Synthesis, Biological Evaluation and Molecular Docking of Novel Thiophene‐Based Indole Derivatives as Potential Antibacterial, GST Inhibitor and Apoptotic Anticancer Agents

Abstract

Heteroaromatic indoles play a leading role in the development of pharmaceutical, medical, chemical and agricultural fields due to their structural properties. In this study, it was first time that biological properties of (antioxidant, antimicrobial, cytotoxic and apoptotis‐induced anticancer) 3‐(5‐bromothiophen‐2‐yl)‐1‐ethyl‐2‐phenyl‐1H‐indole 4 and 3‐([2,2′‐bithiophen]‐5‐yl)‐1‐ethyl‐2‐phenyl‐1H‐indole 5 were described. According to the overall results, while 4 did not show any significant cytotoxic, antioxidant and antimicrobial activities, 5 showed high reducing activity and very strong antibacterial activity against Enterococcus faecalis. Furthermore, 5 showed dose‐dependent cytotoxic effect in all tested cell lines. The EC50 values of the 5 were found to be 16 μM for CaCo‐2, 29 μM for LnCaP, 14 μM for MDA‐MB231, 21 μM for HepG2 and 87 μM for HEK293 cells, respectively. 5 also caused induction of apoptosis and promising glutathione S‐transferase (GST) enzyme inhibition in HepG2 cells. Consequently, 5 could be also considered as a promising medical agent in cancer treatment.

Full text

zBiological Chemistry & Chemical Biology
Synthesis, Biological Evaluation and Molecular Docking of
Novel Thiophene-Based Indole Derivatives as Potential
Antibacterial, GST** Inhibitor and Apoptotic Anticancer
Agents
Metin Konus,*[a] Doğan Çetin,[a] Can Yılmaz,[a] Sevki Arslan,[b] Dogukan Mutlu,[b]
Aslıhan Kurt-Kızıldoğan,[c] Çiğdem Otur,[c] Omruye Ozok,[a, d] Muheb AS Algso,[d] and
Arif Kivrak[d]
Heteroaromatic indoles play a leading role in the development
of pharmaceutical, medical, chemical and agricultural fields due
to their structural properties. In this study, it was first time that
biological properties of (antioxidant, antimicrobial, cytotoxic
and apoptotis-induced anticancer) 3-(5-bromothiophen-2-yl)-1-
ethyl-2-phenyl-1H-indole 4and 3-([2,2’-bithiophen]-5-yl)-1-
ethyl-2-phenyl-1H-indole 5were described. According to the
overall results, while 4did not show any significant cytotoxic,
antioxidant and antimicrobial activities, 5showed high reduc-
ing activity and very strong antibacterial activity against
Enterococcus faecalis. Furthermore, 5showed dose-dependent
cytotoxic effect in all tested cell lines. The EC50 values of the 5
were found to be 16 μM for CaCo-2, 29 μM for LnCaP, 14 μM
for MDA-MB231, 21 μM for HepG2 and 87 μM for HEK293 cells,
respectively. 5also caused induction of apoptosis and promis-
ing glutathione S-transferase (GST) enzyme inhibition in HepG2
cells. Consequently, 5could be also considered as a promising
medical agent in cancer treatment.
1. Introduction
Heteroaromatic compounds such as indole molecules that
benzene ring is associated with 2 and 3 position of pyrole ring,
play a leading role in the development of pharmaceutical,
medical, chemical and agricultural fields due to their structural
properties.[1,2] Indole and related structures are commonly
found in most of the biologically active compounds like
pharmaceuticals and alkaloids.[1,3,4] Therefore, they have played
very critical roles in medicine and biochemistry for pharma-
ceutical synthesis and modification.[4–67] Indole derivatives have
been reported to possess many important medical properties
such as anti-inflammatory,[8] antiallergic,[9] antiviral,[10]
antitumor,[11] antimicrobial[12] antihypertensive[13] and
antioxidant.[14] Owing to the unique structural motifs, indoles
are known as privileged scaffolds that mean they are capable
of serving as ligand for a diverse array of receptors.[6] Indole
and its derivatives have special characteristics similar to the
structure of peptides and may bind reversibly to enzymes.[15]
These provide fabulous opportunities to discover new drugs
with different mode of action.[16] Discovery of new alternative
indole derivatives against common diseases are required to be
researched and developed.[17] In addition, thiophene based
novel organic molecules creates not only new biological
properties[18] but also biocompatible materials.[19,20] Recently, we
designed and synthesized novel benzothiophene derivatives
via electrophilic cyclization reactions. It was investigated that
sulfur and nitrogen atoms may be increased the biological
properties or create new activities.[21]
In the present study, novel indole derivatives, containing
mono- and di-thiophene group, (3-(5-bromothiophen-2-yl)-1-
ethyl-2-phenyl-1H-indole 4 and 3-([2,2’-bithiophen]-5-yl)-1-
ethyl-2-phenyl-1H-indole 5) were synthesized by using coupling
and electrophilic substitution reactions. We were mainly
interested in exploring biological properties of these novel
thiophene based indole derivatives. It was found that designed
indole 5 caused induction of apoptosis and promising gluta-
thione S-transferase (GST) enzyme inhibition together with
high reducing activity and very strong antibacterial activity
against Enterococcus faecalis.
[a] Dr. M. Konus, D. Çetin, Dr. C. Yılmaz, O. Ozok
Department of Molecular Biology and Genetics
Faculty of Sciences
Van Yüzüncü Yil University, 65080, Van, Turkey
E-mail: mkonus@yyu.edu.tr
[b] Prof. S. Arslan, D. Mutlu
Department of Biology
Faculty of Arts and Sciences
Pamukkale University, 20100, Denizli, Turkey
[c] Dr. A. Kurt-Kızıldoğan, Ç. Otur
Department of Agricultural Biotechnology
Faculty of Agriculture
Ondokuz Mayıs University, 55139 Samsun, Turkey
[d] O. Ozok, Muheb AS Algso, Prof. A. Kivrak
Department of Chemistry
Van Yüzüncü Yil University, Van, 65080, Turkey
[**] GST=Glutathione S-Transferases
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/slct.202001523
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2. Results and Discussion
Initially, 3-bromo-1-ethyl-1H-indole (2) was synthesized by
using electrophilic aromatic substation reactions from 1-ethyl-
2-phenyl-1H-indole 1. Then, we used Pd catalyzed Stille cross
coupling reaction for the synthesis of 1-ethyl-2-phenyl-3-
(thiophen-2-yl)-1H-indole 3. Stille coupling reactions are very
useful methods for the formation of new carbon-carbon bond
between organic compounds. When 3-bromo-1-ethyl-1H-indole
2 was treated with 2-(tributylstannyl)thiophene in the presence
of Pd(PPh3)4as catalyst, 82% yields of 1-ethyl-2-phenyl-3-
(thiophen-2-yl)-1H-indole 3 was isolated. After characterization,
second electrophilic aromatic substitution reaction was applied
for the preparation of 3-(5-bromothiophen-2-yl)-1-ethyl-2-
phenyl-1H-indole 4 (92% yield). Finally, we synthesized 3-([2,2’-
bithiophen]-5-yl)-1-ethyl-2-phenyl-1H-indole 5 via Stille cou-
pling reaction. If 3-(5-bromothiophen-2-yl)-1-ethyl-2-phenyl-1H-
indole 4 was allowed to react with 2-(tributylstannyl)thiophene
in the presence of Pd(PPh3)4under reflux for overnight, desired
product 3-([2,2’-bithiophen]-5-yl)-1-ethyl-2-phenyl-1H-indole 5
was obtained in 98 % yields (Figure 1).
Cytotoxic responses of 4 and 5 on four different cancer
lines and one non-tumour cell line were given in Figure 2 and
3. As shown in Figure 1, 3-([2,2’-bithiophen]-5-yl)-1-ethyl-2-
phenyl-1H-indole 5 treatment showed dose-dependent cyto-
toxic effect in all tested cell lines. The EC50 values of the 5 were
found to be 16 μM for CaCo-2, 29 μM for LnCaP, 14 μM for
MDA-MB231, 21 μM for HepG2 and 87 μM for HEK293 cells,
respectively (Figure 2). These results showed that 5 had higher
cytotoxic activity towards all cancer cell lines compared to non-
tumour cell line. On the other hand, we did not observe any
cytotoxic activity at applied doses of 4. Therefore, we did not
include that pure compound following experiments such as
GST inhibition capacity and apoptosis analysis. It is well known
that, natural or synthetic indoles have many biological activities
including cytotoxic activity and many drugs having indole
nucleus are currently used to treat several cancer types.[22] But,
this is the first report that showed cytotoxic activity of 3-([2,2’-
bithiophen]-5-yl)-1-ethyl-2-phenyl-1H-indole 5. Moreover, our
data confirmed that 5 has cytotoxic activity against all cancer
cells more than non-malignant cells that might be valuable.
Figure 1. Synthesis of 3-([2,2’-bithiophen]-5-yl)-1-ethyl-2-phenyl-1H-indole 5.
Figure 2. Determination of cytotoxic effects of compound 5in MDA-MB-231, LNCaP, HEPG2, CaCo-2 and HEK293 cells after 24 h incubation. Cells were treated
with different concentrations of 5(*p<0.05). Results are mean SD values for three independent experiments.
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3. Apoptosis Analysis
Arthur™Image-Based Cytometer was used to analyse whether
5 cause apoptosis or not. For that purpose, Annexin V-FITC
Apoptosis Detection Kit was used as described in methods
section. As can be seen in Figures 4 and S1, after 24 hours of
application with 5, 45% of the HepG2 cell population was
apoptotic, 46% are viable, and 9 % are dead. The ratio of
apoptotic cell population in 5 treatments was nearly 11-fold
higher than that of the control cell population. These results
clearly showed that 5 caused induction of apoptosis and have
cytotoxic effect.
4. GST Activity and Molecular Docking studies
Total GST enzyme activity was determined throughout this
study (Figure 5). Total GST activities for control and 5 treated
cells were found to be 25.5 2.2 and 7.9 0.04 nmol/min/mg
protein, respectively. These results showed that 5 treatment
has caused 69.1% decrease in GST enzyme activity.
In addition to the total GST enzyme activity, molecular
docking studies were performed for compound 5with target
proteins (appropriate GST isozymes); hGST P1-1, A1-1, Theta2-2
and M2-2, in this study. Docking results were analysed based
on their lowest binding energy values, highest binding affinity
Figure 3. Determination of cytotoxic effects of compound 4in MDA-MB-231, LNCaP, HEPG2, CaCo-2 and HEK293 cells after 24 h incubation. Cells were treated
with different concentrations of 4. Results are mean SD values for three independent experiments.
Figure 4. Apoptosis analysis of compound 5by image-based Cytometer.
Following a 24 hour incubation period with 5, cell populations were assessed
for apoptosis. Data are representative of at least three independent experi-
ments. H2O2(200 μM) was used as a positive control. *Significantly different
from the respective control value p <0.05.
Figure 5. Effects of compound 5on total GST enzyme activities in HepG2 cell
line. Data were presented as the meanSD of at least three sets of duplicate
measurements. *Significantly different from the respective control value p<
0.05.
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and drug properties. According to results, the lowest binding
affinities were found to be in between 3.3 to 9,2 kcal/mol.
The lowest binding energy was observed in hGST Theta2-2
with the lowest RMSD lower bound values (1,094 A°) (Table 1
and Figure 6). It is well established that RMSD values 2.0 Å
suggests accuracy of our method and high binding affinity of
our molecule. Moreover, interactive amino acid residues of GST
isozymes were also determined. The most important residues
of this binding site were found to be Ala232, Ala235, Asp104,
Arg107, Arg239, His40, Leu35, Leu119, Lys53, Met236, Pro13
and Trp115 for GST Theta2-2.
GST enzymes play important role in xenobiotics metabolism
and they are one of the important phase 2 enzymes. Moreover,
they are so important in development of resistance to
anticancer agents.[23] Therefore, their inhibition is one of the
strategies for disrupting resistance. In this regard, compound 5
may have important role due to its GST inhibition activity. To
understand the inhibition, molecular docking approaches was
used whether that compound can bind to GST isozymes or not.
The docking analysis showed that 5 could bind to active sites
of all tested GST isozymes. According to RMSD values, it can
bind to hGST Theta2-2 isozyme stronger than other GST
isozymes (Figure 5). As it could be seen in Figure 5, amino acid
residues like Ala232, Ala235, Asp104, Arg107, Arg239, His40,
Leu35, Leu119, Lys53, Met236, Pro13 and Trp115 were involved
in 4 binding to active site of GST Theta2-2. All of these results
showed that compound 5 might be considered as a potential
GST inhibiting agent and it could be used to overcome drug
resistance produced by induction of GST isozymes in many
cancer types. Further studies should be required to confirm
these results in the future.
5. Antioxidant Activity
In DPPH assay, the amount of substance that inhibits 50% of
the radical is expressed as the EC50 value. EC50 value of tested
compound is expected to be lower than standard antioxidants
such as trolox.[24] The EC50 value of the trolox standard was
calculated as 21.9 μM. Although experiments were conducted
up to 78.5 μM for 4 and 77.8 μM for compound 5, the
antioxidant capacities of the indole derivatives tested by this
method could not be determined. Similarly, in galvinoxyl assay,
experiments were carried out from the indole derivatives tested
to a concentration of 248.5 μM for 4 and 246.4 μM for 5,
antioxidant capacity could not be determined.
ABTS assay is based on the principle of decolouring the
ABTS radical cation (ABTS*+) with the effect of antioxidant
compound, similar to DPPH method. This method can be
applied in measuring the activities of both water-soluble and
lipid-soluble antioxidant compounds.[25] It is based on the
principle of increasing the amount of radical swept as the
antioxidant compound increases in the media. EC50 value of
trolox standard was calculated as 5.02 μM. However, EC50 values
could not be calculated because the %RSA value of com-
pounds 4 and 5 was lower than 50 % in the ABTS method.
Therefore, the rates obtained by dividing the %RSA values to
corresponding concentration were used (Table 2). The rates
were obtained as 0.022, 0.038 and 5.17 for 4, 5 and trolox
standard, respectively. According to these ratios, it was seen
that the antioxidant capacities of the 4 and 5 were very low
according to the ABTS method compared to the trolox
standard.
It was previously reported that indole derivatives such as
triazole,[26] tryptophan and tryptamine derivative,[27] substituted
2-arylindoles derivatives, especially fluoro analogs[23] and pyr-
imidine derivatives[28] showed promising antioxidant activity
Table 1. Molecular docking scores of compound 5and GST isozymes.
GST
Name
Ligand Binding
Affinity
RMSDalower
bound
RMSDaupper
bound
Theta2-2 5-1ljr 9 1,094 1,746
M2-2 5-
1hnc 5,1 2,537 6,051
A1-1 5-
1pkw 9,2 1,431 1,805
P1-1 5-6gss 3,3 2,754 4,283
[a] RMSD values of the best scored conformations in reference to the observed
bound conformation.
Figure 6. Compound 5 interacts with Ala232, Ala235, Asp104, Arg107,
Arg239, His40, Leu35, Leu119, Lys53, Met236, Pro13 and Trp115 position
inside the active site of GST Theta2-2.
Table 2. Antioxidant capacities of synthesized indole compounds by ABTS
assay.
Compound Final %RSA Avarage
Conc.* SD Ratio**
(μM) (μM1)
261,56 5,760,57 0,022
4
259,37 9,741,22 0,038
5
19,98 98,210,49 5,17
Trolox
4 3-(5-bromothiophen-2-yl)-1-ethyl-2-phenyl-1H-indole
5 3-([2,2’-bithiophen]-5-yl)-1-ethyl-2-phenyl-1H-indole
SD Standard Deviation
(*) Final concentration of tested compound in reaction medium
(**) %RSA / Final concentration of tested compound
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compared to ascorbic acid and melatonin. Furthermore,
barbitone containing simple indole derivatives showed good
free radical scavenging, total antioxidant and ferric reducing
antioxidant activities compared to chloro and methyl substi-
tuted derivatives. In phosphomolybdenum assay, according to
the calculated proportions of tested indole derivatives, while 4
with 0.91 proportion values showed roughly equal molybde-
num reducing activity compared to trolox standard, compound
5 with 0.63 values showed high molybdenum reducing activity
with proportion value compared to trolox (Table 3).
The FRAP method is based on the principle of the reduction
of a Fe(III)-TPTZ complex to iron Fe(II) form at low pH with the
effect of the antioxidant substance. Comparison of the indole
derivatives (4 and 5) tested with the FRAP method with the
trolox standard was made according to the highest absorbance
values (Table 4). While 69.8 μM concentration of 4 corresponds
to 1.5 μM trolox, 69.2 μM 5 corresponds to concentration of
14.9 μM trolox. Considering the proportion values, both 4 and
5 showed less iron reducing activity with proportion value
compared to trolox.
6. Antimicrobial Activity
Today’s antibacterial drugs are mostly originated from empiri-
cal screening programmes that seek for inhibitor molecules
preventing bacterial growth in a way similar to those discov-
ered in “golden age” of antibacterial drug research. Although
successful progresses in treatment of bacterial infections have
been achieved, the emergence of antimicrobial resistance
increases worldwide and seriously threatens humans globally.
However, there is a serious decrease in the discovery and
development of novel antimicrobial compounds. Therefore,
design and synthesis of novel molecules with unique features
are urgently needed.[29] Unfortunately, compound 4 did not
lead to any antimicrobial activity against indicator microorgan-
isms by agar diffusion assay
while compound 5 (250 μg) showed intermediary level of
antibacterial activity on three gram positive bacteria tested and
also showed antifungal activity against C. albicans ATCC 10231
at moderate level. After the comparison of the MIC values with
CLSI guidelines (CLSI M100-S24, CLSI M38 A and M44 A2), the 5
was found to have a very strong antibacterial activity against E.
faecalis ATCC 29212 corresponding to MIC of 4 μg/mL (Table 5).
Table 3. Antioxidant capacities of synthesized Indole compounds by
phosphomolybdenum assay.
Compound Final
Conc.*
(μM)
Average ABSSD Trolox
Equivalent †
(μM)
Proportion�
495,1 0,4390,024 99,5 0,91
551,9 0,3640,019 82,8 0,63
4 3-(5-bromothiophen-2-yl)-1-ethyl-2-phenyl-1H-indole
5 3-([2,2’-bithiophen]-5-yl)-1-ethyl-2-phenyl-1H-indole
SD Standard Deviation
(*) Final concentration of tested compound in reaction medium
(†) Average ABS/Slope of the standard curve
(�) Final concentration / Trolox equivalent
Table 4. Antioxidant capacities of synthesized Indole compounds by FRAP
assay
Compound Final
Conc.*
(μM)
Average ABSSD Trolox
Equivalent †
(μM)
Proportion�
469.8 0.034 0,007 1.5 46.5
569.2 0.3390.032 14.9 4.6
4 3-(5-bromothiophen-2-yl)-1-ethyl-2-phenyl-1H-indole
5 3-([2,2’-bithiophen]-5-yl)-1-ethyl-2-phenyl-1H-indole
SD Standard Deviation
(*) Final concentration of tested compound in reaction medium
(†) Average ABS/Slope of the standard curve
(�) Final concentration / Trolox equivalent
Table 5. Evaluation of antimicrobial activity of compound 5by agar diffusion and broth microdilution assays.
Microorganism Compound 5
(250 μg)
Amikacin
(30 μg)
Flucanozole
(30 μg)
CLSI
S/I/R* for standards
Compound 5 Amikacin Fluconazole CLSI for MIC
S/I/R
Zone diameter (mm) MIC (μg/ml)
S. aureus
ATCC 25923
160.5 (I) 9 N/D 17/15-16 14 128 8 N/D 16/32/ 64
B. subtilis
ATCC 6633
15 (I) 16 N/D 16/15-16 15 128 1 N/D 16/32/ 64
E. faecalis
ATCC 29212
13 (I) 17 N/D 16/13-15 12 4 (S) 32 N/D 64/128/ 256
E. coli
ATCC 25922
10 (R) 7 N/D 17/12-1411 >512 2 N/D 16/32/ 64
P. aeruginosa
ATCC 27853
6 (R) 18 N/D 17/15-16 14 >512 4 N/D 16/32/ 64
K. pneumoniae
ATCC 700603
6 (R) 8 N/D 15/12-1411 (T) >512 2 N/D 16/32/ 64
C. albicans ATCC 10231 160.5 (I) N/D 18 19/15-1814 256 N/D 1 8/16-32 64
A. niger
ATCC 16404
120.5 (R) N/D 15 18/14-18 <14 >512 N/D 128 4-16
P. erythroseptica 13 N/D** N/D 15 ND 512 N/D 128 N/D
*S. Sensitive, I: Intermediate sensitive, R: Resistant, **N/D: Not Determined
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A weak MIC value of 128 μg/mL was obtained against two
gram positive bacteria, S. aureus ATCC 25923 and B. subtilis
ATCC 6633. Even lower antifungal activity as 256 μg/mL was
obtained against C. albicans ATCC 1023. On the other hand, no
antimicrobial activity was recorded for the remaining fungi and
gram negative bacteria by the use of 5 in broth microdilution
experiment in accordance with the bioassay data.
7. Conclusion
In the present study, 3-([2,2’-bithiophen]-5-yl)-1-ethyl-2-phenyl-
1H-indole derivative 5was synthesized by using electrophilic
aromatic substation reaction and Pd-catalyst Stille coupling
reactions in the first part. According to the overall results, while
3-(5-bromothiophen-2-yl)-1-ethyl-2-phenyl-1H-indole 4did not
show any significant cytotoxic, antioxidant and antimicrobial
activities, 5showed high reducing activity and very strong
antibacterial activity against E. faecalis. In addition, 3-([2,2’-
bithiophen]-5-yl)-1-ethyl-2-phenyl-1H-indole 5could be also
considered as a promising medical agent in cancer treatment.
But, further studies should be required to understand the
action mechanisms of that compound totally.
Supporting Information Summary
Characterization of the compound 4and 5including full 1H-
NMR, 13 C-NMR, FT-IR and HRMS spectra are given with
experimental procedures in supporting information (SI). SI also
include antioxidant capacities and antimicrobial, cytotoxicity
and apoptosis, molecular docking and total GST activity related
procedures. In addition, figure of Annexin Vl staining of HepG2
cancer cells for 24 h with EC50 concentration of compound 5is
also available in SI.
Acknowledgements
The authors thank to Van Yüzüncü Yıl University (FYL-2018-6798)
and Pamukkale University (PAU-BAP-2018-KRM-011) for financial
supporting of reactant and reagents. O. Ozok thanks to YÖK
100/2000 for scholarships. The author (A. Kivrak) would like to
acknowledge networking contribution by the COST Action
CM1407 “Challenging organic syntheses inspired by nature - from
natural products chemistry to drug discovery”.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: antibacterial ·apoptotic anticancer agent ·
cytotoxicity ·GST inhibitor ·indole ·thiophene
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Submitted: April 14, 2020
Accepted: May 6, 2020
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