Synthesis, biological evaluation, and docking study of a series of 1,4-disubstituted 1,2,3-triazole derivatives with an indole-triazole-peptide conjugate

Article abstract of DOI:10.1002/jhet.4020

A series of new compounds containing an indole-triazole-peptide conjugate were designed as potential agents possessing the dual anti-bacterial and anticancer activities. Accordingly, 20 compounds were prepared via a multi-step synthesis involving the copp

Full text of DOI:10.1002/jhet.4020

Received: 23 February 2020
DOI: 10.1002/jhet.4020
Revised: 31 March 2020
Accepted: 20 April 2020
A R T I C L E
Synthesis, biological evaluation, and docking study
of a series of 1,4-disubstituted 1,2,3-triazole derivatives
with an indole-triazole-peptide conjugate
1
2
3
Srinivas Suryapeta | Neeraja Papigani | Venkanna Banothu
|
4
5
6
Pramod Kumar Dubey | Khagga Mukkanti | Sarbani Pal
1
Research and Development Department,
Abstract
Alembic Pharmaceuticals Ltd, Genome
Valley, Shameerpet, Hyderabad, India
A series of new compounds containing an indole-triazole-peptide conjugate
were designed as potential agents possessing the dual anti-bacterial and anti-
cancer activities. Accordingly, 20 compounds were prepared via a multi-step
synthesis involving the copper-catalyzed azide-alkyne cycloaddition (CuAAC)
as a key step in moderate to high yield. All the synthesized compounds were
2
Department of Chemistry, DVR College
of Engineering & Technology, Kashipur
Village, Sangareddy District, Hyderabad,
India
3
Department of Biotechnology, JNTUH,
Hyderabad, India
1
13
purified by chromatographic techniques and characterized by IR, H and
C
4
Department of Chemistry, NIPER,
NMR and mass spectral data. The synthesized derivatives were screened for
their antimicrobial activities against one gram-positive (Staphylococcus aureus)
and three gram-negative (Escherichia coli, Klebsiella pneumonia, and Proteus
vulgaris) bacteria using an agar-well diffusion method. Most of the compounds
showed moderate to reasonable antibacterial activities especially the com-
pound 9e that showed good activities against all the strains. The potential of
DNA gyrase inhibitory activity of this compound was assessed by using molec-
ular docking studies in silico carried out using Autodock Vina software. The
low ΔGbind value (−9.4 Kcal/mol) of compound 9e suggested its good interac-
tions with the target protein in silico. The cytotoxic activities of some of the
compounds synthesized were evaluated via a MTT assay using the human lung
cancer cell line A549. Several compounds showed promising activities among
which compound 9b, 9k, and 9e showed low IC50 values.
Hyderabad, India
5
Center for Chemical Sciences and
Technology, IST JNTUH, Hyderabad,
India
6
Department of Chemistry, MNR
Degree & PG College, Kukatpally,
Hyderabad, India
Correspondence
Sarbani Pal, Department of Chemistry,
MNR Degree & PG College, Kukatpally,
Hyderabad, India.
Email: sarbani277@yahoo.com
1
| INTRODUCTION
example by (a) controlling growth of cancer related bac-
terial infections, (b) protecting patients from the infection
Due to the multidrug resistance of microorganisms, dis-
covery of novel or new antibacterial agents is necessary.
We designed new compounds having peptide triazole
framework which can show both antibacterial and anti-
cancer activity. This class of compounds possessing dual
activities is expected to have promising medicinal impor-
tance due to their ability to suppress bacterial infection
due to downplay of immune system, and (c) decreasing
side effects of presently used medicine against cancer.
[2]
At present combination of antibiotics and anticancer
drugs are used for the treatment of cancer patients. Thus
[
3]
compounds having dual activity are beneficial. Herein
we report the synthesis and biological evaluation of
20 new compounds for this purpose.
[1]
in cancer patients. Indeed, the dual antibacterial and
anticancer activities can benefit in various ways as for
Derivatives of Ibuprofen, a well-known NSAID, possess
a range of biological properties including antimicrobial,
J Heterocyclic Chem. 2020;1–16.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals LLC.
1

2
SURYAPETA ET AL.
FIGURE 1 Examples of known
molecules having the indole ring
2
2
| RESULTS AND DISCUSSION
.1 | Chemistry
H
N
OH
O
Various methods are known for the synthesis of triazole
and related derivatives including 1,2,3-triazoles.
Ibuprofen
O
Indole
[32–41]
NH
O
Among these methods the use of CuAAC reaction has
become a popular and well-known strategy for the con-
struction of 1,2,3-triazole ring. The methodology involved
the use of azides and appropriate alkynes as key starting
materials. We adopted this strategy for the synthesis of
our target compounds. Accordingly, the required alkyne
NH
N
O
N
H
N
NH2
N
N
N
O
Triazole
N
Peptide
N
A
R
7
and azide 8 were prepared as shown in Scheme 1.
Initially, the S-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)
FIGURE 2 Design of new template A for the generation of
library of compounds possessing the potential dual activities
amino)-3-(1H-indole-3-yl)propanoic acid (1) and (2S)-2-
amino-3-phenylpropanamide (2) were reacted in the
presence of coupling reagents, for example, 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride and
hydroxyl benzotriazole, N,N-diisopropylethylamine in dic-
hloromethane (DCM). The corresponding product, that is,
the peptide 3 was obtained as a white solid in 80% yield.
The compound 3 on deprotection of the FMOC group in
the presence of diethylamine in tetrahydrofuran afforded
the desired amine 4 that was isolated as a white solid in
78% yield. The amine 4 was then allowed to couple with
the ibuprofen 5 in the presence of EDC.HCl, HOBT, and
DIPEA in DCM to give product 6 as a white solid in 86%
yield. Finally, the regioselective N-propargylation of the
indole ring of compound 6 was performed using propargyl
bromide in the presence of sodium hydride in DMF to give
the desired terminal alkyne 7 as a white solid in 88% yield.
After successful synthesis of the terminal alkyne 7, the
organic azides 8 were prepared from the corresponding pri-
mary amines following two different routes reported ear-
antifungal, antiviral, and antitumor activities. 4–10] The
1
[
,2,3-triazole framework is an interesting heterocyclic
pharmacophore that attracted attention due to their fasci-
[11–21]
nating biological activities.
The indole ring on the
other hand is another attractive and privileged heterocy-
clic scaffold present in many natural products such as
alkaloids, peptides, plant growth hormone, heteroauxin,
the essential amino acid tryptophan, neurotransmitter
serotonin or 5HT, and various synthetic compounds
[
22–27]
(
Figure 1).
Anderson
-methyltryptophan can inhibit the growth of Escherichia
[28]
has synthesized and demonstrated that
5
coli. After development of genomic and proteomic tech-
nologies, it has been observed that smaller chain peptides
can represent promising alternatives to conventional
[
29–31]
antibiotics and in other therapeutic field.
Taking
into account of such positive aspects and in continuation
of our research in the field of synthesis of small library of
biologically active hybrid molecules we designed a new
template A (Figure 2) which contains tripeptide derived
from NSAID ibuprofen, indole and phenyl alanine amide
with an additional 1,2,3-triazole moiety. One of our pre-
liminary objectives was to establish a rapid synthesis of
compounds based on A under mild conditions. So herein
we represent preliminary results of our study.
[42]
lier.
The terminal alkyne 7 was then allowed to couple
with a series of azides 8 in the presence of CuSO .5H O
4
2
and sodium ascorbate at room temperature using DMF
as a solvent to afford the desired target molecules 9 in
75%-91% yield. All the synthesized target compounds were
purified by column chromatographic techniques and char-
1
13
acterized by IR, H and C NMR and mass spectral data.

SURYAPETA ET AL.
3
NHFmoc
O
NHFmoc
COOH
O
H
H N
2
EDC.HCl
NH2
N
NH2
O
(
+
HOBT,DIPEA,
DCM
N
H
N
H
3)
1
step 1
L-Phenyl alanine
amide
DEA/THF
step 2
2
NH2
O
OH
H
N
EDC.HCl
O
NH
2
O
O
NH
HOBT,DIPEA,
DCM
N
H
O
H
Ibuprofen
N
NH2
O
step 3
5
4
N
H
6
Br
step 4
NaH
DMF
O
NH
CuSO 5H O
4.
2
Na-ascorbate
O
NH
O
+
R-N
3
O
DMF, rt
60-100 min
NH
NH
N
8
NH
2
O
N
N
step 5
N
O
N
NH2
R
9
7
9a R=2,4-di(Me)C
b R= 2,6-di(Me)C H NHCOCH (84%,90mins)
6 3 2
H NHCOCH (81%,90min)
9
6
3
2
8
8
8
8
8
8
8
8
8
a R=2,4-di(Me)C H NHCOCH
9c R= 2-NO C H NHCOCH (84%,80mins)
6
3
H
2
2 6 4 2
b R= 2,6-di(Me)C
c R= 2-NO NHCOCH
d R= 3-NO NHCOCH
e R= 2-ClC NHCOCH
f R= 3-ClC NHCOCH
g R= 4-ClC NHCOCH
h R= 2-CH C H NHCOCH
6
3
NHCOCH
2
9d R= 3-NO C H NHCOCH (90%,90mins)
2 6 4 2
2
C
2
6
C
H
6
4
H
4
2
9e R= 2-ClC H NHCOCH (78%,90mins)
6 4 2
2
6 4 2
9f R= 3-ClC H NHCOCH (87%,90mins)
6
H
4
2
6 4 2
9g R= 4-ClC H NHCOCH (83%,80mins)
6
H
4
2
3 6 4 2
9h R= 2-CH C H NHCOCH (84%,90mins)
6
H
4
2
9i R=C H NHCOCH (90%,90mins)
6
5
2
3
6
4
2
9j R=C
6
H
5
(90%,100mins)
(79%,90mins)
(83%,90mins)
R= 4MeO-2-NO NHCOCH
R= 4MeO-2-NO (82%,80mins)
R= 3-COOHC (88%,80mins)
R= 4-COOHC H (79%,100mins)
i R=C H NHCOCH
9k
9l
6
5
2
R= 2-NO
2 6 4
C H
2 6 4
8
j R=C H
6
5
R= 3-NO C H
8
8
8
8
8
8
k R= 2-NO C H
9m
9n
9o
9p
2
6
4
2
C
6
H
3
2
(86%,100mins)
l R= 3-NO C H
2
6
4
2 6 4
C H
m R= 4MeO-2-NO C H NHCOCH
2
6
3
2
6 4
H
6
n R= 4MeO-2-NO C H
2
6
4
4
o R= 3-COOHC H
6
4
9
q R= 4-COOCH C H NHCOCH (75%,90mins)
3 6 4 2
p R= 4-COOHC H4
6
9
r R= C
6
H
5
CH
2
(89%,85mins)
8
q R= 4-COOCH C H NHCOCH
3 6 4 2
9
9
s R=C H
t R=4-NO C H (85%,80mins)
2 6 4
(80%,90mins)
7
15
8
r R= C H CH
6
5
2
8
8
s R=C H
t R=4-NO
7
15
2
C
6
H
4
SCHEME 1 Synthesis of peptide based novel compounds 9
1
13
The partial representation of H and C NMR spectral data
of compound 9a are presented in Figure 3 where the key
characteristic signals are depicted in red and green color.
This compound possesses three -NH- and one NH2
groups that appeared at 3386, 3281, and 3212 cm in the
corresponding IR spectra. Additionally, the four amide
−1

4
SURYAPETA ET AL.
Gram-positive and Gram-negative bacteria. Particularly,
the MIC of 9a and 9n was found to be 25 μg/mL against
E. coli and S. aureus, respectively. Additionally, compound
9
b and 9k also showed good activity against gram-negative
strain. Nevertheless, the structure activity relationship
SAR) summary of anti-bacterial activities of compound
is presented in Figure 4. It is evident that the activity was
(
9
varied with the change of position and nature of “R” group
attached to the benzene ring connected to the 1,2,3-triazole
moiety via a NHCOCH2 linker. For example, good
activity was observed when the R group presented 2,4-
dimethyl or ortho-nitro, ortho-chloro, or para-carboxylic
acid moiety whereas activity was reduced when R group
was at meta-position representing a nitro or chloro or
carboxylic acid.
2.2.2 | Anti-cancer activity
Having evaluated the antibacterial activities of synthe-
sized compounds we then tested the anti-cancer activities
of these compounds in vitro against the human cancer
cell line, that is, A549 (lung adenocarcinoma epithelial
cell line) using a colorimetric MTT assay and doxorubicin
as the standard drug. Compounds with promising (>50%)
activities were taken for determination of IC50 values.
Results of the active compounds are presented in Table 2.
The compound 9b and 9k showed good activity whereas
1
13
FIGURE 3 Partial representation of H (red) and C NMR
green) spectral data of compound 9a
(
9c, 9e, 9h, 9m, 9o, and 9j showed moderate activity. The
carbonyl groups appeared at 1670, 1669, 1645, and
1
SAR summary of anti-cancer activities of compound
9 against A549 cell line is presented in Figure 5.
640 cm− in the IR spectra.
1
A graphical representation of concentration depen-
dent cytotoxic activity of some selected compounds along
with that of reference compound doxorubicin is shown in
Figure 6. It is evident that all these compounds showed
uniform and consistent increase of cytotoxicity with the
increase of their concentrations.
2
.2 | Biology
2
.2.1 | Antibacterial activity
All the synthesized compounds were screened for their
antimicrobial activities against one gram-positive (Staphy-
lococcus aureus) and three gram-negative (E. coli, Klebsiella
pneumonia, and Proteus vulgaris) bacteria using an agar-
well diffusion method and amoxicillin was used as a refer-
ence compound in this assay. The results, that is, the Zone
of inhibition (mm) and MIC values (μg/mL) obtained are
presented in Table 1. Most of the compounds showed mod-
erate to reasonable activities against all strains. Indeed, the
compound 9e was identified as the most promising among
these compounds as it showed good activity against both
Gram-positive and Gram-negative bacterial species. Indeed,
the compound 9e showed significant inhibitory activity
against E. coli with MIC of 25 μg/mL and was comparable
to the reference compound Amoxycillin. Among other
compounds 9a, 9c, and 9n also showed activities against
Overall, among all compounds synthesized the com-
pound 9e was found to be the most promising one in
terms of anti-cancer as well as anti-bacterial activities.
2.3 | Molecular docking studies analysis
Next, the potential of DNA gyrase inhibitory activity of
compound 9e was assessed by using molecular docking
studies in silico carried out using Autodock Vina software.
Indeed, the binding affinity 9e molecule toward DNA-
gyrase cleavage complex of S. aureus organism's DNA bind-
ing site surrounded by the protein residues were analyzed
using the molecular docking studies. The binding affinity
of the molecule showed strong interactions with the DNA
active site and results are shown in Table 3.

SURYAPETA ET AL.
5
TABLE 1 Antibacterial activities of compound 9
a
b
Zone of inhibition (mm) and MIC (μg/mL)
S. aureus gram
(+ve)
E. coli gram
(−ve)
K. pneumoniae gram
(−ve)
P. vulgaris gram
−ve)
S. no.
Compound
1
2
3
4
5
6
7
8
9
9a
12 ± 0.3 (>200)
14 ± 0.57 (>200)
14 ± 1.52 (>200)
11 ± 0.5 (>200)
16 ± 1.0 (200)
11 ± 0.5 (>200)
12 ± 0.4 (150)
14 ± 0.57 (50)
13 ± 0.57 (100)
13 ± 1.0 (100)
12 ± 0.4 (>200)
11 ± 0.5 (>200)
12 ± 0.57 (150)
15 ± 1.0 (25)
17 ± 0.57 (25)
15 ± 1.0 (>200)
16 ± 0.57 (>200)
12 ± 0.4 (>200)
16 ± 0.57 (25)
13 ± 0.57 (>200)
12 ± 0.5 (>200)
14 ± 1.0 (50)
13 ± 0.4 (>200)
15 ± 0.57 (50)
15 ± 1.0 (50)
13 ± 0.5 (150)
13 ± 0.57 (150)
12 ± 0.57 (150)
11 ± 0.3 (>200)
14 ± 1.0 (100)
14 ± 0.3 (100)
15 ± 0.5 (50)
9b
9c
9d
13 ± 0.57 (150)
14 ± 0.57 (100)
14 ± 1.0 (100)
15 ± 1.0 (100)
13 ± 0.4 (>200)
13 ± 0.57 (>200)
13 ± 0.4 (150)
12 ± 0.4 (>200)
13 ± 1.0 (150)
13 ± 1.0 (150)
14 ± 1.0 (100)
13 ± 1.52 (>200)
12 ± 0.5 (>200)
14 ± 0.57 (50)
12 ± 0.5 (>200)
31 ± 0.2 (25)
9e
9f
9g
9h
12 ± 0.5 (150)
13 ± 0.57 (150)
13 ± 0.3 (150)
12 ± 0.57 (150)
11 ± 0.57 (>200)
10 ± 0.3 (>200)
10 ± 0.5 (>200)
12 ± 1.0 (150)
14 ± 0.4 (100)
13 ± 0.5 (150)
12 ± 0.57 (150)
27 ± 0.6 (25)
9i
15 ± 1.0 (50)
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
9j
14 ± 0.57 (50)
16 ± 1.52 (50)
10 ± 0.4 (>200)
15 ± 0.57 (50)
13 ± 0.57 (>200)
12 ± 0.5 (>200)
16 ± 1.0 (50)
9k
9l
9m
9n
9o
12 ± 0.3 (150)
10 ± 0.57 (>200)
13 ± 0.4 (100)
12 ± 0.5 (>200)
28 ± 0.3 (25)
9p
9r
15 ± 1.0 (100)
15 ± 1.52 (150)
29 ± 0.5 (25)
9s
Amoxycillin
Note: Data are means (n = 3) ± SD of three replicates.
Abbreviations: E. coli, Escherichia coli; K. pneumoniae, Klebsiella pneumonia; P. vulgaris, Proteus vulgaris; S. aureus, Staphylococcus aureus.
a
Zone of inhibition was calculated for stock solution at 0.4 mg/50 μL.
b
Minimal inhibitory concentration (MIC) values of the particular compounds are given within the brackets.
TABLE 2 Cytoxicity (IC50 values) of compound 9 against A549
cell line
IC50 (μg/mL)
S. no.
Compound
A549
17.35
31.95
25.81
28.52
38.68
15.25
34.02
36.85
4.39
1
2
3
4
5
6
7
8
9
9b
9c
9e
9h
9j
9k
9m
9o
FIGURE 4 SAR summary of anti-bacterial activity of
compound 9
Doxorubicin

6
SURYAPETA ET AL.
The crystal structure of the DNA-gyrase cleavage
complex of S. aureus (PDB_ID: 5CDQ) has been consider
for the docking the molecule 9e molecule. The crystal
structure contains an inhibitor Moxifloxacin intercalation
in the major groove of E and F chains of DNA. The DNA
binding protein with A and C chains are stabilizing the
binding of the DNA with the bound Moxifloxacin.
The molecule 9e docked in the intercalation location
of DNA of the DNA-gyrase complex (Figure 7). The mole-
cule bound to the DNA was stabilized by the hydrogen
bonds, hydrophobic interactions, and π-π interaction. The
3-phenylpropane group of the inhibitor molecule showed
π-π interaction. Adenine ring (DA-2013) of the E chain,
Guanine (DG-2009) of the F chain bases and the propane
TABLE 3 Docking score of the compound 9e
Molecule
Binding affinity (in kcal/mol)
FIGURE 5 SAR summary of anti-cancer activity of compound
9e
−9.4
9
against A549 cell line
FIGURE 6 Concentration-
dependent cytotoxic activity of selected
compounds and doxorubicin

SURYAPETA ET AL.
7
FIGURE 7 Molecule 9e docked in
the active site of the DNA-gyrase
cleavage complex of Staphylococcus
aureus (PDB_ID:5CDQ). Inhibitor
molecule shown in green color stick
style and the DNA side chains and
amino acid side chains are shown in line
style
showed CH-π interactions with Thymine ring (DT-8) of
chain F. The peptide carbonyl oxygen of molecule showed
activities especially the compound 9e that showed good
activities against all the strains. The potential of DNA
gyrase inhibitory activity of this compound was assessed
by using molecular docking studies in silico carried out
using Autodock Vina software. The low ΔGbind value
(−9.4 Kcal/mol) of compound 9e suggested its good inter-
actions with the target protein in silico. The cytotoxic
activities of some of the compounds synthesized were
evaluated via a MTT assay using the human lung cancer
cell line A549. Several compounds showed promising
activities among which compound 9b, 9k, and 9e showed
low IC50 values. Overall, the compound 9e appeared to be
promising among all the compounds synthesized and
tested. Thus the indole-triazole-peptide based framework
presented here could be a template for the identification
and development of novel and potential agents having
antibacterial/anticancer dual activities.
bifurcated hydrogen bonds with the NH of the Guanine
2
ring (DG-2010) of E chain and F chains. The binding
affinity of the molecule with DNA gyrase was observed as
−9.4 Kcal/mol. The interaction of DNA bases and the
amino acid side-chains in protein are shown in Figure 7.
3
| CONCLUSIONS
In conclusion, a series of new compounds containing an
indole-triazole-peptide conjugate were designed that were
expected to possess the dual anti-bacterial and anticancer
activities. Accordingly, 20 compounds were prepared via a
multi-step synthesis involving the copper-catalyzed azide-
alkyne cycloaddition (CuAAC) as a key step in moderate
to high yield. All the synthesized compounds were puri-
fied by chromatographic techniques and characterized by
1
13
IR, H and C NMR and mass spectral data. The synthe- 4 | EXPERIMENTAL
sized derivatives were screened for their antimicrobial
activities against one gram-positive (S. aureus) and three 4.1 | Chemistry
gram-negative (E. coli, K. pneumoniae, and P. vulgaris)
bacteria using an agar-well diffusion method. Most of the
compounds showed moderate to reasonable antibacterial
Commercially available chemicals were used directly
without further distillation and recrystallization. Cintex

8
SURYAPETA ET AL.
melting point apparatus was used to check melting point
following open glass capillary method. Perkin-Elmer
IR spectrometer was used to record IR spectra using
reaction mixture was quenched in 35% of ammonium
chloride solution and extracted with DCM (3 × 50 mL),
the organic layer was washed with water and brine solu-
tion, combined organic layer and evaporated solvent
under vacuum, thus the compound 6 were isolated.
KBr pellets. Bruker ACF-300 machine or a Varian
1
3
00 or 400 MHz spectrometer were used to record H and
1
3
CMR using DMSO-d , as solvent tetramethylsilane as
6
an internal reference. Jelol JMC D-300 mass spectrometer
was used to record mass spectra of synthesized com-
pounds. Progress of reactions was monitored routinely by
TLC (thin layer chromatography) in a regular interval.
Crude final compounds were purified by column chroma-
tography using silica gel (100-200 mesh, SRL, India).
4.4 | General procedure for synthesis
of 7
To a stirred solution of compound 6 (14.86 mmol) in
DMF (80 mL) added sodium hydride.
ꢀ
(
29.70 mmol) lot wise at 5-10 C, stirred the contents for
5
minutes, and followed by propargyl bromide (20.79 mmol)
4
of 4
.2 | General procedure for synthesis
addition, this reaction mixture was maintained for 2-4 hours
at RT. The progress of the reaction was monitored at regular
intervals by checking TLC. After completion of the reaction,
reaction mixture was quenched in a crushed ice, thus solid
was separated, filtered the solid under vacuum, washed with
n-hexane and dried the solid under vacuum for 4 hours.
The compound 7 purified by column chromatography by
using silica gel (100-200 mesh) with MeOH/DCM to get
desired product.
(
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-
chloride (6.74 g, 35.16 mmol), and hydroxybenzotriazole
4.75 g, 35.16 mmol), was added to a well-stirred solution
(
of 1 (10.0 g, 23.44 mmol) in DCM (200 mL) and stirred
the contents for 5 minutes at RT, then L-phenyl alanine
amide (2) (23.44 mmol) was added to the above stirred
solution followed by N,N-diisopropylethylamine (6.2 mL)
addition at RT, maintained reaction mixture at RT for
4
-5 hours. The progress of the reaction was monitored by
4.5 | General procedure for synthesis
of 9
at regular intervals by checking TLC, after completion of
the reaction, the reaction mixture was quenched in 35%
of ammonium chloride solution and extracted with DCM
A mixture of azide 8 (1 mmol), an appropriate terminal
alkyne 7 (1 mmol), copper sulfate pentahydrate (49.92 mg,
0.20 mmol) and sodium ascorbate (39.62 mg, 0.20 mmol)
in DMF (3 mL) was stirred vigorously for 10-30 minutes.
The progress of the reaction was monitored by checking
TLC at regular interval. After completion of the reaction,
the reaction mixture was quenched in crushed ice. The
solid separated was filtered, dried, and purified by column
chromatography on silica gel using dichloromethane/
methanol to give desired product.
(3 × 100 mL), the organic layer was washed with water
and brine solution, dried over anhydrous sodium sulfate,
filtered and evaporated under vacuum thus crude prod-
uct 3 obtained was dissolved in THF (200 mL), added
diethyl amine to this stirred the contents for 3-4 hours.
at RT, after completion of the reaction, evaporated the
solvent completely and diethyl ether was added to the
residue. After stirring for 30 minutes the mixture was fil-
tered, thus the compound 4 was isolated.
4
of 6
.3 | General procedure for synthesis
4.5.1 | 2-Amino-N-(1-amino-1-oxo-3-
phenylpropan-2-yl)-3-(1H-indol-3-yl)
propanamide (4)
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride
ꢀ ꢀ
Pale yellow colored solid; m.p.: 146 C-151 C; R : 0.5
f
(
(
EDC.HCl) (25.44 mmol) and 1-hydroxybenzotriazole
HOBT) (25.44 mmol) was added to a well-stirred solution
+
1
(Methanol: DCM 1:9); MS m/z 351.18 (M+1 , 105%); H
of 4 (16.96 mmol) in DCM (60 mL) and stirred the con-
tents for 5 minutes at RT, then Ibuprofen 5(16.96 mmol)
was added to the above stirred solution followed by N,N-
diisopropyl ethylamine (DIPEA) (4.5 mL) addition at RT,
maintained reaction mixture at RT for 4-5 hours the pro-
gress of the reaction was monitored at regular intervals
by checking TLC. After completion of the reaction the
NMR (DMSO-d , 400 MHz) δ 10.92 (s, 1H), 8.02 (d, 6.4 Hz,
1H), 7.57-7.51 (m, 2H), 7.36 (d, 7.6 Hz, 1H), 7.21-6.98
6
(m, 9H), 3.47 (d, 4 Hz, 1H), 3.15-2.84 (m, 3H), 2.70-2.50
13
(m, 1H), 1.98-1.72 (m, 2H).
CNMR (DMSO-d6,
100 MHz) 174.23, 172.81, 137.49, 136.33, 129.36, 127.98,
127.49, 126.28, 123.90, 120.95, 118.47, 118.31, 111.42,
110.51, 55.37, 52.83, 37.82, 30.52.

SURYAPETA ET AL.
9
4
.5.2 | (S)-N-((S)-1-Amino-1-oxo-3-
phenylpropan-2-yl)-3-(1H-indol-3-yl)-2-((S)-
-(4-isobutyl phenyl)propanamido)
propanamide (6)
4.54-4.38 (m, 2H), 3.60 (q, 7.2 Hz, 1H), 3.08-2.71 (m, 4H),
2.37 (d, 7.2 Hz, 2H), 2.23 (s, 3H), 2.15 (s, 3H), 1.80-1.73
1
3
2
(m, 1H), 1.24 (d, 7.2 Hz, 3H), 0.83 (d, 6.4 Hz, 6H).
C
NMR (DMSO-d , 100 MHz) δ 173.39, 172.50, 170.99,
6
164.20, 143.53, 143.45, 139.21, 139.06, 139.00, 137.72,
ꢀ
ꢀ
+
Pale yellow colored solid; m.p.: 225 C-230 C; R : 0.6
137.61, 136.04, 134.61, 134.59, 132.83, 131.44, 130.88,
129.21, 129.07, 128.63, 128.04, 128.00, 127.94, 127.80,
127.03, 126.94, 126.82, 126.72, 126.49, 126.22, 126.12,
124.70, 121.08, 118.56, 110.27, 110.04, 53.63, 53.43, 53.28,
51.79, 44.24, 40.65, 37.52, 29.57, 22.16, 20.42, 18.58,
18.20, 17.65.
f
1
(Methanol: DCM 1:9); MS m/z 539.30 (M+1 , 100%); H
NMR (DMSO- d , 400 MHz) δ 10.74 (s, 1H), 8.03 (d, 8 Hz,
6
1
5
H), 7.92-7.87 (m, 1H), 7.59-7.45 (m, 1H), 7.32 (d, 5.8 Hz,
H), 7.30-6.90 (m, 10H), 4.55-4.37 (m, 2H), 3.64-3.56
(
(
(
m, 1H), 3.11-2.90 (m, 4H), 2.37 (d, 7.2 Hz, 2H), 1.8-1.74
m, 1H), 1.24 (d, 7.2 Hz, 3H), 0.83 (d, 6.4 Hz, 6H). CNMR
DMSO-d , 100 MHz) δ 173.27, 172.53, 171.07, 156.93,
13
6
137.58, 137.07, 136.02, 133.08, 129.11, 129.06, 128.34,
127.92, 127.48, 126.58, 126.50, 126.10, 125.34, 123.50,
120.81, 118.18, 111.24, 110.15, 105.63, 55.11, 53.64, 53.39,
44.64, 37.55, 27.68, 18.55.
4.5.5 | N-(1-Amino-1-oxo-3-phenylpropan-
2-yl)-3-(1-((1-(2-((2,6-dimethylphenyl)
amino)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)
methyl)-1H-indol-3-yl)-2-(2-(4-isobutylphenyl)
propanamido)propanamide (9b)
ꢀ
ꢀ
+
4
.5.3 | (S)-N-((S)-1-Amino-1-oxo-3-
Off white colored solid; m.p.: 225 C-230 C; R : 0.54
f
phenylpropan-2-yl)-2-((S)-2-(4-isobutylphenyl)
propanamido)-3-(1-(prop-2-yn-1-yl)-1H-indol-
(Methanol: DCM 1:9); MS m/z 781.41 (M+1 , 100%); IR
(νmax in cm ): 3382, 3283, 3209, 2955, 2378, 2313, 1669,
1664, 1642, 1638, 1539, 1228, 1049, 740, 698. H NMR
DMSO-d , 400 MHz) δ 8.1-7.9 (m, 3H), 7.60-6.90 (m,
−
1
1
3-yl)propanamide (7)
(
6
ꢀ
ꢀ
Pale yellow colored solid; m.p.: 214 C-218 C; R : 0.65
20H), 5.40 (s, 1H), 5.29 (s, 1H), 5.27 (s, 1H), 5.23 (s, 1H),
4.54-4.36 (m, 2H), 3.60 (q, 6.8 Hz, 1H), 3.02-2.73 (m, 4H),
2.37 (d, 6.8 Hz, 2H), 2.11 (s, 6H), 1.80-1.74 (m, 1H), 1.24
f
+
1
(Methanol: DCM 1:9); MS m/z 577.31 (M+1 , 100%); H
NMR (DMSO- d , 400 MHz) δ 8.07 (d, 6.4 Hz, 1H),
6
1
3
7
7
.95-7.89 (m, 1H), 7.62 (d, 7.6 Hz, 1H), 7.48-7.41 (m, 1H),
.33-7.20 (m, 3H), 7.18-6.97 (m, 10H), 6.86 (s, 1H), 5.00
(d, 6.8 Hz, 3H), 0.82 (d, 6.8 Hz, 6H). C NMR (DMSO-d6,
100 MHz) δ 173.40, 172.61, 170.99, 163.93, 143.53, 143.46,
139.22, 139.06, 139.02, 137.71, 137.60, 135.02, 134.13,
129.21, 129.07, 128.64, 128.56, 128.00, 127.94, 127.70,
127.03, 126.95, 126.85, 126.70, 126.22, 124.60, 121.08,
121.04, 118.62, 118.56, 110.03, 53.62, 53.53, 53.28, 51.52,
44.23, 40.66, 37.53, 29.56, 22.16, 18.61, 18.19, 17.95.
(s, 1H), 4.83 (s, 1H), 4.57-4.39 (m, 2H), 3.61 (q, 7.2 Hz,
1
1
6
1
1
1
5
H), 3.36 (s, 1H), 3.11-2.73 (m, 4H), 2.38 (d, 7.6 Hz, 2H),
.80-1.75 (m, 1H), 1.28-1.17 (m, 3H), 0.84 (d, 6.4 Hz,
H). CNMR (DMSO-d , 100 MHz) δ 173.27, 172.53,
71.07, 156.93, 137.58, 137.07, 136.02, 133.08, 129.11,
29.06, 128.34, 127.92, 127.48, 126.58, 126.50, 126.10,
25.34, 123.50, 120.81, 118.18, 111.24, 110.15, 105.63,
5.11, 53.64, 53.39, 44.64, 37.55, 27.68, 18.55.
13
6
4.5.6 | N-(1-Amino-1-oxo-3-phenylpropan-
2
3
-yl)-2-(2-(4-isobutylphenyl)propanamido)-
-(1-((1-(2-((2-nitrophenyl)amino)-
4
.5.4 | N-(1-Amino-1-oxo-3-phenylpropan-
2-oxoethyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-
indol-3-yl)propanamide (9c)
2-yl)-3-(1-((1-(2-((2,4-dimethylphenyl)
amino)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)
methyl)-1H-indol-3-yl)-
ꢀ
ꢀ
Off white colored solid; m.p.: 199 C-203 C; R : 0.58
f
+
2-(2-(4-isobutylphenyl)propanamido)
(Methanol: DCM 1:9); MS m/z 798.37 (M+1 , 100%);
IR(νmax in cm ): 3282, 3176, 1672, 1640, 1511, 1354,
222, 1053, 737, 694. H NMR (DMSO-d , 400 MHz) δ
8.08 (t, 8 Hz, 1H), 7.99-7.87 (m, 3H), 7.74-7.66 (m, 2H),
7.6-7.52 (m, 1H), 7.48-7.38 (m, 2H), 7.34-6.90 (m, 15H),
5.40 (s, 1H), 5.35 (s, 1H), 5.33 (s, 1H), 5.23 (s, 1H),
4.54-4.38 (m, 2H), 3.60 (q, 7.2 Hz, 1H), 3.07-2.73 (m, 4H),
2.37 (d, 7.2 Hz, 2H), 1.82-1.73 (m, 1H), 1.25 (d, 6.8 Hz,
3H), 0.82 (d, 6.4 Hz, 6H). C NMR (DMSO-d , 100 MHz)
δ 173.40, 172.62, 171.01, 164.87, 143.58, 142.27, 139.07,
−
1
propanamide (9a)
1
1
6
ꢀ
ꢀ
+
Off white colored solid; m.p.: 224 C-228 C; R 0.54
f;
(
(
Methanol: DCM 1:9); MS m/z 781.41 (M+1 , 100%); IR
νmax in cm ): 3386, 3281, 3212, 2950, 2375, 2317, 1670,
669, 1645, 1640, 1540, 1226, 1045, 745, 695. H NMR
−1
1
1
(
DMSO-d , 400 MHz) δ 9.97 (s, 1H), 8.07 (t, 8 Hz, 1H),
6
13
7
5
.9-7.89 (m, 2H), 7.60-7.44 (m, 2H), 7.25-6.90 (m, 17H),
.40 (s, 1H), 5.28 (s, 1H), 5.26 (s, 1H), 5.23 (s, 1H),
6

10
SURYAPETA ET AL.
1
1
1
1
4
39.01, 137.71, 137.61, 134.13, 130.31, 129.21, 129.07,
28.63, 128.00, 127.94, 127.03, 126.95, 126.82, 126.72,
26.22, 125.82, 125.44, 125.04, 124.79, 124.68, 121.07,
18.57, 110.30, 110.07, 109.79, 53.63, 53.53, 53.45, 51.84,
4.23, 40.62, 37.53, 29.55, 22.16, 18.57, 18.19.
4.5.9 | N-(1-Amino-1-oxo-3-phenylpropan-
2-yl)-3-(1-((1-(2-((3-chlorophenyl)amino)-
2-oxo ethyl)-1H-1,2,3-triazol-4-yl)methyl)-
1H-indol-3-yl)-2-(2-(4-isobutylphenyl)
propanamido)propanamide (9f)
ꢀ
ꢀ
Off colored solid; m.p.: 210 C-215 C; R : 0.60 (Methanol:
f
+
−1
4
2
3
2
.5.7 | N-(1-Amino-1-oxo-3-phenylpropan-
-yl)-2-(2-(4-isobutylphenyl)propanamido)-
-(1-((1-(2-((3-nitrophenyl)amino)-
DCM 1:9); MS m/z 787.34 (M+1 , 100%); IR (ν
in cm ):
max
3401, 3282, 3199, 2955, 2379, 2312, 1673, 1665, 1642, 1546,
1
1463, 1262, 737, 692. H NMR (DMSO-d , 400 MHz)
6
-oxoethyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-
δ 8.10-7.74 (m, 4H), 7.61-6.90 (m, 20H), 5.41 (s, 1H), 5.28
(s, 1H), 5.26 (s, 1H), 5.24 (s, 1H), 4.53-4.38 (m, 2H), 3.60
indol-3-yl)propanamide (9d)
(
q, 6.8 Hz, 1H), 3.07-2.71 (m, 4H), 2.36 (d, 6.8 Hz, 2H),
ꢀ
ꢀ
+
Off white colored solid; m.p.: 197 C-201 C; R : 0.56
1.80-1.73 (m, 1H), 1.25 (d, 7.2 Hz, 3H), 0.82 (d, 6.8 Hz,
f
13
(Methanol: DCM 1:9); MS m/z 798.37 (M+1 , 100%); IR
6H). C NMR (DMSO-d , 100 MHz) δ 173.38, 172.60,
6
−1
(νmax in cm ): 3285, 3172, 1670, 1642, 1513, 1353, 1224,
170.38, 164.56, 143.64, 139.76, 139.08, 137.71, 135.67,
135.52, 133.14, 130.61, 129.21, 129.07, 128.63, 127.81,
127.93, 127.01, 126.94, 126.22, 126.11, 124.77, 124.66,
123.47, 118.66, 118.57, 117.57, 110.31, 110.07, 53.62, 53.53,
53.30, 52.07, 44.22, 40.65, 37.53, 29.56, 22.16, 18.56, 18.18.
1
1054, 738, 693. H NMR (DMSO-d , 400 MHz) δ 8.57
6
(
(
(
(
(
s, 1H), 8.10-7.86 (m, 4H), 7.65-7.45 (m, 3H), 7.34-6.90
m, 16H), 5.42 (s, 1H), 5.33 (s, 1H), 5.30 (s, 1H), 5.24
s, 1H), 4.54-4.35 (m, 2H), 3.64-3.55 (m, 1H), 3.07-2.73
m, 4H), 2.36 (d, 7.2 Hz, 2H), 1.81-1.7;0 (m, 1H), 1.24
13
d, 7.6 Hz, 3H), 0.82 (d, 6.4 Hz, 6H). C NMR (DMSO-d6,
100 MHz) δ 172.65, 171.93, 170.73, 166.30, 141.71, 139.19,
139.01, 137.72, 136.55, 130.40, 129.22, 128.62, 128.00,
127.01, 126.94, 125.53, 125.48, 121.21, 121.10, 114.46,
113.80, 113.32, 110.09, 109.15, 53.62, 53.44, 52.07, 51.58,
44.21, 40.65, 37.53, 29.55, 22.15, 18.57, 18.18.
4.5.10 | N-(1-Amino-1-oxo-3-phenylpropan-
2-yl)-3-(1-((1-(2-((4-chlorophenyl)amino)-
2-oxo ethyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-
indol-3-yl)-2-(2-(4-isobutylphenyl)
propanamido)propanamide (9g)
ꢀ
ꢀ
+
Pale yellow colored solid; m.p.: 211 C-216 C; R : 0.62
f
4
2
2
1
.5.8 | N-(1-Amino-1-oxo-3-phenylpropan-
-yl)-3-(1-((1-(2-((2-chlorophenyl)amino)-
-oxo ethyl)-1H-1,2,3-triazol-4-yl)methyl)-
H-indol-3-yl)-2-(2-(4-isobutylphenyl)
(Methanol: DCM 1:9); MS m/z 787.34 (M+1 , 100%); IR
−1
(νmax in cm ): 3400, 3281, 3198, 2954, 2378, 2311, 1672,
1
1664, 1641, 1545, 1462, 1261, 736, 691. H NMR (DMSO-d ,
6
400 MHz) δ 8.10-7.88 (m, 3H), 7.60-6.55 (m, 21H), 5.40
(s, 1H), 5.26 (s, 1H), 5.24 (d, 2.4 Hz, 1H), 4.52-4.38 (m, 2H),
propanamido)propanamide (9e)
3.63-3.57 (m, 1H), 3.06-2.71 (m, 4H), 2.36 (d, 7.2 Hz, 2H),
ꢀ
ꢀ
+
Light yellow colored solid; m.p.: 208 C-211 C; R : 0.60
1.80-1.73 (m, 1H), 1.24 (d, 7.2 Hz, 3H), 0.82 (d, 6.4 Hz, 6H).
f
13
(Methanol: DCM 1:9); MS m/z 787.34 (M+1 , 100%); IR
C NMR (DMSO-d , 100 MHz) δ 172.60, 172.51, 170.99,
6
−1
(
νmax in cm ): 3403, 3284, 3199, 2957, 2380, 2314, 1674,
164.56, 139.76, 133.14, 130.61, 129.21, 129.07, 128.63, 127.99,
127.93, 127.02, 126.94, 124.66, 123.47, 118.66, 118.57, 117.57,
52.07, 44.23, 37.53, 29.56, 22.16, 18.56, 18.18.
1
1
666, 1643, 1547, 1464, 1263, 739, 694. H NMR (DMSO-
d6, 400 MHz) δ 8.08 (t, 8 Hz, 1H), 8.00-7.94 (m, 2H), 7.89
(
(
(
(
(
1
1
1
1
1
1
5
1
s, 1H), 7.71 (d, 8 Hz, 1H), 7.60-7.44 (m, 3H), 7.34-6.90
m, 16H), 5.40 (s, 1H), 5.37 (s, 1H), 5.35 (s, 1H), 5.23
s, 1H), 4.52-4.38 (m, 2H), 3.60 (q, 7.2 Hz, 1H), 3.03-2.73
m, 4H), 2.37 (d, 7.2 Hz, 2H), 1.82-1.75 (m, 1H), 1.24
4.5.11 | N-(1-Amino-1-oxo-3-phenylpropan-
2-yl)-2-(2-(4-isobutylphenyl)propanamido)-
3-(1-((1-(2-oxo-2-(o-tolylamino)ethyl)-1H-
1,2,3-triazol-4-yl)methyl)-1H-indol-3-yl)
propanamide (9h)
13
d, 7.2 Hz, 3H), 0.82 (d, 6.4 Hz, 6H). C NMR (DMSO-d6,
00 MHz) δ 173.30, 172.50, 170.90, 164.79, 143.52, 139.01,
37.74, 137.71, 137.60, 137.09, 136.88, 135.66, 135.52,
34.08, 133.85, 129.39, 129.57, 129.21, 129.12, 129.07,
28.56, 127.94, 127.03, 126.95, 126.87, 126.81, 126.71,
26.62, 126.22, 126.18, 126.14, 126.11, 125.77, 124.81,
24.71, 121.07, 118.57, 110.29, 110.05, 109.87, 53.63,
3.54, 53.43, 51.83, 44.20, 40.63, 37.53, 29.56, 22.16,
8.58, 18.19.
ꢀ
ꢀ
Off white colored solid; m.p.: 210 C-214 C; R : 0.56
f
+
(Methanol: DCM 1:9); MS m/z 767.40 (M+1 , 100%); IR (ν
in cm ): 3381, 3282, 3207, 2954, 2376, 2312, 1668, 1664, 1641,
1638, 1539, 1228, 1048, 740, 697. H NMR (DMSO-d6,
max
−1
1
400 MHz) δ 9.75 (s, 1H), 8.10-7.91 (m, 3H), 7.6-6.90 (m, 20H),

SURYAPETA ET AL.
11
5
3
2
.4 (s, 1H), 5.30 (d, 8.8 Hz, 1H), 5.23 (s, 1H), 4.56-4.36 (m, 2H),
.60 (q, 7.2 Hz, 1H), 3.10-2.71 (m, 4H), 2.37 (d, 6.8 Hz, 2H),
.20 (s, 3H), 1.82-1.72 (m, 1H), 1.24 (d, 7.2 Hz, 3H), 0.82 (d,
4.5.14 | N-(1-Amino-1-oxo-3-phenylpropan-
2-yl)-2-(2-(4-isobutylphenyl)propanamido)-
3-(1-((1-(2-nitrophenyl)-1H-1,2,3-triazol-4-yl)
methyl)-1H-indol-3-yl)propanamide (9k)
13
6.4 Hz, 6H). C NMR (DMSO-d , 100 MHz) δ 172.55, 171.94,
6
1
1
1
1
70.98, 164.27, 143.47, 139.01, 138.95, 137.67, 137.02, 135.97,
35.44, 130.38, 129.21, 129.08, 128.64, 128.56, 127.99, 127.94,
27.02, 126.99, 126.94, 126.85, 126.11, 123.47, 121.05, 118.11,
09.99, 109.40, 53.29, 52.90, 52.81, 51.82, 44.22, 40.39, 37.53,
9.57, 22.16, 18.54, 18.16, 17.73.
ꢀ ꢀ
Yellow colored solid; m.p.: 194 C-198 C; R : 0.62 (Methanol:
f
+
−1
DCM 1:9); MS m/z 741.35 (M+1 , 100%); IR (ν
in cm ):
max
3357, 3280, 3209, 2925, 2427, 1677, 1640, 1636, 1517, 1310,
1
2
1220, 1031, 851, 789, 696. H NMR (DMSO-d , 400 MHz) δ
6
8.51 (s, 1H), 8.38 (s, 1H), 8.20-7.96 (m, 3H), 7.89-7.47 (m,
5H), 7.35-6.90 (m, 13H), 5.51 (s, 1H), 5.34 (s, 1H), 4.57-4.38
4
.5.12 | N-(1-Amino-1-oxo-3-phenylpropan-
-yl)-2-(2-(4-isobutylphenyl)propanamido)-
-(1-((1-(2-oxo-2-(o-tolylamino)ethyl)-1H-
,2,3-triazol-4-yl)methyl)-1H-indol-3-yl)
(m, 2H), 3.58 (q, 7.2 Hz, 1H), 3.10-2.67 (m, 4H), 2.36-2.31
(m, 2H), 1.80-1.71 (m, 1H), 1.25 (d, 3.2 Hz, 3H), 0.83-0.78
2
3
1
13
(m, 6H). C NMR (DMSO-d , 100 MHz) δ 173.27, 172.62,
6
171.02, 144.71, 139.19, 139.01, 137.74, 137.62, 135.69, 135.59,
134.29, 134.24, 129.20, 129.05, 128.62, 128.56, 128.00, 127.94,
propanamide (9i)
127.32, 127.29, 126.97, 126.89, 126.11, 125.45, 124.43, 121.18,
ꢀ
ꢀ
+
Pale yellow colored solid; m.p.: 196 C-200 C; R : 0.54
118.68, 110.33, 55.43, 53.56, 51.06, 44.20, 40.50, 37.52, 31.25,
29.55, 29.50, 22.14, 18.49, 18.03.
f
(Methanol: DCM 1:9); MS m/z 753.38 (M+1 , 100%); IR
−1
(νmax in cm ): 3398, 3284, 2954, 1667, 1604, 1549, 1228,
1
1051, 735, 695. H NMR (DMSO-d , 400 MHz) δ 8.07
6
(
t, 7.6 Hz, 1H), 7.99-7.89 (m, 2H), 7.60-7.44 (m, 4H),
4.5.15 | N-(1-Amino-1-oxo-3-phenylpropan-
2-yl)-2-(2-(4-isobutylphenyl)propanamido)-
3-(1-((1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl)
methyl)-1H-indol-3-yl)propanamide (9l)
7
4
2
0
1
1
1
1
5
.33-6.91 (m, 18H), 5.40 (s, 1H), 5.26 (s, 1H), 5.24 (s, 2H),
.54-4.37 (m, 2H), 3.60 (q, 6.8 Hz, 1H), 3.08-2.67 (m, 4H),
.37 (d, 7.2 Hz, 2H), 1.80-1.72 (m, 1H), 1.24 (d, 7.6 Hz, 3H),
13
.82 (d, 6.8 Hz, 6H). C NMR (DMSO-d , 100 MHz) δ
6
ꢀ
ꢀ
+
73.39, 172.36, 170.99, 164.07, 143.82, 139.07, 139.00, 137.95,
37.60, 136.89, 136.87, 135.25, 134.91, 134.13, 129.21, 129.07,
28.86, 128.63, 128.00, 127.94, 127.03, 126.95, 126.11, 124.78,
23.72, 121.05, 119.14, 113.88, 11.30, 109.79, 53.63, 53.28,
2.97, 52.10, 44.22, 40.65, 37.53, 29.57, 22.16, 18.55, 18.19.
Light brown colored solid; m.p.: 195 C-197 C; R : 0.62
f
(Methanol: DCM 1:9); MS m/z 741.35 (M+1 , 100%); IR
(νmax in cm ): 3401, 3281, 2980, 2379, 1709, 1678, 1642,
1540, 1283, 1110, 1028, 855, 741, 699. H NMR (DMSO-d ,
−1
1
6
400 MHz) δ 8.8-8.60 (m, 2H), 8.38-8.27 (m, 2H), 8.13-7.99
(
5
m, 2H), 7.85-7.49 (m, 3H), 7.38-6.75 (m, 14H), 5.52 (s, 1H),
.39 (s, 1H), 4.57-4.39 (m, 2H), 3.55 (q, 7.2 Hz, 1H),
3.11-2.71 (m, 4H), 2.28 (dd, 6.8 Hz, 38 Hz, 2H), 1.75-1.64
4
2
3
1
.5.13 | N-(1-Amino-1-oxo-3-phenylpropan-
-yl)-2-(2-(4-isobutylphenyl)propanamido)-
-(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-
H-indol-3-yl)propanamide (9j)
13
(m, 1H), 1.22 (d, 6.8 Hz, 3H), 0.82-0.74 (m, 6H). C NMR
(DMSO-d , 100 MHz) δ 172.64, 172.55, 170.88, 148.40,
138.98, 137.98, 137.74, 137.05, 136.96, 135.58, 131.46, 131.39,
6
129.20, 129.05, 128.58, 128.38, 127.99, 127.93, 126.91, 126.71,
ꢀ
ꢀ
Off white colored solid; m.p.: 180 C-188 C; R : 0.60
125.88, 122.97, 121.84, 121.61, 121.19, 114.62, 110.67, 110.45,
53.64, 53.42, 52.95, 44.12, 37.51, 29.54, 22.08, 18.39, 17.73.
f
+
(Methanol: DCM 1:9); MS m/z 696.36 (M+1 , 100%);
−1
IR (νmax in cm ): 3365, 3286, 3200, 2926, 2380, 2315, 1706,
1
1676, 1642, 1339, 1222, 1032, 851, 742, 695. H NMR
(
DMSO-d , 400 MHz) δ 8.58 (s, 1H), 8.45 (s, 1H), 8.11-8.01
4.5.16 | N-(1-Amino-1-oxo-3-phenylpropan-
2-yl)-2-(2-(4-isobutylphenyl)propanamido)-
3-(1-((1-(2-((4-methoxy-2-nitrophenyl)amino)-
2-oxoethyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-
indol-3-yl)propanamide (9m)
6
(m, 2H), 7.88-7.80 (m, 2H), 7.64-7.44 (m, 5H), 7.37-6.85
(m, 13H), 5.49 (s, 1H), 5.33 (s, 1H), 4.59-4.37 (m, 2H),
3
.63-3.50 (m, 1H), 3.10-2.72 (m, 4H), 2.36-2.37 (m, 2H),
1
.78-1.66 (m, 1H), 1.23 (d, 6.8 Hz, 3H), 0.82-0.77 (m, 6H).
1
3
C NMR (DMSO-d , 100 MHz) δ 173.49, 172.63, 171.05,
6
ꢀ
ꢀ
+
1
1
1
1
5
45.14, 144.87, 139.17, 139.00, 138.94, 137.63, 136.49, 136.44,
35.64, 129.80, 129.76, 129.20, 129.05, 128.62, 128.51, 128.16,
28.00, 127.93, 126.94, 126.84, 126.79, 126.10, 121.26, 121.19,
21.15, 119.92, 119.85, 118.67, 110.61, 110.29, 109.74, 53.66,
3.59, 53.46, 44.19, 40.67, 37.50, 29.55, 22.14, 18.37, 17.97.
Pale yellow colored solid; m.p.: 225 C-230 C; R : 0.56
f
(Methanol: DCM 1:9); MS m/z 828.38 (M+1 , 100%); IR
(νmax in cm ): 3366, 3290, 3197, 2925, 1639, 1542, 1463,
1238, 1038, 804, 740. H NMR (DMSO-d , 400 MHz)
−
1
1
6
δ 8.42 (s, 1H), 8.31 (s, 1H), 8.12-7.96 (m, 3H), 7.74-7.61

12
SURYAPETA ET AL.
(m, 3H), 7.55-6.92 (m, 15H), 5.48 (s, 2H), 5.32 (s, 2H),
4.5.19 | 4-(4-((3-(3-((1-Amino-1-oxo-3-
4
3
1
.55-4.36 (m, 2H), 3.92 (s, 3H), 3.58 (q, 7.2 Hz, 1H),
.09-2.69 (m, 4H), 2.36-2.31 (m, 2H), 1.79-1.72 (m, 1H),
.24 (d, 6.4 Hz, 3H), 0.81 (t, 6.8 Hz, 6H). C NMR
phenylpropan-2-yl)amino)-
2-(2-(4-isobutylphenyl) propanamido)-
3-oxopropyl)-1H-indol-1-yl)methyl)-1H-
1,2,3-triazol-1-yl)benzoic acid (9p)
13
(DMSO-d , 100 MHz) δ 173.27, 172.52, 170.88, 160.16,
6
1
1
1
1
5
44.93, 144.45, 139.00, 138.90, 137.73, 137.65, 135.68,
35.59, 129.21, 129.05, 128.72, 128.68, 128.61, 128.11,
28.00, 127.94, 126.97, 126.90, 126.75, 124.70, 121.81,
21.75, 121.43, 119.30, 118.67, 110.50, 56.55, 53.65, 5360,
3.51, 44.21, 40.65, 37.52, 37.52, 29.56, 22.15, 18.50, 18.06.
ꢀ
ꢀ
+
Pale yellow colored solid; m.p.: 208 C-212 C; R : 0.52
f
(Methanol: DCM 1:9); MS m/z 740.35 (M+1 , 100%); IR
(νmax in cm ): 3401, 3292, 3210, 2953, 1709, 1673, 1641,
1540, 1284, 1180, 1109, 855, 740, 696. H NMR (DMSO-d ,
−1
1
6
400 MHz) δ 10.81(s, 1H), 8.65 (s, 1H), 8.51 (s, 1H), 8.14-7.92
(m, 6H), 7.64-7.49 (m, 2H), 7.34-6.83 (m, 13H), 5.51 (s, 1H),
4
2
3
1
.5.17 | N-(1-Amino-1-oxo-3-phenylpropan-
-yl)-2-(2-(4-isobutylphenyl)propanamido)-
-(1-((1-(4-methoxy-2-nitrophenyl)-1H-
,2,3-triazol-4-yl)methyl)-1H-indol-3-yl)
5.35 (s, 1H), 4.58-4.39 (m, 2H), 3.55 (q, 6.8 Hz, 1H), 3.10-2.72
(m, 4H), 2.30 (dd, 7.2 Hz, 2H), 1.79-1.66 (m, 1H), 1.24-1.22
13
(m, 3H), 0.82-0.75 (m, 6H). C NMR (DMSO-d , 100 MHz)
6
δ 173.27, 172.58, 172.71, 169.88, 144.02, 137.76, 137.63,
136.45, 135.14, 133.77, 133.60, 130.93, 130.91, 129.20, 129.05,
propanamide (9n)
128.59, 128.48, 128.19, 128.00, 127.94, 126.94, 126.82, 125.32,
ꢀ
ꢀ
+
Off white colored solid; m.p.: 208 C-212 C; R : 0.60
119.78, 119.61, 119.54, 118.71, 111.47, 110.71, 109.74, 53.64,
53.20, 52.71, 4.22, 40.65, 37.51, 29.52, 22.13, 18.29, 17.93.
f
(Methanol: DCM 1:9); MS m/z 771.36 (M+1 , 100%); IR
−1
(
νmax in cm ): 3366, 3291, 3197, 2925, 1639, 1542, 1463,
1
1
8
6
4
3
1
238, 1038, 804, 741. H NMR (DMSO-d , 400 MHz) δ
6
.41 (s, 1H), 8.31 (s, 1H), 8.09-7.93 (m, 2H), 7.74-7.39 (m,
H), 7.33-6.92 (m, 13H), 5.48 (s, 1H), 5.32 (s, 1H),
.54-4.39 (m, 2H), 3.91 (s, 3H), 3.58 (q, 7.2 Hz, 1H),
.09-2.71 (m, 4H), 2.36-2.32 (m, 2H), 1.79-1.70 (m, 1H),
.24 (d, 6.8 Hz, 3H), 0.81 (t, 7.6 Hz, 6H). C NMR
DMSO-d , 100 MHz) δ 172.60, 17.02, 170.88, 160.17,
4.5.20 | Methyl-4-(2-(4-((3-(3-((1-amino-
1-oxo-3-phenylpropan-2-yl)amino)-2-
(2-(4-isobutyl phenyl)propanamido)-
3-oxopropyl)-1H-indol-1-yl)methyl)-1H-
1,2,3-triazol-1-yl)acetamido)benzoate (9q)
13
(
6
ꢀ
ꢀ
1
1
1
5
44.93, 144.43, 144.22, 139.20, 139.03, 137.73, 137.62,
29.21, 129.05, 128.73, 128.61, 128.58, 128.00, 127.93,
26.7, 126.90, 121.16, 119.30, 118.66, 110.50, 56.55, 53.64,
3.56, 53.44, 44.22, 40.64, 37.52, 29.56, 22.14, 18.50 18.06.
Pale yellow colored solid; m.p.: 235 C-239 C; R : 0.50
f
+
(Methanol: DCM 1:9); MS m/z 811.39 (M+1 , 100%); IR (ν
in cm ): 3402, 3291, 3211, 2954, 1708, 1672, 1641, 1540,
1283, 1179, 1109, 855, 739, 695. H NMR (DMSO-d6,
max
−1
1
400 MHz) δ 8.08 (t, 8 Hz, 1H), 7.96-7.90 (m, 4H), 7.67
(d, 8.8 Hz, 2H), 7.61-7.45 (m, 2H), 7.27-6.91 (m, 15H), 5.41 (s,
4
.5.18 | 3-(4-((3-(3-((1-Amino-1-oxo-3-
1H), 5.30 (d, 8.8 Hz, 2H), 5.24 (s, 1H), 4.54-4.38 (m, 2H), 3.82
(s, 3H), 3.60 (q, 7.2 Hz, 1H), 3.05-2.73 (m, 4H), 2.36 (dd,
2.4 Hz, 7.2 Hz, 2H), 1.78-1.74 (m, 1H), 1.25 (d, 7.6 Hz, 3H),
phenylpropan-2-yl)amino)-
2-(2-(4-isobutylphenyl) propanamido)-
3-oxopropyl)-1H-indol-1-yl)methyl)-1H-
1,2,3-triazol-1-yl)benzoic acid (9o)
13
0.82 (d, 6.4 Hz, 6H). C NMR (DMSO-d , 100 MHz) δ 173.40,
6
172.61, 170.99, 165.68, 164.78, 143.65, 142.70, 139.19, 138.99,
137.60, 135.53, 130.37, 129.21, 129.07, 128.62, 127.99, 127.94,
ꢀ
ꢀ
+
Off white colored solid; m.p.: 207 C-210 C; R : 0.50
127.02, 126.95, 126.82, 126.71, 126.22, 126.10, 124.77, 124.44,
118.63, 110.31, 110.06, 109.86, 53.62, 53.53, 53.30, 52.17,
51.91, 44.22, 40.67, 37.53, 29.56, 22.15, 18.56, 18.19.
f
(Methanol: DCM 1:9); MS m/z 718.44 (M+1 , 100%); IR
−1
(νmax in cm ): 3392, 3281, 3198, 2425, 1673, 1637, 1540,
1
1338, 1218, 1029, 928, 739, 699. H NMR (DMSO-d6,
400 MHz) δ 10.80 (s, 1H), 8.23-7.90 (m, 4H), 7.62-6.90
(
m, 19H), 5.50 (s, 1H), 5.31 (s, 1H), 4.58-4.38 (m, 2H), 3.59
4.5.21 | N-(1-Amino-1-oxo-
(q, 7.2 Hz, 1H), 3.07-2.75 (m, 4H), 2.36 (d, 6.8 Hz, 2H),
3-phenylpropan-2-yl)-3-(1-((1-benzyl-1H-
1,2,3-triazol-4-yl methyl)-1H-indol-3-yl)-
2-(2-(4-isobutylphenyl)propanamido)
propanamide (9r)
1
.82-1.70 (m, 1H), 1.23 (d, 6.2 Hz, 3H), 0.83 (d, 5.6 Hz, 6H).
1
3
C NMR (DMSO-d , 100 MHz) δ 173.46, 173.27, 171.02,
6
1
1
1
5
66.58, 141.31, 139.16, 137.58, 135.95, 130.77, 129.23, 129.08,
28.64, 125.56, 128.00, 127.94, 127.19, 127.01, 126.85, 126.22,
26.12, 123.46, 118.12, 111.13, 110.09, 109.82, 53.62, 53.49,
3.26, 44.22, 40.65, 37.59, 29.56, 22.18, 18.61, 17.98.
ꢀ
ꢀ
+
Pale yellow colored solid; m.p.: 185 C-13 C; R : 0.64
(Methanol: DCM 1:9); MS m/z 710.38 (M+1 , 100%); IR
f

SURYAPETA ET AL.
13
−
1
13
(
νmax in cm ): 3395, 3289, 3203, 2379, 1677, 1635, 1510,
6.4 Hz, 20.8 Hz, 6H). C NMR (DMSO-d , 100 MHz) δ
6
1
1
8
7
5
3
1
318, 1036, 746, 698. H NMR (DMSO-d , 400 MHz) δ
173.30, 172.64, 170.85, 146.60, 146.57, 145.98, 145.75,
140.69, 140.62, 139.12, 139.01, 137.75, 137.63, 135.63,
129.25, 129.19, 129.05, 128.59, 128.46, 128.21, 128.00,
126.92, 126.82, 126.22, 126.11, 125.46, 125.40, 121.68,
121.22, 120.45, 118.76, 118.74, 110.79, 110.52, 109.71,
53.62, 53.54, 51.30, 44.20, 40.59, 37.52, 29.53, 22.11,
18.26, 17.90.
6
.07 (t, 8 Hz, 1H), 7.98-7.88 (m, 2H), 7.60-7.41 (m, 2H),
.34-6.87 (m, 19H), 5.52 (s, 1H), 5.48 (s, 1H), 5.35 (s, 1H),
.18 (s, 1H), 4.52-4.37 (m, 2H), 3.58 (q, 7.2 Hz, 1H),
.03-2.73 (m, 4H), 2.38-2.32 (m, 2H), 1.79-1.73 (m, 1H),
.24 (d, 7.2 Hz, 3H), 0.82 (d, 6.8 Hz, 6H). C NMR
DMSO-d , 100 MHz) δ 173.28, 172.50, 171.91, 144.04,
13
(
6
1
1
1
1
3
39.17, 139.02, 137.60, 135.91, 135.63, 129.21, 129.07,
28.68, 128.64, 128.07, 127.99, 127.94, 127.87, 127.02,
26.92, 126.11, 123.26, 123.12, 121.07, 118.63, 118.58,
10.29, 109.81, 53.62, 53.54, 53.28, 52.71, 44.22, 40.70,
7.53, 29.57, 22.15, 18.51, 18.12.
4.6 | Antibacterial activity
4.6.1 | Test organisms and culture
condition
4
3
1
2
.5.22 | N-(1-Amino-1-oxo-
Four bacterial strains including three Gram-negative and
one Gram-positive were used for the determination of
antibacterial activity of the synthesized compounds. All
four bacterial strains were donated by Department of
Microbiology, Osmania General Hospital, and Hydera-
bad. Standard microbiological methods were used to
check purity of all bacterial strains. Mueller Hinton Agar
(MHA) slants were used to store bacterial stock culture
-phenylpropan-2-yl)-3-(1-((1-heptyl-1H-
,2,3-triazol-4-yl) methyl) -1H-indol-3-yl)-
-(2-(4-isobutylphenyl)propanamido)
propanamide (9s)
ꢀ
ꢀ
+
Pale yellow colored solid; m.p.: 175 C-179 C; R : 0.62
f
(
(
Methanol: DCM 1:9); MS m/z 718.44 (M+1 , 100%); IR
νmax in cm ): 3372, 3291, 2925, 1641, 1538, 1464, 1223,
−1
ꢀ
and temperature was well maintained by 4 C.
1
1
051, 739, 696. H NMR (DMSO-d , 400 MHz) δ 8.07-7.1
6
(m, 3H), 7.49-6.89 (m, 16H), 5.35 (s, 1H), 5.19 (s, 1H),
4
3
1
.54-4.38 (m, 2H), 4.27-4.20 (m, 2H), 3.59 (q, 6.8 Hz, 1H),
.07-2.73 (m, 4H), 2.36 (t, 7.2 Hz, 2H), 1.82-1.69 (m, 3H),
.25-1.19 (m, 11H), 0.83-0.81 (m, 9H). C NMR (DMSO-
4.6.2 | Determination of antibacterial
activity
13
d6, 100 MHz) δ 173.25, 172.49, 171.01, 143.67, 139.19,
Antibacterial activities of test compounds were performed
[
43,44]
1
1
1
5
2
39.01, 138.95, 137.60, 136.96, 135.49, 129.21, 129.07,
28.63, 128.58, 127.90, 126.82, 126.10, 125.09, 122.90,
22.82, 121.03, 118.80, 118.54, 110.28, 109.79, 53.63,
3.54, 53.48, 53.32, 44.22, 40.80, 37.52, 31.01, 29.63, 29.57,
7.97, 29.53, 27.97, 25.74, 22.15, 22.91, 18.54, 18.08.
by an agar-well diffusion method.
Amoxycillin was
taken as the positive references at a concentration of
0.1 mg per 50 μL. DMSO was used as a negative control.
The bacterial strains were reactivated from stock cultures
by transferring into Mueller-Hinton broth and incubating
ꢀ
6
at 37 C for 18 hours. A final inoculums containing 10
6
colonies forming units (1 x 10 CFU/mL) was added asep-
tically to MHA medium and poured into sterile petri dis-
hes. Test compounds were dissolved in DMSO to prepare
solution. 0.4 mg/50 μL was added to wells (8 mm in diam-
eter) punched on agar surface. Plates were incubated
4
3
2
3
4
.5.23 | N-(1-Amino-1-oxo-
-phenylpropan-2-yl)-
-(2-(4-isobutylphenyl)propanamido)-
-(1-((1-(4-nitrophenyl)-1H-1,2,3-triazol-
-yl)methyl)-1H-indol-3-yl)
ꢀ
overnight at 37 C and diameter of inhibition zone (DIZ)
propanamide (9t)
around each well was measured in mm. Each experiment
was repeated three times (triplicates).
The anti-bacterial activity was investigated by deter-
mining the minimum inhibitory concentrations (MICs).
ꢀ
ꢀ
Brown colored solid; m.p.: 195 C-199 C; R : 0.60
f
+
(
(
Methanol: DCM 1:9); MS m/z 741.35 (M+1 , 100%); IR
νmax in cm ): 3373, 3287, 3197, 2995, 1672, 1642, 1528,
−1
MIC of compounds was assessed using the broth micro-
1
[45]
1
4
8
5
340, 1234, 1041, 853, 742, 693, 423. H NMR (DMSO-d ,
dilution method.
Each test compound was dissolved in
6
00 MHz) δ 8.73 (s, 1H), 8.55 (s, 1H), 8.40-8.36 (m, 2H),
.20-8.01 (m, 4H), 7.65-7.45 (m, 2H), 7.38-6.80 (m, 13H),
.53 (s, 1H), 5.38 (s, 1H), 4.60-4.39 (m, 2H), 3.56
dimethyl sulfoxide (DMSO, Fisher Chemicals) to give a
stock solution. Minimum Inhibitory Concentration
(MIC) is the lowest concentration of an anti-microbial
growth that will inhibit the visible growth of a microor-
ganism after overnight incubation.
(q, 7.2 Hz, 1H), 3.11-2.72 (m, 4H), 2.35-2.24 (m, 2H),
1
.74-1.65 (m, 1H), 1.24 (d, 7.2 Hz, 3H), 0.78 (dd,

14
SURYAPETA ET AL.
Compound preparation
cells are then solubilized with a DMSO and the released,
solubilized formazan reagent is measured spectrophoto-
metrically at 570 nm.
Compounds were weighed individually 1 mg and dissolved
in methanol for final stock concentration as 1 mg/mL as
same sample, standard amoxicillin also prepared.
Procedure
[46]
Culture preparation
Cell viability was evaluated by the MTT Assay
with
Loop of culture was inoculated in 3 mL of nutrient broth
and incubated at 37 C for overnight in shaking incubator.
three independent experiments with six concentrations of
compounds in triplicates. Cells were trypsinized and per-
form the tryphan blue assay to know viable cells in cell
suspension. Cells were counted by haemocytometer and
ꢀ
Inoculum preparation
3
From overnight grown culture, 20 μL of culture was
taken and inoculated in 1.5 mL of nutrient broth and
added different concentrations of compound and was
seeded at density of 5.0 × 10 cells/well in 100 μL media
in 96 well plate culture medium and incubated overnight
ꢀ
at 37 C. After incubation, take off the old media and add
ꢀ
incubated at 37 C for overnight in an incubator.
fresh media 100 μL with different concentrations of test
compound in wells in 96 plates. After 48 hours, discard
the drug solution and add the fresh medic with MTT
Result
-1)
After 24 hours of compound treatment, tubes were
observed and results were noted.
solution (0.5 mg/mL was added to each well and plates
ꢀ
were incubated at 37 C for 3 hours. At the end of incuba-
tion time, precipitates are formed as a result of the reduc-
tion of the MTT salt to chromophore formazan crystals
by the cells with metabolically active mitochondria. The
optical density of solubilized crystals in DMSO was mea-
sured at 570 nm on a microplate reader. The percentage
growth inhibition was calculated using the following for-
mula and concentration of test drug needed to inhibit
cell growth by 50% values is generated from the dose-
response curves for each cells using with origin software.
4
.7 | In vitro cytotoxicity
DMEM (Dulbecco's modified Eagles medium), MTT
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bro-
[
mide], trypsin, and EDTA Phosphate Buffered Saline (PBS)
were purchased from Sigma Chemicals Co. (St. Louis, MO)
and Fetal Bovine Serum (FBS) was purchased from Gibco.
2
25 and 75 cm flask and 96 well plates were purchased
from Eppendorf India.
% Inhibition = ½ðControl – TreatmentÞ=Controlꢁ × 100:
The Cancer cell line A549 was purchased from NCCS,
Pune and the cells were maintained in DMEM sup-
plemented with 10% FBS and the antibiotics penicillin/
−1
streptomycin (0.5 mL ), in atmosphere of 5% CO /95%
4.8 | Docking study
2
ꢀ
air at 37 C.
Molecular docking studies were performed in order to
predict the interaction of synthesized compounds with
the binding sites of DNA-gyrase cleavage complex of
S. aureus (Gram-positive bacteria) with PDB_ID:5CDQ is
4
.7.1 | MTT assay for cytotoxicity
[
47,48]
Preparation of test compound
carried out using Autodock Vina software
source molecular docking software.
open
For MTT assay, each test compounds were weighed sepa-
rately and dissolved in DMSO. With media make up the
final concentration to 1 mg/mL and the cells were treated
with series of concentrations from 10 to 100 μg/mL.
4.8.1 | Docking method
Principle
Molecular docking studies of molecule 9e into the crystal
structures of DNA-gyrase cleavage complex of S. aureus
(Gram-positive bacteria) with PDB_ID:5CDQ is carried out
MTT Assay is a colorimetric assay that measures the reduc-
tion of yellow 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl
tetrazolium bromide (MTT) by mitochondrial succinate
dehydrogenase. The assay depends both on the number of
cells present and on the assumption that dead cells or their
products do not reduce tetrazolium. The MTT enters the
cells and passes into the mitochondria where it is reduced
to an insoluble, dark purple colored formazan crystals. The
[47,48]
using Autodock Vina software,
open source molecular
docking software. We have generated a grid box with
desired parameters around the active site of DNA-gyrase
[49]
cleavage complex of S. aureus
(PDB_ID:5CDQ) as cen-
tre: x = 40.123, y = −46.732, z = 64.933 and grid box size:
x = 25, y = 39, z = 29 with 1 Å grid spacing. We generated

SURYAPETA ET AL.
15
1
0 conformations in each docking output by using
[19] S. Shafi, M. M. Alam, N. Mulakayala, C. Mulakayala,
G. Vanaja, A. M. Kalle, R. Pallu, M. S. Alam, Eur. J. Med.
Chem. 2012, 49, 324.
advanced Genetic algorithm method in vina Protein/DNA
complex and molecule input preparations and docking
output analysis were carried out using MGLTools-1.5.6
software.
[20] J. Mareddy, K. S. S. Praveena, N. Suresh, A. Jayashree, S. Roy,
D. Rambabu, N. Y. S. Murthy, S. Pal, Lett. Drug Des. Discov.
2013, 10, 343.
[
21] S. P. O. Assis, M. T. D. Silva, R. N. D. Oliveira, V. L. M. Lima,
Sci. World J. 2012, 2012, 925925. https://doi.org/10.1100/2012/
925925.
ACKNOWLEDGMENT
The authors S. Srinivas and P. Neeraja are thankful to
Alembic Pharmaceuticals Ltd, Hyderabad, India and
DVR College of Engineering & Technology, Hyderabad,
India for constant encouragement and support. We also
thank to CFRD, Osmania University, Hyderabad, India
and JNTU, Hyderabad, India.
[22] A. R. Saundane, A. Halu, K. N. Mathada, Int. J. Pharm. Pharm.
Sci. 2014, 6, 534.
[
[
23] T. P. Singh, O. M. Singh, Mini. Rev. Med. Chem. 2018, 18, 9.
24] K. Kerstin, V. Sylvia, B. Stefan, J. Beilstein, Org. Chem. 2012, 8,
1191.
[25] A. Pews-Davtyan, T. Annegret, S. Anne-Caroline, O. Stefanie,
J. F. Moritz, R. Arndt, B. Matthias, Org. Biomol. Chem. 2010, 8,
ORCID
1149.
Sarbani Pal https://orcid.org/0000-0003-1730-0782
[26] A. Baeyer, Chem. Ber. 1880, 13, 2254.
[27] F. Kogl, A. J. Haagens-Smith, H. Erxleben, Z. Physiol. Chem.
1
933, 214, 241.
REFERENCES
[
[
28] T. F. Anderson, Science 1945, 101, 565.
29] R. E. W. Hancock, D. S. Chapple, Antimicrob. Agents
Chemother. 1999, 43, 1317.
30] M. Zasloff, Curr. Opin. Immunol. 1992, 4, 3.
31] D. J. Carik, D. P. Fairle, S. Liras, D. Price, Chem. Biol. Drug
Des. 2013, 81, 136.
32] S. M. Gomha, S. M. Riyadh, Molecules 2011, 16, 8244. https://
doi.org/10.3390/molecules16108244.
[
[
[
1] M. Paul, A. Gafter-Gvili, A. Fraser, L. Leibovici, Eur. J. Clin.
Microbiol. Infect. Dis. 2007, 26, 825. https://doi.org/10.1007/
s10096-007-0375-4.
2] K. Alibek, A. Bekmurzayeva, A. Mussabekova, B. Sultankulov,
Infect. Agent Cancer 2012, 7, 33. https://doi.org/10.1186/1750-
[
[
9
378-7-33.
[
3] N. Kuntala, J. R. Telu, V. Banothu, N. S. Babu, J. S. Anireddy,
S. Pal, MedChemComm 2015, 6, 1612.
[
33] A. O. Abdelhamid, S. M. Gomha, N. A. Abdelriheem,
S. M. Kandeel, Molecules 2016, 21, 929. https://doi.org/10.
[
[
4] M. Amir, S. Kumar, Acta Pharm. 2007, 57, 315.
5] P. D. Soldato, R. Sorrentino, A. Pinto, Trends Pharmacol. Sci
3390/molecules21070929.
1
999, 20, 319.
6] C. Velazquez, P. N. Praveen Rao, E. E. Knaus, J. Med. Chem.
005, 48, 4061.
7] G. Jones, H. Bundgaard, Design of Prodrugs, Elsevier Science
Publishers, Amsterdam, The Netherlands 1985, p. 199.
[
[
[
[
[
[
34] A. O. Abdelhamid, S. M. Gomha, S. M. Kandeel, J. Heterocycl.
[
[
[
[
Chem. 2017, 54, 1529.
35] F. B. Essa, A. Bazbouz, S. Alhilalb, S. A. Ouf, S. M. Gomha,
Res. Chem. Intermed. 2018, 44, 5345.
2
36] S. M. Gomha, S. A. Ahmed, A. O. Abdelhamid, Molecules
8] N. Mamatha, N. S. Babu, K. Mukkanti, S. Pal, Molbank 2011,
2
015, 20, 1357. https://doi.org/10.3390/molecules20011357.
37] S. M. Gomha, M. G. Badry, M. M. Abdalla, J. Heterocycl. Chem.
016, 53, 558.
4
, M741.
9] N. Futaki, S. Takahashi, M. Yokoyama, I. Arai, S. Higuchi,
2
S. Otomo, Prostaglandins 1994, 47, 55.
38] S. M. Gomha, H. M. Abdel-Aziz, M. G. Badry, M. M. Abdalla,
J. Heterocycl. Chem 2019, 56, 1275.
39] K. Bozorov, J. Zhao, H. A. Aisa, Bioorg. Med. Chem. 2019, 27,
[
10] L. V. Reddy, A. Suman, S. S. Beevi, L. N. Mangamuri,
K. Mukkanti, S. Pal, J. Braz. Chem. Soc. 2010, 21, 98. https://
doi.org/10.1590/S0103-50532010000100015.
3511.
[
[
[
11] B. S. Holla, M. Mahalinga, M. S. Karthikeyam, B. Poojary,
P. M. Akberali, N. S. Kumari, Eur. J. Med. Chem. 2005, 40, 1173.
12] H. Behbehani, H. M. Ibrahim, S. Makhseed, H. Mahamoud,
Eur. J. Med. Chem. 2011, 46, 1813.
13] F. Reck, F. Zhou, M. Girardot, G. Kern, C. J. Eyermann,
N. J. Hales, R. R. Ramsay, M. B. Gravestock, J. Med. Chem.
[
[
[
[
40] Z. Xu, S. J. Zhao, Y. Liu, Eur. J. Med. Chem. 2019, 183, 111700.
41] K. Lal, P. Yadav, Anticancer Agents Med. Chem. 2018, 18, 21.
42] F. Nemati, A. Elhampour, J. Appl. Chem. 2012, 7, 29.
43] V. Banothu, U. Adepally, J. Lingam, Int J. Pharm. Pharm. Sci.
2017, 9, 192.
[
44] V. Banothu, C. Neelagiri, U. Adepally, J. Lingam,
K. Bommareddy, Phytochem. Biol. 2017, 55, 1155.
45] M. A. Jennifer, J. Antimicrob. Chemother. 2001, 48, 5.
46] A. Venkanna, B. Siva, B. Poornima, P. R. Rao Vadaparthi,
K. R. Prasad, K. A. Reddy, G. B. P. Reddy, K. S. Babu,
Fitoterapia 2014, 95, 102.
47] O. Trott, A. Olson, J. Comput. Chem. 2010, 31, 455.
48] G. M. Morris, R. Huey, W. Lindstrom, M. F. Sanner, R. K. Belew,
D. S. Goodsell, A. J. Olson, J. Comput. Chem. 2009, 16, 2785.
49] P. F. Chan, V. Srikannathasan, J. Huang, H. Cui,
A. P. Fosberry, M. Gu, M. M. Hann, M. Hibbs, P. Homes,
2
005, 48, 499.
[
[
[
[
[
14] O. A. Phillips, E. E. Udo, M. E. A. Hamid, R. Varghese, Eur.
J. Med. Chem. 2009, 44, 3217.
15] N. G. Aher, V. S. Pore, N. N. Mishra, A. Kumar, P. K. Shukla,
A. Sharma, M. K. Bhat, Bioorg. Chem. Lett. 2009, 19, 759.
16] J. N. Sangshetti, R. R. Nagawade, D. B. Shinde, Bioorg. Med.
Chem. Lett. 2009, 19, 3564.
17] D. C. Chan, C. A. Laughton, S. F. Queener, S. F. Stevens, Bio-
org. Med. Chem. 2002, 10, 3001.
18] E. M. Guantai, K. Ncokazi, T. J. Egan, J. Gut, J. P. Rosenthal,
P. J. Smith, K. Chibale, Bioorg. Med. Chem. 2010, 18, 8243.
[
[
[
[
[

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SURYAPETA ET AL.
K. Ingraham, J. Pizzollo, C. Shen, A. J. Shillings,
C. E. Spitzfaden, R. Tanner, A. J. Theobald, R. A. Stavenger,
B. D. Bax, M. N. Gwynn, Nat Commun. 2015, 6, 10048. https://
doi.org/10.1038/ncomms10048.
How to cite this article: Suryapeta S, Papigani N,
Banothu V, Dubey PK, Mukkanti K, Pal S.
Synthesis, biological evaluation, and docking study
of a series of 1,4-disubstituted 1,2,3-triazole
derivatives with an indole-triazole-peptide
conjugate. J Heterocyclic Chem. 2020;1–16. https://
doi.org/10.1002/jhet.4020
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