New imidazo[2,1-: B] thiazole-based aryl hydrazones: Unravelling their synthesis and antiproliferative and apoptosis-inducing potential

Article abstract of DOI:10.1039/d0md00188k

Herein, we have designed and synthesized new imidazo[2,1-b]thiazole-based aryl hydrazones (9a-w) and evaluated their anti-proliferative potential against a panel of human cancer cell lines. Among the synthesized compounds, 9i and 9m elicited promising cytotoxicity against the breast cancer cell line MDA-MB-231 with IC50 values of 1.65 and 1.12 μM, respectively. Cell cycle analysis revealed that 9i and 9m significantly arrest MDA-MB-231 cells in the G0/G1 phase. In addition, detailed biological studies such as annexin V-FITC/propidium iodide, DCFH-DA, JC-1 and DAPI staining assays revealed that 9i and 9m triggered apoptosis in MDA-MB-213 cells. Overall, the current work demonstrated the cytotoxicity and apoptosis-inducing potential of 9i and 9m in breast cancer cells and suggested that they could be explored as promising antiproliferative leads in the future. This journal is

Full text of DOI:10.1039/d0md00188k

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RESEARCH ARTICLE
New imidazoij2,1-b]thiazole-based aryl
hydrazones: unravelling their synthesis and
Cite this: DOI: 10.1039/d0md00188k
antiproliferative and apoptosis-inducing potential†
ab
ab
c
Mohd Adil Shareef, Ganthala Parimala Devi, Sunitha Rani Routhu,
C. Ganesh Kumar,
c
bd
Ahmed Kamal and Bathini Nagendra Babu *ab
Herein, we have designed and synthesized new imidazoij2,1-b]thiazole-based aryl hydrazones (9a–w) and
evaluated their anti-proliferative potential against a panel of human cancer cell lines. Among the
synthesized compounds, 9i and 9m elicited promising cytotoxicity against the breast cancer cell line MDA-
MB-231 with IC50 values of 1.65 and 1.12 μM, respectively. Cell cycle analysis revealed that 9i and 9m
significantly arrest MDA-MB-231 cells in the G0/G1 phase. In addition, detailed biological studies such as
annexin V-FITC/propidium iodide, DCFH-DA, JC-1 and DAPI staining assays revealed that 9i and 9m
triggered apoptosis in MDA-MB-213 cells. Overall, the current work demonstrated the cytotoxicity and
apoptosis-inducing potential of 9i and 9m in breast cancer cells and suggested that they could be explored
as promising antiproliferative leads in the future.
Received 4th June 2020,
Accepted 19th June 2020
DOI: 10.1039/d0md00188k
rsc.li/medchem
m
membrane potential (ΔΨ ) and causing mitochondrial
Introduction
5
dysfunction which eventually triggers apoptosis. The
differentiation in ROS levels among normal and cancer cells
may possibly offer a prospect of selectively inducing cancer
Despite meticulous efforts in anticancer drug development,
the treatment of malignancy still remains an unsolved
challenging health problem. The existing anticancer drugs
encounter limitations including drug toxicities due to non-
specificity, low efficacy and emergence of multidrug
resistance. Therefore, there is
development of new chemical entities which can prevail over
the aforementioned limitations. Dysregulation of apoptosis
is well recognised as a hallmark of cancer. A number of new
6
cell demise. So far, a number of ROS-inducing agents with
7
,8
proven anticancer efficacy have been identified.
Indeed, the pharmacophore hybridization approach is a
rational approach in drug design which enables us to
introduce key pharmacophoric subunits into a single moiety.
The designed hybrids bearing two scaffolds, if tested, may
exhibit synergistic biological activity and reduced side
a critical need for the
1
2
9
apoptosis-inducing agents have been identified by
researchers. In this context, induction of apoptosis via
altering the apoptotic pathways has been an emerging
effects. The imidazoij2,1-b]thiazole motif has been extensively
studied by a vast number of medicinal chemists because of
its biologically significant properties including anticancer,
anti-hypertensive, antimicrobial, and anti-inflammatory
3
approach in the treatment of cancer. Recent reports have
1
0
revealed that mitochondria are strongly associated with
apoptotic pathways and are the major contributor to ROS
activities. It is reported to be a core nucleus of levamisole
1
1
(I), an anti-helminthic and immunomodulator drug.
4
production. It is evident that excessive levels of ROS enhance
Moreover, imidazoij2,1-b]thiazoles were found to be effective
basal oxidative stress thereby altering the mitochondrial
in postsurgical treatment of Dukes' C colon cancer along with
5
-flurouracil (5-FU). Recently, numerous derivatives of
imidazoij2,1-b]thiazoles (II–VI) have been reported as potent
anti-proliferative agents exhibiting various molecular
(Fig. 1). Therefore, conjugation of this versatile
a
Department of Fluoro-Agrochemicals, CSIR-Indian Institute of Chemical
12–14
mechanisms
Technology, Tarnaka, Hyderabad, India. E-mail: bathini@iict.res.in
b
Academy of Scientific and Innovative Research, Ghaziabad 201 002, India
pharmacophore with other bioactive frameworks might be an
exciting tactic in exploration of newer potent chemotherapeutics.
c
Organic Synthesis and Process Chemistry Division, CSIR-Indian Institute of
Chemical Technology, Tarnaka, Hyderabad 500007, India
d
Likewise, the N-acylhydrazone (NAH) motif is
a
School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New
therapeutically versatile framework for the design and
development of newer privileged scaffolds eliciting remarkably
Delhi 110062, India
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
15
d0md00188k
extensive biological activities. It can be straightforwardly
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Fig.
3
Design strategy of new imidazoij2,1-b]thiazole-based aryl
hydrazones (9a–w).
Fig.
1 Structure of levamisole and some imidazoij2,1-b]thiazole
derivatives exhibiting anti-proliferative activity.
2-bromoacetophenones (1a–d) and 2-aminothiazole (2) in
equimolar quantities were refluxed in acetone for 6–8 h
followed by addition of 2N HCl. The reaction was again
refluxed for 1–2 h to yield imidazoij2,1-b]thiazoles (4a–d).
These intermediates were later subjected to Vilsmeier–Haack
reaction conditions to obtain the corresponding imidazoij2,1-
synthesised via a condensation reaction. Moreover, various
drugs such as azumolene, carbazochrome, dantrolene,
nitrofurantoin, nifuroxazide, etc. endowed with the
N-acylhydrazone (NAH) backbone are presently used in the
clinic. In addition, a number of potential anticancer leads such
as LASSBio-1586 (VII), PAC-1 (VIII) and aldoxorubicin (Fig. 2) are
1
9
b]thiazole carboxaldehydes (5a–d).
Similarly, substituted
benzoic acids were subjected to esterification to obtain the
corresponding esters which upon further treatment with
hydrazine hydrate in ethanol under reflux conditions
16
now in pre-clinical and/or clinical trials. Consequently, these
facts suggested that the N-acylhydrazone (NAH) motif could be
incorporated for the search of newer cytotoxic agents in the
17
current research context.
Encouraged by the bioactivities of imidazoij2,1-b]thiazoles
and N-acylhydrazones, and in progression with our
exploitation towards the development of newer apoptosis
1
8
inducers,
we herein synthesized imidazoij2,1-b]thiazole-
based aryl hydrazones by hybridizing the imidazoij2,1-
b]thiazole motif and N-acylhydrazone moiety (Fig. 3). The
synthesized compounds were tested for their antiproliferative
activity. The promising activity observed encouraged us to
investigate the effect of these compounds on apoptosis.
Chemistry
Imidazoij2,1-b]thiazole-based aryl hydrazones (9a–w) were
synthesized as shown in Scheme 1. At first, substituted
Scheme
hydrazones (9a–w). Reagents and conditions: (i) acetone, reflux, 6–8 h;
ii) 2N HCl, reflux, 1–2 h, 85–90%; (iii) POCl , DMF, reflux, 8–12 h, 80–
8%; (iv) H SO , EtOH, reflux, 2–3 h, 90–95%; (v) NH NH ·5H O, EtOH,
1 Synthesis of new imidazoij2,1-b]thiazole-based aryl
(
3
8
2
4
2
2
2
Fig.
2
Structures of some N-acyl hydrazone (NAH) derivatives
reflux, 6–8 h, 82–89%; (vi) EtOH, few drops of glacial acetic acid, reflux,
3–6 h, 72–85%.
exhibiting anti-proliferative activity.
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2
0
provided the aryl hydrazide precursors (8a–f). Lastly, the
corresponding imidazoij2,1-b]thiazole carboxaldehydes (5a–d)
were condensed with appropriate aryl hydrazide precursors
9i and 9m exhibited significant cytotoxicity with IC50 values
ranging between 1.12 and 5.2 μM against the tested cell
lines. Interestingly, compounds 9i and 9m exhibited
promising cytotoxicity against the breast cancer line (MDA
MB-231) with IC50 values of 1.65 and 1.12 μM, respectively.
From a structure–activity relationship perspective, it was
observed that compound 9m was the most potent wherein
R1 was substituted with electronegative substituent 4-F and
(
8a–f) in absolute ethanol in the presence of a catalytic
amount of glacial acetic acid for 3–6 h to attain the final
compounds (9a–w) in good yields. The structure of all the
titled compounds was established by suitable spectroscopic
techniques.
R
2
was substituted with an electron donating 3,4,5-
trimethoxy group; while in the case of compound 9i, both
R1 and R2 were substituted by electron donating groups
such as 4-methoxy and 3,4,5-trimethoxy, respectively, which
exhibited promising cytotoxicity as compared to other
screened molecules in the series. Furthermore, in the case
of compound 9a, which was one of the potential
compounds, R1 was unfunctionalized and R2 was
substituted with an electron donating 3,4,5-trimethoxy
group. Overall, electron donating substituents such as 3,4,5-
trimethoxy and hydroxyl were found to be favourable for
Biological evaluation
Anti-proliferative activity. The synthesized imidazoij2,1-
b]thiazole-based aryl hydrazones (9a–w) were tested for their
antiproliferative activity in selected human cell lines of
prostate cancer (DU-145), breast cancer (MDA-MB-231),
cervical cancer (HeLa), lung cancer (A549) and normal
embryonic kidney cancer cells (HEK-293) by using the MTT
2
1
assay. The IC50 values (μM) are presented in Table 1.
The cell lines MDA-MB-231 (ATCC No. HTB-26), HEK-293
(
(
ATCC No. CRL-1268), DU-145 (ATCC No. HTB-81), HeLa
ATCC No. CCL-2) and A549 (ATCC No. CCL-185) were
cytotoxicity at R , while there was no noteworthy alteration
in the cytotoxicity by switching from electron donating
2
purchased from ATCC. The synthesized compounds were
tested on other cancer cell lines [prostate cancer (DU-145),
cervical cancer (HeLa) and lung cancer (A549)] and were
found to be unresponsive at levels below 5 micromolar
concentration. Among the tested derivatives, compounds 9a,
groups to electron donating groups at R1.
Cell cycle analysis
The potential compounds 9i and 9m were further studied for
growth inhibition of cancer cells by arresting the cell cycle
checkpoint that facilitates the development of potent cytotoxic
2
2
agents. MDA-MB-231 cells were treated with 1 μM of test
compounds 9i and 9m for 24 h wherein doxorubicin was used
Table
1 Antiproliferative activity of the synthesized imidazoij2,1-
b]thiazole-based aryl hydrazones (9a–w)
23
as a positive control. Flow cytometry revealed that test
a
compounds 9i and 9m caused the G0/G1 cell cycle arrest with
72.4% and 75.8% cells accumulated (Fig. 4) when compared
to untreated cells (control). The positive control, doxorubicin
treatment, caused accumulation of 81% of cells in the G0/G1
phase (Fig. 4). In Fig. 4, M4 represents the G0/G1 phase while
M5 and M6 represent the S phase and G2/M phase,
respectively. Cell cycle analysis suggested that there is a
significant increase in the arrest of cells in the G0/G1 phase
when compared to the control.
IC50 values in μM of the synthesized compounds
b
c
CODE
MDA-MB-231
HEK-293
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
3.1 ± 0.82
12.3 ± 0.52
18.6 ± 0.22
>50
24.6 ± 1.2
d
—
—
—
—
—
—
—
12.9 ± 0.39
21.0 ± 0.32
15.3 ± 0.44
21.4 ± 0.29
1.65 ± 0.37
17.2 ± 0.18
20.8 ± 0.29
25.5 ± 0.32
1.12 ± 0.43
11.8 ± 0.32
18.0 ± 0.39
14.0 ± 0.35
35.5 ± 0.38
15.3 ± 0.24
19.8 ± 0.23
>50
39.9 ± 1.1
—
—
—
Quantification of apoptosis by the annexin V-FITC/propidium
iodide staining assay
48.1 ± 0.53
In order to determine the apoptotic induced cell death,
—
—
—
—
—
—
—
—
—
—
—
annexin
V FITC and propidium iodide staining was
performed by using an annexin V-FITC apoptosis detection
24
kit. The results were interpreted as the percentage of total
cells appearing in each quadrant. This assay facilitates the
s
t
u
v
w
detection of live cells (Q1-LL; AV−/PI−), early apoptotic cells
14.6 ± 0.17
24.2 ± 0.24
15.7 ± 0.49
0.8 ± 0.09
(
Q1-LR; AV+/PI−), late apoptotic cells (Q1-UR; AV+/PI+) and
necrotic cells (Q1-UL; AV−/PI+). In this study, MDA-MB-231
cells were treated with the tested compounds for 24 h at 1
and 2 μM concentrations, respectively. The distribution of
apoptotic and necrotic cells upon treatment with various
concentrations of 9i and 9m is shown in Fig. 5. The results to
this regard are presented in Table 2. The results indicated
Doxorubicin
a
Concentration required to inhibit 50% of cell growth and the
values represent the mean of three independent experiments.
Breast cancer. Normal human embryonic kidney cells. Not
b
c
d
determined; bold values signify promising activity.
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Fig. 4 Flow cytometric analysis in the MDA-MB-231 breast cancer cell line after treatment with compounds 9i and 9m at 1 μm concentration for
4 h. Graphical representation of cell cycle analysis. M4 represents the G0/G1 phase; M5 and M6 represent the S phase and G2/M phase,
2
respectively.
Fig. 5 Annexin V-FITC/propidium iodide dual staining assay.
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Table 2 Distribution of apoptotic cells based on annexin-V FITC experiments
Lower left
Lower right
Upper right
Upper left
Sample (concentration)
Live cells (%)
Early apoptosis (%)
Late apoptosis (%)
Necrosis (%)
MDA-MB-231 (untreated)
Doxorubicin (1 μM)
Doxorubicin (2 μM)
99.9 ± 0.02
79.9 ± 0.012
58.6 ± 0.013
67.6 ± 0.08
55.8 ± 0.34
81.6 ± 0.23
61.5 ± 0.12
0.0
0.0
0.1 ± 0.04
0.1 ± 0.023
8.3 ± 0.024
6.0 ± 0.025
6.1 ± 0.021
0.1 ± 0.06
9.2 ± 0.056
19.2 ± 0.23
27.8 ± 0.11
16.8 ± 0.27
35.0 ± 0.21
17.5 ± 0.01
23.7 ± 0.23
0.8 ± 0.01
5.3 ± 0.01
8.3 ± 0.03
3.1 ± 0.04
0.8 ± 0.06
5.6 d± 0.03
9i (1 μM)
9i (2 μM)
9m (1 μM)
9m (2 μM)
Note: the experiment was performed in triplicate and the results are represented as mean ± standard deviation.
that the percentage of early apoptotic cells in compound-
treated wells considerably increased when compared with the
control and standard drug. The results revealed that these
compounds induced cell death via early apoptosis in a
concentration-dependent manner in human breast cancer
cells.
Quantitative estimation of ROS generation by DCFH-DA staining
Increased levels of intracellular reactive oxygen species (ROS)
may cause oxidative damage leading to loss of mitochondrial
membrane potential which further leads to initiation of the
26
intrinsic pathway of apoptosis and eventual cell death. Hence
efforts were made to determine the effect of compounds 9i and
9m on the intracellular ROS generation through a peroxide
sensitive fluorescent dye, 2′-7′-dichlorodihydro-fluorescein
diacetate (DCFH-DA), staining method in MDA-MB-231 cells.
DAPI staining
27
DAPI (4′,6-diamidino-2-phenylindole) is a nuclear stain that
can envisage nuclear morphological changes which are
characteristic features of apoptosis. DAPI stains the apoptotic
cells in bright colour because of the condensed nucleus which
DCFH-DA is a non-fluorescent cell permeable dye which upon
entering the cells becomes oxidized by esterases in the cytosol
and converts into non-diffusible green fluorescent DCF.
Treatment with compounds 9i and 9m for 6 h resulted in a
considerable rise in DCFH-DA fluorescence when compared to
control cells, demonstrating the ROS accumulating potential of
the compounds which signifies that the compounds promote
apoptosis (Fig. 7).
2
5
is a characteristic feature of apoptosis. Therefore, DAPI
staining of compounds 9i and 9m (1 μM) in the breast cancer
cell line (MDA-MB-231) was carried out to study the
morphological changes induced by doxorubicin (1 μM) which
was used as the standard, and the cells were treated for 48 h.
The control cells displayed large sized intact nuclei, while 9i
and 9m treated cells displayed fragmented, abnormally
shaped nuclei characteristic of apoptosis. In addition, higher
numbers of condensed apoptotic cells were observed in 9i
and 9m treated samples (Fig. 6).
Analysis of mitochondrial membrane potential by JC-1
staining
The alteration of the mitochondrial electrochemical potential
(MMP) gradient (ΔΨ ) is known as an early event in drug-
m
Fig. 6 Effect of compounds 9i and 9m on the nuclear morphology of MDA-MB-231 cells stained with DAPI. The images were captured using a
fluorescence microscope at 100× magnification.
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an FAC Scan (Becton Dickinson) in the FL1 and FL2 channels
to detect the mitochondrial potential. In the X-axis, FL1H
represents mean fluorescence units in the green filter. FL2H
represents mean fluorescence units in the red filter. The
Y-axis represents mean fluorescence units.
Conclusion
In the present study, we have synthesized a series of
imidazoij2,1-b]thiazole-based aryl hydrazones (9a–w) and
evaluated them for their anti-proliferative activity. Among
them, 9a, 9i and 9m exhibited significant cytotoxicity with
IC50 values ranging between 1.12 and 5.2 μM against the
tested cell lines. Interestingly, compounds 9i and 9m
exhibited promising cytotoxicity against the breast cancer cell
line MDA-MB-231 with IC50 values of 1.65 and 1.12 μM,
respectively. Further, 9i and 9m exhibited a significant
increase in the arrest of cells in the G0/G1 phase of the cell
cycle when compared to the control. Detailed biological
studies, including the annexin V-FITC assay, DAPI staining,
DCFH-DA assay and JC-1 staining, suggested that these
potential compounds induce apoptosis in the breast cancer
cell line. Based on these results, compounds 9i and 9m were
found to be effective cytotoxic agents and could be further
developed as prime anti-proliferative agents.
Fig.
7 Effect of compounds 9i and 9m on intracellular reactive
oxygen species (ROS) levels. Mean FL1H represents fluorescence units
in the green filter.
Conflicts of interest
The authors declare no conflict of interest.
Acknowledgements
The authors would like to thank CSIR, UGC and UGC-MANF,
New Delhi for the funding and the Director, CSIR-IICT for the
support (Manuscript Communication number: IICT/Pubs./
Fig. 8 Effect of compounds 9i and 9m on mitochondrial potential
m
(ΔΨ ).
2019/396).
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