
cytotoxic activity compared to other substituted analogues.
Based on these analyses, all the novel synthesized hybrids
have potential cytotoxic activity and further structural modi-
fcation of these derivatives may produce signifcant cyto-
toxic agents.
7. Taban IM, Elshihawy H, Torun B, Zucchini B, Williamson CJ,
Altuwairigi D, Ngu AST, McLean KJ, Levy CW, Sood S, Marino
LB, Munro AW, de Carvalho LPS, Simons C (2017) Novel aryl
substituted pyrazoles as small molecule inhibitors of cytochrome
P450 CYP121A1: synthesis and antimycobacterial evaluation. J
Med Chem 60:10257–10267. https://doi.org/10.1021/acs.jmedc
hem.7b01562
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Snyder JP, Krystal M, Wilson LJ, Liotta DC (2015) Pyrazolo-
piperidines exhibit dual inhibition of CCR5/CXCR4 HIV entry
and reverse transcriptase. ACS Med Chem Lett 6:753–757. https
://doi.org/10.1021/acsmedchemlett.5b00036
Supplementary
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cular and antimicrobial evaluation of 3-(4-chlorophenyl)-4-substi-
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https://doi.org/10.1016/j.bmcl.2012.05.063
1H NMR, 13C NMR, IR, HRMS and ESI–MS spectra of
all these synthesized novel hybrids were provided in
supplementary.
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Recent advances on the green synthesis and antioxidant activi-
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Acknowledgements The authors thank the Head, Department of
Chemistry, Osmania University, Hyderabad for providing laboratory
facilities. Kolluri Prashanth Kumar is thankful to UGC, New Delhi, for
providing fellowship. One of the authors N. J. P. Subhashini is grateful
to OU-DST PURSE-II/60/2018-2019 and SAP program, Department
of Chemistry, Osmania University, Hyderabad, for providing fnancial
assistance. We thank the CFRD analytical department for providing
spectral analysis facilities.
11. Kamal A, Shaik AB, Jain N, Kishor C, Nagabhushana A, Supriya
B, Kumar GB, Chourasiya SS, Suresh Y, Mishra RK, Addlagatta
A (2015) Design and synthesis of pyrazole–oxindole conju-
gates targeting tubulin polymerization as new anticancer agents.
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boxamide and pyrazole–pyrimidine derivatives: synthesis and
anticancer activity. Eur J Med Chem 90:889–896. https://doi.
org/10.1016/j.ejmech.2014.12.013
Compliance with ethical standards
13. Bekhit AA, Hassan AMM, Abd El Razik HA, El-Miligy MMM,
El-Agroudy EJ, Bekhit DA (2015) New heterocyclic hybrids of
pyrazole and its bioisosteres: design, synthesis and biological
evaluation as dual acting antimalarial-antileishmanial agents.
Eur J Med Chem 94:30–44. https://doi.org/10.1016/j.ejmec
h.2015.02.038
Conflict of interest The authors have declared no confict of interest.
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