Conventional and microwave-assisted synthesis of new indole-tethered benzimidazole-based 1,2,3-triazoles and evaluation of their antimycobacterial, antioxidant and antimicrobial activities

Article abstract of DOI:10.1007/s11030-018-9828-1

A new series of triheterocycles containing indole–benzimidazole-based 1,2,3-triazole hybrids have been synthesized in good yields via a microwave-assisted click reaction. All the compounds were characterized by IR, (Formula presented.) NMR, (Formula presented.) NMR and mass spectroscopy and were evaluated for their in vitro antitubercular activity against the Mycobacterium tuberculosis H37Rv strain. Compounds 4b, 4h and 4i displayed highly potent antitubercular activity with MIC 3.125–6.25 (Formula presented.). The antioxidant potential was evaluated using 2,2-diphenyl-1-picryl hydrazine and (Formula presented.) radical scavenging activity, and compounds 4e,4f and 4g showed excellent radical scavenging activity with (Formula presented.) values in the range of 08.50–10.05 (Formula presented.). Furthermore, the compounds were evaluated for antimicrobial activity against numerous bacterial and fungal strains, and compounds 4b, 4c and 4h were found to be the most promising potential antimicrobial molecules with MIC 3.125–6.25 (Formula presented.).

Full text of DOI:10.1007/s11030-018-9828-1

Molecular Diversity
https://doi.org/10.1007/s11030-018-9828-1
ORIGINAL ARTICLE
Conventional and microwave-assisted synthesis of new
indole-tethered benzimidazole-based 1,2,3-triazoles and evaluation
of their antimycobacterial, antioxidant and antimicrobial activities
1
1
1
1
Dongamanti Ashok · Srinivas Gundu · Vikas Kumar Aamate · Mohan Gandhi Devulapally
Received: 27 October 2017 / Accepted: 8 April 2018
©
Springer International Publishing AG, part of Springer Nature 2018
Abstract
A new series of triheterocycles containing indole–benzimidazole-based 1,2,3-triazole hybrids have been synthesized in good
1
13
yields via a microwave-assisted click reaction. All the compounds were characterized by IR, H NMR, C NMR and mass
spectroscopy and were evaluated for their in vitro antitubercular activity against the Mycobacterium tuberculosis H37Rv
strain. Compounds 4b, 4h and 4i displayed highly potent antitubercular activity with MIC 3.125–6.25 μg/mL. The antioxidant
potential was evaluated using 2,2-diphenyl-1-picryl hydrazine and H2O2 radical scavenging activity, and compounds 4e,4f
and 4g showed excellent radical scavenging activity with IC50 values in the range of 08.50–10.05 μg/mL. Furthermore, the
compounds were evaluated for antimicrobial activity against numerous bacterial and fungal strains, and compounds 4b, 4c
and 4h were found to be the most promising potential antimicrobial molecules with MIC 3.125–6.25 μg/mL.
Keywords Indole · Benzimidazole · 1, 2, 3-Triazole · Click chemistry · Microwave irradiation · Antitubercular · Antioxidant ·
Antimicrobial
Introduction
teria toward chemotherapeutics of available marketed drugs
demanded the search for new chemical entities which can
serve better treatment against tuberculosis [2–4].
Mycobacterium tuberculosis (MTB) bacterium causes the
infectious disease tuberculosis (TB) by affecting the lungs. In
latent tuberculosis, the MTB presents in the body in an inac-
tive form and does not show any symptoms and is not con-
tagious. Active TB infection occurs much higher in persons
suffering from other impaired immune systems like HIV and
malnutrition [1]. Thus, as resistant strains of Mycobacterium
tuberculosis (MTB) have slowly emerged, treatment failure
is the main reality. However, various drugs such as strepto-
mycin, rifampicin, isoniazid, ethionamide, ethambutol and
pyrazinamide are employed for the treatment of tuberculo-
sis. Since these drugs take more than six months to cure TB,
severe side effects and attaining multidrug resistance by bac-
The presence of free radicals in the body leads to oxidative
stress which causes neurodegenerative diseases including
Alzheimer’s disease and Parkinson’s disease. Other disorders
include chronic fatigue syndrome, rheumatoid arthritis and
blood vessel disorders such as heart attacks and atheroscle-
rosis [5,6]. Thus, treatment with antioxidants is potentially a
way to overcome oxidative stress. On the other hand, antimi-
crobialtherapyhaslongbeenfacingtheproblemofresistance
of microorganisms. Multidrug resistance by bacterial strains
claims for the search of new antimicrobial agents, which have
a broad spectrum of activity against the resistant microorgan-
isms.
Benzimidazole is an important pharmacophore in drug
discovery process since it exhibits various categories of
therapeutic properties such as antibacterial, antioxidants,
antitubercular, anticancer, antitumor[7–9], antiamoebic, hor-
mone modulators, anti-inflammatory [10–12] and antiviral
activity [13]. Benzimidazole derivatives are known to exhibit
anticanceractivityandhighlevelsofcytotoxicityagainstcan-
cer cell lines [14]. In addition, benzimidazole derivatives can
bind to biomolecules in living systems due to their struc-
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s11030-018-9828-1) contains supplementary
material, which is available to authorized users.
B Dongamanti Ashok
ashokdou@gmail.com
1
Department of Chemistry, Green and Medicinal Chemistry
Laboratory, Osmania University, Hyderabad, Telangana
500007, India
1
23

Molecular Diversity
Fig. 1 Commercially available indole, benzimidazole and 1,2,3-triazole drugs
tural similarity with some naturally occurring compounds.
Indomethacin is used as anti-inflammatory drug comprised
of indole nucleus, and bendazol is used as antispasmodic
drug comprised of a benzimidazole nucleus (Fig. 1).
3-carbaldehyde (1) in the presence of potassium carbonate
in dry acetone at reflux temperature [26]. Compound 2 was
further reacted by heating at reflux temperature with o-
phenylenediamine (OPDA) in chloroform for 6 h afforded
compound 3. Compound 3 coupled with variously substi-
tuted azides by azide–alkyne cycloaddition reaction to afford
title compounds 4a–j. The variously substituted azides were
achieved following a reported protocol [27,28]. In order to
develop a high-yield synthetic protocol for the synthesis of
title compounds 4a–j, a preliminary study was carried out for
the synthesis of compound 4f in the presence of different cat-
alysts and solvents under conventional and microwave irra-
diation conditions (Table 1). The reaction was carried out in
different solvent mixtures including THF:H2O, EtOH:H2O
and DMF:H2O in the presence of two Cu catalysts, namely
(i) CuSO4.5H2O with sodium ascorbate and (ii) CuI alone.
Based on our preliminary results, the reaction using CuI
in DMF:H2O (1:3) under microwave irradiation gave better
yield. In addition, a comparison study of the reaction using
CuI in DMF:H2O (1:3) under conventional and microwave
irradiation condition demonstrates that the reaction time is
reduced from 12 h to 8 min, respectively, and the yield is
increased from 40–52% to 76–85%, respectively (Table 2).
The formation of all the title compounds was confirmed
1,2,3-Triazoles are an important class of bioactive
molecules due to their wide range of applications as phar-
maceutical agents [15]. A large variety of therapeutic agents
are comprised of 1,2,3-triazole nucleus in it, such as anti-
fungal [16], antibacterial [17], antiallergic [18], anti-HIV
[
19], antitubercular [20] and anti-inflammatory agents [21].
Tazobactam is a β-lactam antibiotic drug, and rufinamide is
an anticonvulsant drug containing the 1,2,3-triazole motif
(Fig. 1). Microwave-assisted synthesis has gained much
interest due to the rapid synthesis of heterocyclic compounds,
which are not easily accessible by conventional synthetic
techniques. More recently, this way we extended our research
program to synthesize bioactive heterocyclic compounds
[
1
22,23]. Reports for the synthesis of benzimidazole-based
,2,3-triazoles under microwave irradiation conditions are
scare to find in the literature compared to conventional
methods. Microwave irradiation offers rapid, simple and eco-
friendly parameters for the synthesis of a variety of organic
molecules in higher yields and shorter reaction times.
Based on the pharmacological profile of indole, benz-
imidazole and 1,2,3-triazole scaffolds, and the advantages
of microwave technology, it is worthwhile to design and
synthesize new prototypes with indole, benzimidazole and
1
13
by IR, H NMR, C NMR and mass spectral analysis. The
IR spectra of 4f displayed a characteristic N–H absorption
−1
−1
1
band at 3060 cm and C=N stretching at 1580 cm . The H
NMR spectrum of 4f exhibited a broad singlet at δ 12.55 cor-
responding to the NH proton, a singlet at δ 8.62 was assigned
to the triazole-H, a singlet at δ 5.68 corresponds to the NCH2
protons and a singlet at δ 3.82 belongs to the OCH3 protons.
In the 13C-NMR spectrum, the OCH3 carbon appeared at δ
1,2,3-triazole scaffolds in a single molecular framework. In
continuation of our endeavors toward the development of
anti-infective agents [24,25], the potency to exhibit anti-
tubercular, antioxidant and antimicrobial activities of final
compounds was reported.
5
5.7 and the NCH2 carbon at δ 40.6. In the mass spectrum,
+
the base signal at m/z 421 appeared as [M+H] .
Results and discussion
Chemistry
Biological activity
The sequence of the reactions employed for the con-
structionofnovelindole–benzimidazole-based1,2,3-triazole
hybrids is demonstrated in Scheme 1. Compound 2 was
synthesized by treating propargyl bromide with 1H-indole-
Antitubercular activity
The title compounds were screened in vitro for their
inhibitory potency against M. tuberculosis H37Rv using
1
23

Molecular Diversity
Scheme 1 Synthetic route for the indole–benzimidazole-based 1,2,3-triazole hybrids
Table 1 Preliminary catalyst and solvent study for the synthesis of compound 4f
Entry
Catalyst
Solvent
Conventional heating
Microwave irradiation
Time (h)
Yield (%)
Time (min)
Yield (%)
4
4
4
4
4
4
4
4
4
4
4
4
f1
CuSO4 · 5H2O, sodium ascorbate
THF:H2O (1:2)
THF:H2O (1:3)
EtOH:H2O (1:2)
EtOH:H2O (1:3)
DMF:H2O (1:2)
DMF:H2O (1:3)
THF:H2O (1:2)
THF:H2O (1:3)
EtOH:H2O (1:2)
EtOH:H2O (1:3)
DMF:H2O (1:2)
DMF:H2O (1:3)
36
36
24
24
24
24
24
24
24
24
12
12
16
14
17
20
31
34
16
20
32
36
40
42
15
15
15
15
15
15
10
10
10
10
8
18
19
24
32
35
40
24
32
41
47
55
77
f2
CuSO4 · 5H2O, sodium ascorbate
f3
CuSO4 · 5H2O, sodium ascorbate
f4
CuSO4 · 5H2O, sodium ascorbate
f5
CuSO4 · 5H2O, sodium ascorbate
f6
CuSO4 · 5H2O, sodium ascorbate
f7
CuI
CuI
CuI
CuI
CuI
CuI
f8
f9
f10
f11
f12
8
1
23

Molecular Diversity
Table 2 Comparison of yields of compounds 4a–j under different syn-
thetic conditions
incorporation of the electron-withdrawing nitro group and
electronegative Cl and trifluoromethyl groups on the phenyl
ring was highly favored for antitubercular activity.
Compound
Conventional
Time (h)
MWI
Yield (%)
Time (min)
Yield (%)
We calculated various physicochemical parameters such
asclogP, drugscoreanddrug-likenessof4a–jusingtheOsiris
Property Explorer software [29]. For all the compounds, the
calculated clogP values were found to be below 5 according
to Lipinski’s rule-of-5 [30]. The majority of the commercial
drugs show positive drug score values. As can be observed
in Table 3, our theoretical data showed that compounds 4a–j
also exhibited positive values for drug score.
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
12
12
12
12
12
12
12
12
12
12
51
52
47
40
51
42
50
50
45
52
8
8
8
8
8
8
8
8
8
8
81
76
80
85
79
77
82
80
76
77
g
h
i
Antioxidant activity
j
The antioxidant ability of the new library was evaluated by
DPPH and H2O2 radical scavenging assay. Natural antioxi-
dant ascorbic acid and synthetic antioxidant BHT (butylated
hydroxytoluene) were employed as standard antioxidants.
Most of the compounds potentially inhibited DPPH radi-
cal compared to the standard (Table 4). Compounds 4e, 4f
and4gwith4-methyl, 2-methoxyand4-methoxysubstitution
on phenyl ring, respectively, showed potent radical scaveng-
ing ability on the DPPH, with IC50 values of 10.04 ± 1.10,
8.52 ± 0.57 and 9.25 ± 0.85 μg/mL, respectively. These
results were lower than the standards (AA and BHT with
13.62± 0.69 and 17.16± 0.25 μg/mL, respectively), indicat-
ing that compounds 4e, 4f, and 4g emerged as highly potent
antioxidant molecules toward DPPH. These results demon-
strate that the presence of methyl and methoxy substituents
at ortho and para positions of phenyl nucleus played a sig-
nificant role in exhibiting the antioxidant activity.
the resazurin microtiter assay (REMA). Rifampicin and
isoniazid were used as positive controls. The in vitro antimy-
cobacterial test results were expressed as minimal inhibition
concentration (MIC) in μg/mL, or with respect to the molec-
ular weight of final products in μM (values in parentheses)
and are tabulated in Table 3. Amongst the series, compound
4h emerged as best antitubercular drug candidate by inhibit-
ing the growth of the MTB strain with MIC = 3.125 μg/mL
(
7.1 μM) (control rifampicin MIC = 0.04 μg/mL and iso-
niazid MIC = 0.38 μg/mL). The best activity of 4h may
be attributed to the presence of nitro group on phenyl ring
at ortho position and was highly favored for antitubercular
activity. Compound 4b (MIC = 6.25 μg/mL (14.7 μM))
with chloro substitution, compound 4i (MIC = 6.25 μg/mL
The same series was screened for H2O2 radical scaveng-
ing potency. In Table 4, compounds 4e, 4f and 4g exhibited
highest H2O2 scavenging effect with potent IC50 values of
11.19± 0.60, 10.18± 0.75 and 10.76± 0.42 μg/mL, respec-
(14.2 μM)) with trifluoromethyl substitution and compound
4j (MIC = 12.5 μg/mL (28.4 μM)) with benzyl substitu-
tion exhibited moderate antitubercular activity. Notably, the
Table 3 Antimycobacterial
Compound
M. tuberculosis H37Rv*
clogP#
Drug-likeness#
Drug score#
activity (MIC in μg/mL, and
μM) and pharmacological
parameters for bioavailability of
compounds (4a–j)
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
25 (32.0)
6.25 (14.7)
12.5 (29.4)
25 (61.8)
>50
3.30
3.91
3.91
3.64
3.64
3.23
3.23
2.38
4.15
3.55
2.26
− 1.02
0.10
− 0.14
0.31
0.50
0.38
0.41
0.40
0.34
0.44
0.36
0.30
0.24
0.47
0.20
0.06
− 0.51
− 1.73
− 0.39
− 1.76
− 5.47
− 6.76
− 0.16
10.16
>50
g
h
i
50(119.0)
3.125 (7.1)
6.25 (14.2)
12.5 (28.4)
0.04 (0.04)
0.38 (2.7)
j
Rifampicin
Isoniazid
− 5.06
*
Micromolar values in parentheses Conversion formula: MIC(μM) = [{MIC(μg/mL)÷MW}×1000]
#
Obtained from molecular Osiris Property Explorer
1
23

Molecular Diversity
Table 4 Antioxidant activity of compounds (4a–j)
were obtained as minimum inhibitory concentration (MIC)
in μg/mL (Table 5). As observed from Table 5, com-
pounds 4b (3.125–6.25μg/mL) (Ar = 2-chlorophenyl), 4c
Compound
Scavenging activity (IC50μg/mL)
DPPH
H2O2
(3.125–6.25μg/mL) (Ar = 4-chlorophenyl) and 4h (3.125–
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
14.45 ± 1.04
15.32 ± 0.45
18.54 ± 0.58
14.08 ± 0.42
10.04 ± 1.10
08.52 ± 0.57
09.25 ± 0.85
22.72 ± 0.76
24.40 ± 0.29
21.07 ± 0.40
13.62 ± 0.69
17.16 ± 0.25
15.61 ± 0.54
17.05 ± 0.71
18.24 ± 0.49
16.52 ± 1.20
11.19 ± 0.60
10.18 ± 0.75
10.76 ± 0.42
28.12 ± 0.84
23.25 ± 0.93
18.53 ± 0.75
16.83 ± 0.48
17.62 ± 0.87
6.25μg/mL) (Ar = 2-nitrophenyl) those have electron-
withdrawing nitro group and electronegative substituents
on the phenyl ring exhibited more potent inhibition against
bacterial strains. On the other hand, methyl and methoxy
substituents exhibited poor antimicrobial activity. It can be
concluded that the nitro group and chloro substituents on the
phenyl ring have strong effect on antibacterial activity [31].
The same library was tested for the antifungal activity
against Candida albicans (ATCC 10231) and Aspergillus
niger (ATCC 9029). In Table 5, compounds 4b (Ar = 2-
chlorophenyl), 4c (Ar = 4-chlorophenyl) and 4h (Ar =
2-nitrophenyl) were exhibited moderate antifungal activity
withtheMIC6.25, 6.25 −12.5and6.25μg/mL, respectively.
The remaining compounds exhibited poor antifungal ability.
g
h
i
j
AA*
BHT#
*
Ascorbic acid
#
Butylated hydroxytoluene
Lower IC50 values indicate better radical scavenging ability
Conclusion
tively. The rest of the compounds exhibited least-to-moderate
antioxidant activity. It is obvious from the screening of
antioxidant activity that the compounds with methyl and
methoxy groups on the phenyl ring were highly favored for
radical scavenging activity.
In summary, we synthesized a novel library of indole–
benzimidazole-based 1,2,3-triazole derivatives under con-
ventionalandmicrowaveirradiationconditions. Themicrowave
irradiation method was proved to be highly efficient as the
reactions completed with high yields in short reaction time.
All the target compounds were tested for antimycobacterial
activity, and compounds 4b, 4h and 4i exhibited signifi-
cant potency. The antioxidant activity screening revealed that
compounds 4e, 4f and 4g were found to be potent radical
scavenging agents. In addition, the antimicrobial activity of
the title compounds demonstrated that compounds 4b, 4c and
4h were more potent against pathogenic bacteria and fungi.
Antimicrobial activity
The series 4a–j was tested for their antibacterial activity
against gram-positive Staphylococcus aureus (ATCC 6538),
Bacillus subtilis (ATCC 6633) and gram-negative Proteus
vulgaris (ATCC 29213), Escherichia coli (ATCC 11229).
Gentamicin was used as standard, and the activity results
Table 5 Antimicrobial activity
Compound
Gram-positive bacteria
Gram-negative bacteria
Fungal strains
(MIC in μg/mL) of newly
B. subtilis
S. aureus
E. coli
P. vulgaris
A. niger
C. albicans
synthesized compounds
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
25
25
50
25
12.5
6.25
12.5
50
25
3.125
6.25
50
6.25
3.125
25
6.25
6.25
25
6.25
6.25
12.5
25
6.25
6.25
12.5
50
25
50
25
50
50
50
50
25
100
50
50
g
h
i
12.5
3.125
50
12.5
3.125
25
25
50
100
6.25
25
3.125
50
6.25
50
6.25
25
j
12.5
1.56
–
12.5
1.56
–
25
12.5
3.125
–
25
50
Gentamicin
Fluconazole
DMSO
1.56
–
–
–
3.125
–
1.56
–
–
–
–
–
1
23

Molecular Diversity
Experimental
General procedure for synthesis of compounds
4a–j)
(
Chemistry
Conventional method
All chemicals and reagents used in this study were obtained
from Sigma-Aldrich and were used as received without fur-
ther purification unless mentioned. A Shimadzu FTIR 8400
S spectrometer was employed to record the IR spectra υ˜ in
To a mixture of compound 3 (1 mmol) and azide (1 mmol)
in DMF/H2O (1:3) (20 mL), CuI (9.5 mg, 0.05 mmol) was
◦
added and heated for 12 h at 80 C. After completion of reac-
tion (as indicated by TLC), the reaction mixture was added to
−1
cm (KBr). Melting points were recorded on Stuart SMP3
melting-point apparatus and are uncorrected. Mass spectra
30 mL of ice-cold water, washed twice with brine. The crude
was extracted with ethyl acetate, concentrated under reduced
pressureandcolumnpurifiedusinghexane/ethylacetate(3:1)
to afford compound 4.
(EI)wererecordedonaFinniganMAT1020massspectrome-
ter, inm/z. ABrukerAvance-400spectrometerwasemployed
1
13
to record the H NMR and C NMR spectra using tetram-
ethylsilane as standard and CDCl3, DMSO-d6 as solvents.
Microwave-assisted synthesis
1
In H NMR spectra, the signals were recorded as singlet (s),
To a mixture of compound 3 (1 mmol) and azide (1 mmol) in
DMF/H2O (1:3) (4 mL), CuI (9.5 mg, 0.05 mmol) was added.
The resulting mixture was capped in a closed vessel and sub-
jected to microwave irradiation at 180 W for 8 min. After
completion of reaction (as indicated by TLC), the reaction
mixture was added to 30 mL of ice-cold water, washed twice
with brine. The crude was extracted with ethyl acetate, con-
centrated under reduced pressure and column purified using
hexane/ethyl acetate (3:1) to afford compound 4.
doublet (d), triplet (t), quartet (q) and multiplet (m). Karlo
Erba 1106 elemental analyzer was used to record the ele-
mental analyses. Silica gel percolated TLC plates of Merck
60 F254 were employed to monitor the reaction progress,
and spots were visualized with UV light. CEM Discover
microwave system was used to carry out microwave irra-
diation experiments. The reaction temperature in microwave
irradiation experiments was monitored using an IR sensor.
2
-(1-((1-Phenyl-1H-1,2,3-triazol-4-yl)methyl)-
H-indol-3-yl)-1H -benzo[d]imidazole (4a)
General procedure for the synthesis of
1
1
-(prop-2-yn-1-yl)-1H-indole-3-carbaldehyde (2)
◦
−1
Pale white solid; m.p.: 120–122 C. IR (KBr, cm ): 3125
To a stirred solution of 1H-indole-3-carbaldehyde (1) (145
mg, 1 mmol) in dry acetone (5mL) in the presence of anhy-
drous K2CO3 (210 mg, 1.5 mmol), propargyl bromide (118
mg, 1mmol)wasaddedandthereactionmixturewasrefluxed
for 4 h. After completion of the reaction, the solvent was
evaporated under vacuum, and the solid residue was puri-
fied by column chromatography using hexane/ethyl acetate
1
(N–H), 1576 (C=N). H-NMR (400 MHz, DMSO-d6) δ:
12.48 (bs, 1H, NH), 8.60 (s, 1H, triazole-H), 8.57 (d, 1H,
J = 7.46 Hz, Ar–H), 8.32 (s, 1H, indole-H), 7.79–7.77 (m,
2H, Ar–H), 7.59 (d, 1H, J = 7.52 Hz, Ar–H), 7.56–7.54 (m,
3H, Ar–H), 7.34–7.28 (m, 3H, Ar–H), 7.15–7.08 (m, 3H, Ar–
13
H), 5.65 (s, 2H, NCH2). C-NMR (100 MHz, DMSO-d6) δ:
ꢀꢀ
ꢀꢀ
ꢀ
1
1
1
51.42 (C-1 ), 146.69 (C-3 ), 143.44 (C–Ar), 136.40 (C-9 ),
31.21 (C-4), 128.49 (C-2 ), 126.84 (C–Ar), 125.41 (C–Ar),
22.54 (C–Ar), 121.32 (C–Ar), 120.67 (C–Ar), 120.35 (C–
(
7:3) as eluent to afford 1-(prop-2-yn-1-yl)-1H-indole-3-
ꢀ
◦
carbaldehyde (2). Yield: 76 %; M.P.: 128 C.
ꢀ
Ar), 112.20 (C-5), 110.19 (C–Ar), 105.47 (C-3 ), 41.72 (C,
NCH2). LC-MS: m/z 390 (M) . Anal. Calc. for C24H18N6:
+
C, 73.83; H, 4.65; N, 21.52. Found: C, 73.86; H, 4.67; N,
General procedure for the synthesis of
21.56.
2
-(1-(prop-2-yn-1-yl)-1H-indol-3-yl)-1H-benzo[d]
imidazole (3)
2
-(1-((1-(2-Chlorophenyl)-1H-1,2,3-triazol-4-
To a well-stirred solution of 1-(Prop-2-yn-1-yl)-1H-indole-
yl)methyl)-1H-indol-3-yl)-1H-benzo[d]imidazole
3-carbaldehyde (2) (183 mg, 1 mmol) in CHCl3 (5 mL), few
(4b)
drops of AcOH and o-Phenylenediamine (108 mg, 1 mmol)
were added and refluxed for 6 h. After completion of reac-
tion (monitored by TLC), the reaction mixture was poured
into ice-cold water, then extracted with ethyl acetate and
dried over Na2SO4 and column purified using hexane/ethyl
◦
−1
Pale white solid; m.p.: 123–125 C. IR (KBr, cm ): 3112
1
(N–H), 1569 (C=N). H-NMR (400 MHz, CDCl3) δ: 10.01
(bs, 1H, NH), 8.25–8.23 (m, 1H, Ar–H), 7.89 (s, 1H,
triazole-H), 7.63 (s, 1H, indole-H), 7.52–7.48 (m, 3H, Ar–
H), 7.45–7.32 (m, 4H, Ar–H), 7.23–7.20 (m, 2H, Ar–H),
acetate (4:1) to afford 2-(1-(prop-2-yn-1-yl)-1H-indol-3-yl)-
◦
13
1
H-benzo[d]imidazole (3). Yield: 84 %; M.P.: 142 C.
7.15–7.12 (m, 2H, Ar–H), 5.29 (s, 2H, NCH2). C-NMR
1
23

Molecular Diversity
ꢀ
ꢀ
ꢀꢀ
(
(
(
100 MHz, CDCl3) δ: 148.39 (C-1 ), 143.09 (C-3 ), 137.67
1H, indole-H), 7.53–7.50 (m, 2H, Ar–H), 7.40–7.38 (d, 1H,
J = 8.28 Hz, Ar–H), 7.36–7.34 (d, 1H, J = 6.52 Hz, Ar–H),
7.20–7.12 (m, 6H, Ar–H), 5.21 (s, 2H, NCH2), 2.34 (s, 3H,
ꢀ
ꢀ
C–Ar), 136.31 (C-9 ), 134.43 (C-4), 130.97 (C-2 ), 130.67
C–Ar), 129.53 (C–Ar), 128.66 (C–Ar), 127.88 (C–Ar),
27.71 (C–Ar), 125.50 (C–Ar), 124.45 (C–Ar), 123.09 (C–
1
CH3). 13C-NMR (100 MHz, DMSO-d6) δ: 148.76 (C-1 ),
ꢀꢀ
ꢀ
ꢀ
ꢀ
Ar), 122.44 (C–Ar), 121.60 (C–Ar), 120.78 (C–Ar), 114.21
143.97 (C-3 ), 139.05 (C–Ar), 138.30 (C-9 ), 136.32 (C-4),
ꢀ
ꢀ
(
C-5), 110.17 (C–Ar), 105.88 (C-3 ), 41.85 (C, NCH2). LC-
134.24 (C-2 ), 130.15 (C–Ar), 129.15 (C–Ar), 125.65 (C–
+
MS: m/z 425 (M+H) . Anal. Calc. for C24H17ClN6: C,
7.84; H, 4.03; N, 19.78. Found: C, 67.87; H, 4.06; N, 19.82.
Ar), 122.29 (C–Ar), 121.53 (C–Ar), 120.98 (C–Ar), 120.38
ꢀ
6
(C-5), 120.25 (C–Ar), 114.38 (C-3 ), 110.10 (C–Ar), 106.44
(
C–Ar), 41.89 (C, NCH2), 21.05 (C, ArCH3). LC-MS: m/z
+
2
-(1-((1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl)
405 (M+H) . Anal. Calc. for C25H20N6: C, 74.24; H, 4.98;
N, 20.78. Found: C, 74.28; H, 5.01; N, 20.81.
methyl)-1H-indol-3-yl)-1H-benzo[d]imidazole (4c)
◦
−1
White solid; m.p.: 140–143 C. IR (KBr, cm ): 3118 (N–
1
H), 1552 (C=N). H-NMR (400 MHz, CDCl3) δ: 8.27–8.25
2
-(1-((1-(2-Methoxyphenyl)-1H-1,2,3-triazol-4-
yl)methyl)-1H-indol-3-yl)-1H-benzo[d]imidazole
4f)
(
d, 1H, J = 8.03 Hz, Ar–H), 7.86 (s, 1H, triazole-H), 7.61
(s, 1H, indole-H), 7.56–7.53 (m, 2H, Ar–H), 7.49–7.47 (d,
(
2
H, J = 8.78 Hz, Ar–H), 7.43–7.41 (d, 2H, J = 7.02 Hz,
Ar–H), 7.38–7.36 (d, 3H, J = 8.78 Hz, Ar–H), 7.20–7.18
m, 2H, Ar–H), 5.31 (s, 2H, NCH2). C-NMR (100 MHz,
◦
−1
White solid. m.p.: 126–128 C. IR (KBr, cm ): 3060 (N–
H), 1580 (C=N). H-NMR (400 MHz, DMSO-d6) δ: 12.55
1
3
(
1
ꢀ
ꢀ
ꢀꢀ
DMSO-d6) δ: 151.43 (C-1 , 145.89 (C-3 ), 144.29 (C–Ar),
1
1
Ar), 121.13 (C–Ar), 112.30 (C-5), 111.18 (C–Ar), 105.54
(
Calc. for C24H17ClN6: C, 67.84; H, 4.03; N, 19.78. Found:
C, 67.88; H, 4.06; N, 19.81.
(
bs, 1H, NH), 8.62 (s, 1H, triazole-H), 8.56–8.54 (d, 1H,
J = 7.52 Hz, Ar–H), 8.29 (s, 1H, indole-H), 7.81–7.79 (d,
H, J = 8.03 Hz, Ar–H), 7.62–7.60 (d, 1H, J = 7.52 Hz,
Ar–H), 7.55–7.49 (m, 3H, Ar–H), 7.30–7.23 (m, 3H, Ar–H),
.18–7.10 (m, 3H, Ar–H), 5.68 (s, 2H, NCH2), 3.82 (s, 3H,
ꢀ
ꢀ
36.41 (C-9 ), 132.32 (C-4), 128.25 (C-2 ), 126.27 (C–Ar),
24.75 (C–Ar), 123.61 (C–Ar), 121.90 (C–Ar), 121.07 (C–
1
ꢀ
+
C-3 ), 41.71 (C, NCH2). LC-MS: m/z 425 (M+H) . Anal.
7
1
3
ꢀꢀ
OCH3). C-NMR (100 MHz, DMSO-d6) δ: 151.15 (C-1 ),
ꢀ
ꢀ
ꢀ
148.60 (C-3 ), 142.20 (C–Ar), 135.96 (C-9 ), 130.43 (C-4),
ꢀ
128.61 (C-2 ), 125.34 (C–Ar), 125.31 (C–Ar), 122.11 (C–
2
-(1-((1-(m-Tolyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-
indol-3-yl)-1H-benzo[d]imidazole
4d)
Ar), 121.36 (C–Ar), 120.91 (C–Ar), 120.54 (C–Ar), 120.39
ꢀ
(C–Ar), 112.66 (C-5), 110.37 (C–Ar), 106.11 (C-3 ), 55.77
(
+
(
C, OCH3), 40.60 (C, NCH2). LC-MS: m/z 421 (M+H) .
Anal. Calc. for C H20N6O: C, 71.41; H, 4.79; N, 19.99.
Found: C, 71.45; H, 4.82; N, 20.04.
◦
−1
25
Pale white solid; m.p.: 135–137 C. IR (KBr, cm ): 3122
(
8
1
N–H), 1563 (C=N); H-NMR (400 MHz, CDCl3) δ: 8.23–
.21 (m, 1H, Ar–H), 7.91 (s, 1H, triazole-H), 7.68 (s, 1H,
indole-H), 7.44–7.42 (m, 3H, Ar–H), 7.39 (s, 1H, Ar–H),
.30–7.28 (d, 3H, J = 9.78 Hz, Ar–H), 7.17–7.15 (t, 4H, J
3.26 Hz, J = 9.03 Hz, Ar–H), 5.12 (s, 2H, NCH2), 2.33 (s,
H, CH3). C-NMR (100 MHz, DMSO-d6) δ: 148.17 (C-
), 143.89 (C-3 ), 139.95 (C–Ar), 137.17 (C-9’), 136.48
C-4), 136.23 (C-2 ), 129.92 (C–Ar), 129.67 (C–Ar), 129.45
C–Ar), 125.33 (C–Ar), 123.12 (C–Ar), 122.58 (C–Ar),
21.64 (C-5), 121.00 (C–Ar), 120.74 (C-3 ), 120.60 (C–Ar),
17.45 (C–Ar), 114.10 (C–Ar), 110.15 (C–Ar), 105.31 (C–
Ar), 41.86 (C, NCH2), 21.30 (C, ArCH3). LC-MS: m/z 405
M+H) . Anal. Calc. for C H20N6: C, 74.24; H, 4.98; N,
0.78. Found: C, 74.27; H, 5.02; N, 20.82.
7
2-(1-((1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-
yl)methyl)-1H-indol-3-yl)-1H-benzo[d]imidazole
(4g)
=
1
3
3
ꢀ
ꢀ
ꢀꢀ
1
ꢀ
◦ −1
White solid. m.p.: 129–133 C. IR (KBr, cm ): 3150 (N–
(
1
(
1
H), 1562 (C=N). H-NMR (400 MHz, DMSO-d ) δ: 12.52
6
ꢀ
(bs, 1H, NH), 8.82 (s, 1H, triazole-H), 8.56–8.53 (d, 1H, J
= 7.02 Hz, Ar–H), 8.24 (s, 1H, indole-H), 7.80–7.72 (m, 2H,
Ar–H), 7.62–7.44 (m, 3H, Ar–H), 7.30–7.25 (m, 2H, Ar–H),
1
+
(
2
7.17–7.07 (m, 4H, Ar–H), 5.66 (s, 2H, NCH ), 3.81 (s, 3H,
2
5
1
3
ꢀꢀ
2
OCH ). C-NMR (100 MHz, DMSO-d ) δ: 159.28 (C-1 ),
3
6
ꢀꢀ
ꢀ
1
48.89 (C-3 ), 143.58 (C–Ar), 136.47 (C-9 ), 129.86 (C-4),
128.84 (C-2 ), 128.79 (C–Ar), 125.64 (C–Ar), 122.47 (C–
ꢀ
2
-
-(1-((1-(p -Tolyl)-1H-1,2,3-triazol-4-yl)methyl)-1H
indol-3-yl)-1H-benzo[d]imidazole (4e)
Ar), 121.98 (C–Ar), 121.77 (C–Ar), 121.72 (C–Ar), 120.71
ꢀ
(
C–Ar), 114.83 (C-5), 110.58 (C–Ar), 106.46 (C-3 ), 55.52
◦
−1
+
White solid. m.p.: 121–124 C. IR (KBr, cm ): 3118 (N–
H), 1554 (C=N). H-NMR (400 MHz, CDCl3) δ: 8.27–8.25
(C, OCH3), 41.00 (C, NCH2). LC-MS: m/z 421 (M+H) .
1
Anal. Calc. for C H20N6O: C, 71.41; H, 4.79; N, 19.99.
25
(d, 1H, J = 8.03 Hz, Ar–H), 7.86 (s, 1H, triazole-H), 7.59 (s,
Found: C, 71.44; H, 4.83; N, 20.03.
1
23

Molecular Diversity
2
-(1-((1-(2-Nitrophenyl)-1H-1,2,3-triazol-4-
for C H20N6: C, 74.24; H, 4.98; N, 20.78. Found: C, 74.27;
H, 5.01; N, 20.82.
2
5
yl)methyl)-1H-indol-3-yl)-1H-benzo[d]imidazole (4h)
◦
−1
Pale white solid. m.p.: 122–125 C. IR (KBr, cm ): 3124
(
8
1
N–H), 1562 (C=N). H-NMR (400 MHz, DMSO-d6) δ:
.15–8.13 (d, 1H, J = 8.03 Hz, Ar–H), 8.03–8.01 (d, 1H,
J = 7.52 Hz, Ar–H), 7.90 (s, 1H, triazole-H), 7.75–7.64 (m,
H, Ar–H), 7.54–7.48 (m, 4H, Ar–H), 7.20–7.14 (m, 4H, Ar–
H), 7.18–7.14, 5.33 (s, 2H, NCH2). C-NMR (100 MHz,
DMSO-d6) δ: 151.81 (C-1 ), 147.29 (C-3 ), 144.43 (C–Ar),
Biological assays
Antitubercular activity
3
1
3
The drug susceptibility and evaluation of MIC of the title
compounds against M. tuberculosis H37Rv were performed
using the resazurin microtiter assay (REMA) protocol [32].
The synthesized compounds were screened against M. tuber-
culosis H37Rv using serial dilution technique in Middle-
brook 7H9 broth medium. Rifampicin and isoniazid were
used as standard drugs. Each compound (2 mg) was dissolved
in 1 mL of DMSO. The serial dilution of each compound was
prepared using 96-well microtiter plate, and 100 mL of MTB
cell suspension in nutrient media was added to each well.
After 7 days of incubation, resazurin dye solution (0.02%
w/v dissolved in distilled water) was added to each well and
again incubated for 1 day. The MIC was determined by the
minimumconcentrationofcompoundthatinhibitsthegrowth
of MTB that is indicated by a color change from nonfluores-
cent blue to fluorescent pink color. The MIC values were
calculated by visual inspection for each well showing more
than 90% inhibition.
ꢀꢀ
ꢀꢀ
ꢀ
ꢀ
1
1
36.34 (C-9 ), 132.01 (C-4), 128.44 (C–Ar), 126.74 (C-2 ),
26.27 (C–Ar), 123.74 (C–Ar), 121.4 (C–Ar), 121.05 (C–
Ar), 120.74 (C–Ar), 112.26 (C-5), 110.64 (C–Ar), 105.88
ꢀ
+
(
C-3 ), 41.95 (C, NCH2). LC-MS: m/z 436 (M+H) . Anal.
Calc. for C24H17N7O2: C, 66.20; H, 3.94; N, 22.52. Found:
C, 66.23; H, 3.97; N, 22.56.
2
-(1-((1-(3-(Trifluoromethyl)phenyl)-1H-1,2,3-
triazol-4-yl)methyl)-1H-indol-3-yl)-1H-
benzo[d]imidazole (4i)
◦
−1
Pale white solid. m.p.: 128–130 C. IR (KBr, cm ): 3112
(
1
N–H), 1552 (C=N). H-NMR (400 MHz, DMSO-d6) δ:
12.28 (bs, 1H, NH), 8.52 (s, 1H, triazole-H), 8.42–8.40 (d,
1H, J = 7.62 Hz, Ar–H), 8.31 (s, 1H, indole-H), 7.81–7.77
(m, 2H, Ar–H), 7.58 (s, 1H, Ar–H), 7.56–7.54 (m, 3H, Ar–
H), 7.30–7.26 (m, 2H, Ar–H), 7.19–7.15 (m, 3H, Ar–H),
1
3
5
1
9
.36 (s, 2H, NCH2). C-NMR (100 MHz, DMSO-d6) δ:
Antioxidant activity
ꢀꢀ
ꢀꢀ
52.24 (C-1 ), 146.48 (C-3 ), 144.72 (C–Ar), 136.09 (C-
), 131.17 (C-4), 127.81 (C–Ar), 126.44 (C-2 ), 125.62
ꢀ
ꢀ
DPPH radical scavenging activity
(
1
4
C–Ar), 123.20 (C–Ar), 121.49 (C, CF3), 121.08 (C–Ar),
ꢀ
20.77 (C–Ar), 112.45 (C-5), 111.24 (C–Ar), 105.76 (C-3 ),
The radical scavenging potency of the compounds was tested
from the bleaching of the purple colored methanol solution of
DPPH [33]. To 4 mL of methanol solution of DPPH (0.004%
+
1.59 (C, NCH2). LC-MS: m/z 459 (M+H) . Anal. Calc. for
C H17F3N6: C, 65.50; H, 3.74; N, 18.33. Found: C, 65.53;
H, 3.77; N, 18.37.
2
5
(w/v)), 1 mL of 5, 10, 25, 50 and 100 μg/mL concentrations
of the test compounds in methanol was added. This mixture
was incubated for 30 min at room temperature, and later
the absorbance was recorded against blank at 517 nm. The
resultwasmeasuredasthepercentofinhibitionoffreeradical
production from DPPH and was calculated by the following
equation.
2
-(1-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)-1H-
indol-3-yl)-1H-benzo[d]imidazole (4j)
◦
−1
Pale white solid. m.p.: 131–134 C. IR (KBr, cm ): 3118
1
(N–H), 1564 (C=N). H-NMR (400 MHz, DMSO-d6) δ:
12.35 (bs, 1H, NH), 8.62 (s, 1H, triazole-H), 8.54–8.52 (d,
1
H, J = 7.56 Hz, Ar–H), 8.30 (s, 1H, indole-H), 7.76–7.74
%of scavenging = [(A control − A sample)/A control] × 100
(
7
(
m, 2H, Ar–H), 7.62–7.60 (d, 1H, J = 7.42 Hz, Ar–H), 7.52–
.48 (m, 3H, Ar–H), 7.36–7.31 (m, 3H, Ar–H), 7.12–7.07
m, 3H, Ar–H), 5.31 (s, 2H, NCH2), 5.26 (s, 2H, Ph −
CH2). C-NMR (100 MHz, DMSO-d6) δ: 152.60 (C-1 ),
where A control is the absorbance of the control reaction and
A sample is the absorbance of the test compound. Tests were
performed in triplicate.
1
3
ꢀꢀ
ꢀꢀ
145.39 (C-3 ), 143.34 (C–Ar), 135.77 (C-9’), 131.56 (C-4),
ꢀ
127.20 (C–Ar), 126.44 (C-2 ), 125.14 (C–Ar), 122.69 (C–
Hydrogen peroxide (H O ) scavenging activity
2 2
Ar), 121.57 (C–Ar), 120.43 (C–Ar), 120.01 (C–Ar), 112.37
ꢀ
(C-5), 110.56 (C–Ar), 105.77 (C-3 ), 52.71 (C, PhCH2),
Various concentrations of the test compounds (5, 10, 25, 50
and 100 μg/mL) were prepared in phosphate buffer. A solu-
+
41.35 (C, NCH2). LC-MS: m/z 405 (M+H) . Anal. Calc.
1
23

Molecular Diversity
tion of H2O2 (40 mM) was prepared in phosphate buffer
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absorbance value of the resulting mixture was recorded at
230 nm. The percent of inhibition of free radical production
from H2O2 was calculated using the above equation.
6
. Aldawsari FS, Aguiar RP, Wiirzler LA, Aguayo-Ortiz R, Aljuhani
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sterile cork borer, 6-mm-depth wells were made into each
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for fungi. After incubation, the diameter of the zone of inhi-
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manner of their concentration. All the tubes were incubated
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◦
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◦
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Acknowledgements The authors are thankful to the Head, Department
of Chemistry, Osmania University, for providing laboratory facilities
and CFRD, OU, for providing spectral analysis. Srinivas Gundu is
thankfultotheCouncilofScientificandIndustrialResearch, NewDelhi,
for the award of the senior research fellowship.
1
1
Compliance with ethical standards
Conflict of interest The authors confirm that this article content has no
conflict of interest.
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