Ultrasound-assisted, one-pot, three-component synthesis and antibacterial activities of novel indole derivatives containing 1,3,4-oxadiazole and 1,2,4-triazole moieties

Article abstract of DOI:10.1016/j.crci.2015.09.005

Thirteen novel indole derivatives were efficiently synthesized through ultrasound irradiation by using 4-amino-5-(1H-indol-3-yl)-4H-[1,2,4]triazole-3-thiol (8) and 2-mercapto-5-substituted-1,3,4-oxadiazoles (5a-m). Compared with conventional and microwave methods, yields increased to 82-93%, and reaction times decreased to 15-35 min. The structures of these novel compounds were characterized by spectral data and elemental analysis. Two out of the synthesized compounds (10f and 10l) exhibited excellent activity against Staphylococcus aureus and Escherichia coli, and thus warrant further research.

Full text of DOI:10.1016/j.crci.2015.09.005

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CRAS2C-4141; No. of Pages 8
C. R. Chimie xxx (2015) xxx–xxx
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Comptes Rendus Chimie
www.sciencedirect.com
Full paper/M e´ moire
Ultrasound-assisted, one-pot, three-component synthesis and
antibacterial activities of novel indole derivatives containing
1,3,4-oxadiazole and 1,2,4-triazole moieties
Zhichuan Shi *, Zhigang Zhao *, Meiwei Huang, Xiaolin Fu
College of Chemistry and Environmental Protection Engineering, Southwest University for Nationalities, 610041 Chengdu, PR China
A R T I C L E I N F O
A B S T R A C T
Article history:
Thirteen novel indole derivatives were efficiently synthesized through ultrasound
irradiation by using 4-amino-5-(1H-indol-3-yl)-4H-[1,2,4]triazole-3-thiol (8) and 2-
mercapto-5-substituted-1,3,4-oxadiazoles (5a–m). Compared with conventional and
microwave methods, yields increased to 82–93%, and reaction times decreased to
Received 13 July 2015
Accepted after revision 10 September 2015
Available online xxx
15–35 min. The structures of these novel compounds were characterized by spectral data
Keywords:
and elemental analysis. Two out of the synthesized compounds (10f and 10l) exhibited
excellent activity against Staphylococcus aureus and Escherichia coli, and thus warrant
further research.
1
1
,3,4-oxadiazole
,2,4-triazole
Indole
ß 2015 Acad e´ mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Antibacterial activity
Ultrasound irradiation
1
. Introduction
Heterocyclic compounds are well-known pharmaceu-
Indoles exhibit relatively low toxicity, high biocompat-
ibility, and several pharmacological activities [10,11]. Sev-
eral 3-substituted indole derivatives have been used as
materials for agrochemicals and pharmaceuticals [12–
14]. Furthermore, compounds containing 1,3,4-oxadiazole
or 1,2,4-triazole rings have been found in many natural
products, and have thus become the focus of intense
research in recent years on account of their pharmacologi-
cal activities [15]. Indole unit modification has been widely
reported, with a few studies about indole derivatives
containing both 1,3,4-oxadiazole and 1,2,4-triazole moie-
ties. According to the pharmacodynamic principle of
superposition, 3-substituted indole derivatives containing
both 1,3,4-oxadiazole and 1,2,4-triazole groups potentially
exhibit effective antibacterial activity.
Green chemistry has been a major inspiration for
organic chemists to develop environment-friendly
methods for the synthesis of organic compounds with
biological value. In recent years, ultrasound irradiation has
been utilized to accelerate a number of synthetically useful
reactions [16]. Ultrasonic synthesis is a well-established
tically active products, and the development of simple and
efficient methods of synthesis of compounds incorporating
heterocyclic rings has given a new dimension to drug
discovery [1]. 1,2,4-triazole and 1,3,4-oxadiazole are
important five-membered heterocyclic compounds, which
are of great research interest because of their distinct
structures with potential applications in synthetic and
medicinal chemistry. Heterocyclic compounds containing
1
,2,4-triazole and 1,3,4-oxadiazole nuclei have been tested
for a wide spectrum of biological activities, including
antimicrobial, antitubercular, antiviral, analgesic, antican-
cer [2–7], and other biological properties, such as
genotoxicity and lipid peroxidation [8,9].
*
Corresponding authors.
E-mail addresses: szc169@163.com (Z. Shi), zzg63129@163.com
(Z. Zhao).
http://dx.doi.org/10.1016/j.crci.2015.09.005
631-0748/ß 2015 Acad e´ mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
1
Please cite this article in press as: Shi Z, et al. Ultrasound-assisted, one-pot, three-component synthesis and
antibacterial activities of novel indole derivatives containing 1,3,4-oxadiazole and 1,2,4-triazole moieties. C. R. Chimie
(2015), http://dx.doi.org/10.1016/j.crci.2015.09.005

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Z. Shi et al. / C. R. Chimie xxx (2015) xxx–xxx
N
R1
SH
N
N
N
S
N
N
N
S
O
N
NH2
N
SH
Br
N
O
K2CO3
NH2
+
+
))))
N
H
Br
R1
N
H
8
5a-m
9
10a-m
R1
10d
4-CH3
10e
10j 4-Br
1
0c 3-CH3
2-OCH3
=
10a
H
10b 2-CH3
1
0f 4-OCH3
0k 2,4-CH3
10f 2-OCH2CH3
10l 4-NH2
10h 4-F
10m NA
10i 4-Cl
1
Scheme 1. Synthesis protocol of title compounds 10a–m.
technique in green chemistry that has many advantages
compared with the conventional methods, such as
enhancement of reactions rates and yield as well as
modification of the reaction pathway, greater selectivity,
simplicity of operation, and energy-saving protocols. This
approach led to the development of a simple purification
procedure that also fulfils the concept of green chemistry
2. Results and discussion
We compared the synthesis of 10a–m using ultrasound
irradiation, microwave method, and conventional method
to study the advantages of the ultrasonic-enhanced
reaction. Compared with conventional thermal heating,
ultrasonic irradiation decreased the reaction time from
540–900 min to 15–35 min and increased the yields from
40–68% to 82–93% (Table 1). Compared with the micro-
wave method, ultrasonic irradiation increased the yields
from 62–86% to 82–93%, and both methods required
almost the same reaction time. Thus, ultrasonic irradiation
allows a rapid, environment-friendly, and efficient organic
synthesis methodology.
[
17,18].
Our research group has previously reported micro-
wave-assisted synthesis of novel Schiff bases derived
from 4-amino-3-[3-(1-benzyl)indole]-5-thiomethyl-1,2,4-
triazole [19]. A number of these compounds showed strong
antibacterial activity. As a further development of our
green agenda [20,21], we report an efficient, high yield,
and environment-friendly ultrasound synthesis of novel
indole derivatives containing 1,3,4-oxadiazole and 1,2,
Assignment of the selected characteristic infrared (IR)
bands of the positions of indole derivatives (10a–m)
revealed valuable information about the structure of the
compounds. All the compounds exhibited a characteristic
4
-triazole moieties (Scheme 1), as well as an evaluation of
the antibacterial activities of these compounds against
four pathogenic strains, namely, Escherichia coli (ATCC
À1
strong absorption in the 3208–3452 cm region from the
3
5218), Bacillus subtilis (ATCC 6633), Pseudomonas
aeruginosa (ATCC 27853), and Staphyloccocus aureus
ATCC 6538).
v(N–H) stretching vibration. The IR spectra showed
absorption bands characteristic of C5N stretching in the
À1
(
1603–1625 cm region. Intense absorption bands in the
Table 1
Comparison of synthesis of 10a–m using ultrasound irradiation, microwave method, and conventional method.
1
Compd.
R
Conventional method
Ultrasound method
Microwave method
t (min)
Yield (%)
t (min)
Yield (%)
t (min)
Yield (%)
1
1
1
1
1
1
1
1
1
1
1
1
1
0a
0b
0c
0d
0e
0f
H
600
780
720
660
720
540
600
840
840
840
720
900
780
56
47
53
62
54
68
57
39
47
42
51
40
42
20
25
30
15
20
15
20
30
30
30
20
35
30
83
82
87
92
86
93
86
82
88
86
85
86
82
15
18
20
12
15
10
16
20
20
20
15
22
20
72
69
72
80
77
86
75
68
74
62
79
72
68
2-CH
3-CH
4-CH
3
3
3
2-OCH
4-OCH
2-OCH
4-F
3
3
2
0g
0h
0i
CH
3
4-Cl
0j
4-Br
0k
0l
3,5-CH
3
4-NH
2
a
0m
NA
a
Naphthalene.
Please cite this article in press as: Shi Z, et al. Ultrasound-assisted, one-pot, three-component synthesis and
antibacterial activities of novel indole derivatives containing 1,3,4-oxadiazole and 1,2,4-triazole moieties. C. R. Chimie
(2015), http://dx.doi.org/10.1016/j.crci.2015.09.005

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3
Table 2
Antibacterial activities of 10a-m: Zone of inhibition.
a,b
Compounds
Zone of inhibition (mm)
B. subtilis
S. aureus
E. coli
P. aeruginosa
1
1
1
1
1
1
1
1
1
1
1
1
1
0a
0b
0c
0d
0e
0f
–
11.3 Æ 0.3
–
12.1 Æ 0.2
–
–
–
–
–
11.5 Æ 0.4
20.3 Æ 0.3
15.2 Æ 0.2
23.8 Æ 0.3
11.8 Æ 0.2
15.6 Æ 0.3
12.0 Æ 0.3
–
15.6 Æ 0.2
21.8 Æ 0.1
15.8 Æ 0.3
23.2 Æ 0.2
–
–
–
16.3 Æ 0.3
–
–
18.7 Æ 0.3
18.0 Æ 0.3
0g
0h
0i
–
20.3 Æ 0.4
15.3 Æ 0.4
12.6 Æ 0.2
–
–
–
–
0j
–
–
0k
0l
–
–
15.1 Æ 0.2
21.1 Æ 0.2
15.6 Æ 0.2
22.9 Æ 0.4
25.3 Æ 0.5
–
15.9 Æ 0.2
21.5 Æ 0.2
–
20.9 Æ 0.2
25.3 Æ 0.3
11.2 Æ 0.4
23.5 Æ 0.3
29.6 Æ 0.5
–
0m
–
Amoxicillin
Ciprofloxacin
DMSO
25.9 Æ 0.4
30.0 Æ 0.3
–
23.5 Æ 0.2
31.4 Æ 0.4
–
a
Zone of inhibitions less than 10 mm are not shown in the table.
b
Reference and compounds (40
mg/mL).
À1
1
162–1250, 942–1081, and 699–750 cm regions were
against S. aureus than the standard reference drug
attributed to the (C–S), (N–N) and (C–S) stretching
v
v
v
(amoxicillin). The minimum inhibitory concentration
vibrations, respectively. Further evidence of indole deri-
(MIC) values ranged from 2–8
mg/mL (10l and 10f) and
vatives was obtained from the proton nuclear magnetic
16 g/mL (10d). Most of compounds showed poor activity
m
1
resonance ( H NMR) spectra. The peaks between
d
11.62–
against Gram-positive B. subtilis. Table 3 shows that the
methoxy derivative 10f and amino-containing 10l were
effective at inhibiting Gram-positive S. aureus and E. coli.
Determination of MIC and half-maximal inhibitory
concentration (IC50) of the active compounds suggested
that amino-containing derivative 10l showed maximum
activity against most of the strains tested, with MIC of
1
1.79 ppm could be assigned to the protons of the indole–
NH. Moreover, NH protons resonated between 5.92–
.19 ppm as a singlet integrating two protons. In addition,
the two triplet peaks at 3.58–3.94 ppm and 3.71–4.76 ppm
were attributed to the S–CH group. The aromatic protons
2
d
6
2
appeared at their usual values. The mass spectra showed
the expected high-intensity molecular peaks.
8
m
g/mL for E. coli, 8
P. aeruginosa and 2
demonstrated notable activity against S. aureus, with MIC
values at 2 g/mL and IC50 at 1.2 g/mL, showing its
m
g/mL for B. subtilis, 16
mg/mL for
The preliminary results of the antibacterial assays
indicated that some of the compounds exhibited moderate
to good activity against E. coli and S. aureus. As shown in
Table 2, 10b and 10j did not exhibit potent inhibition
activity against any of the bacterial strains tested. Notably,
mg/mL for S. aureus. Compound 10l
m
m
potential as a drug against S. aureus. The importance of this
study lies in the possibility that the new compounds might
be more effective against bacteria. A thorough investiga-
tion of the structure–activity relationship, toxicity, and
1
0d was effective in inhibiting Gram-positive bacteria
S. aureus, and 10l and 10f were significantly more active
Table 3
Antibacterial activities of 10a–m: minimum inhibitory concentration (MIC) and half-maximal inhibitory concentration (IC50).
Compounds
B. subtilis
S. aureus
E. coli
P. aeruginosa
MIC
IC50
MIC
IC50
MIC
IC50
MIC
IC50
1
1
1
1
1
1
1
1
1
1
1
1
1
0a
0b
0c
0d
0e
0f
>128
>128
>128
128
>64
>64
>64
>64
>64
18.5
>64
8.5
64
44.5
>64
32.3
8.5
64
35.5
>64
17.9
8.3
>128
>128
128
64
>64
>64
>64
33.8
>64
17.2
>64
>64
>64
>64
33.6
8.2
>128
64
>128
32
16
16
>128
32
32
16.9
4.6
32
16.4
4.5
>128
32
8
8
0g
0h
0i
128
64
44.5
16.4
35.8
>64
>64
1.2
128
32
>64
16.3
32.1
>64
16.4
4.7
128
128
>128
>128
64
16
32
>128
>128
>128
8
>64
>64
>64
4.9
64
64
0j
>128
128
2
>128
64
0k
0l
8
16
0m
>128
2
>64
1
64
45.8
6.4
32
16.1
7.3
>128
4
>64
2.5
Amoxicillin
16
16
Ciprofloxacin
0.128
0.1
3.12
1.82
0.25
0.18
0.5
0.41
MIC and IC50 are given in
mg/mL
Please cite this article in press as: Shi Z, et al. Ultrasound-assisted, one-pot, three-component synthesis and
antibacterial activities of novel indole derivatives containing 1,3,4-oxadiazole and 1,2,4-triazole moieties. C. R. Chimie
(2015), http://dx.doi.org/10.1016/j.crci.2015.09.005

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1
13
biological effects of the novel compounds may facilitate
the design of more potent antibacterial agents for
therapeutic use.
(400 MHz for H and 100 MHz for C) spectrometer at
room temperature using DMSO-d as a solvent and TMS as
the internal standard. IR spectra were recorded on a
700 PerkinElmer FTIR spectrometer on KBr disks. Mass
6
1
3
. Conclusion
spectra were obtained on a Finnigan LCQ-DECA instru-
ment. Elemental analyses (C, H, and N) were performed
with an Elementar vario MICRO cube auto analyzer, and
the results agreed with the calculated values. All the
experiments were monitored by thin-layer chromatogra-
phy (TLC) on pre-coated silica gel plates. All reactions were
performed in a commercial ultrasound and microwave
combination apparatus (XH-300UL, ultrasound 25 kHz
frequency 0–1,500 W, microwave 0–1,000 W 2,450 MHz,
Beijing Xianghu Science and Technology Development Co.
LTD, Beijing, China). Hydrazide (3) [22], 2-mercapto-5-
substituted-1,3,4-oxadiazoles (5a-m) [23], indole 3-car-
boxylic acid hydrazide (7) [24], and 4-amino-5-(1H-indol-
3-yl)-4H-[1,2,4]triazole-3-thiol (8) [19] were prepared
according to previously reported methods (Scheme 2).
The melting points of 2-mercapto-5-substituted-1,3,4-
oxadiazole 5a–m are shown in Table 4.
An ultrasonic-assisted synthesis method was devel-
oped for the preparation of novel indole derivatives
containing 1,3,4-oxadiazole and 1,2,4-triazole moieties.
Compared with the conventional and microwave methods,
the present method has many advantages such as shorter
reaction times, high yields, and compliance with green
chemistry. Compound 10l exhibited promising antibacte-
rial activity against S. aureus similar to that of the standard
drugs amoxicillin and ciprofloxacin, indicating that this
compound is a promising antibacterial compound for
further research. Compounds 10f and 10l exhibited
potency against Gram-positive E. coli similar to that of
amoxicillin; thus, these compounds are almost comparable
to amoxicillin, indicating that they are potentially impor-
tant pharmacophores for the design of novel antibacterial
agents. Studies to establish their in vitro efficacy and safety
are recommended for further development.
4.2. Compound 8
4
. Experimental
4-amino-5-(1H-indol-3-yl)-4H-[1,2,4]triazole-3-thi-
1
ol: brown solid, yield 80%, mp 258–259 8C (ethanol).
NMR (400 MHz, DMSO-d ): 5.90 (s, 2H, NH
t, J = 7.2 and 8.0 Hz, 1H, Indol–H), 7.28 (t, J = 6.8 and 8.0 Hz,
H
4.1. Apparatus, materials and analysis
6
d
H
2
), 7.22
(
All chemicals were obtained from commercial sup-
1H, Indol–H), 7.56 (d, J = 8.0 Hz, 1H, Indol–H), 8.16 (d,
J = 7.6 Hz, 1H, Indol–H), 8.47 (d, J = 2.8 Hz, 1H, Indol–H),
pliers, and the solvents were purified before use. The
melting points were obtained on a micro-melting point
system with an uncorrected thermometer. The NMR
spectra were measured on an Agilent-NMR-VNMRS400
1
3
11.80 (s, 1H, NH), 13.73 (s, 1H, SH). C NMR (100 MHz,
DMSO-d ): 100.97, 112.45, 120.98, 121.21, 122.88,
125.13, 128.33, 136.14, 147.62, 165.62.
6
d
C
Scheme 2. Synthesis protocol of 5a–m and 8.
Please cite this article in press as: Shi Z, et al. Ultrasound-assisted, one-pot, three-component synthesis and
antibacterial activities of novel indole derivatives containing 1,3,4-oxadiazole and 1,2,4-triazole moieties. C. R. Chimie
(2015), http://dx.doi.org/10.1016/j.crci.2015.09.005

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5
Table 4
Melting points of 2-mercapto-5-substituted-1,3,4-oxadiazoles.
1
Product Formula
R
Melting point
8C)
Literature melting
(
point (8C)
5
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
C
C
C
C
C
C
C
C
C
C
C
C
C
8
9
9
9
9
9
H
H
H
H
H
H
6
8
8
8
8
N
N
N
N
N
N
2
2
2
2
2
2
OS
OS
OS
OS
H
217–218
164–165
205–206
150–151
212–213
203–204
195–196
157–158
174–175
205–206
237–238
240–241
215–216
218 [23]
2-CH
3-CH
4-CH
3
3
3
164–166 [25]
205 [23]
150 [23]
O
O
2
S
S
2-OCH
4-OCH
2-OCH
4-F
3
3
2
213–215 [26]
204 [23]
8
2
g
h
i
10
8
H
10
N
2
O
2
S
CH
3
195–197 [27]
156–158 [28]
175 [23]
H
5
5
5
FN
2
OS
OS
8
H
ClN
BrN
2
4-Cl
j
8
H
2
OS
OS
4-Br
205 [29]
k
l
10
H
10
N
2
3,5-CH
3
237–240 [25]
239–240 [29]
215–216 [30]
8
H
7
N
3
OS
OS
4-NH
2
a
m
12
H
8
N
2
NA
a
Naphthalene.
4.3. Ultrasound irradiation for the preparation of 10a–m
6.4 Hz, 2H, CH
2 2
), 6.09 (s, 2H, NH ), 7.11 (t, J = 7.6 and 7.2 Hz,
1H, Indol–H), 7.17 (t, J = 7.6 and 7.2 Hz, 1H, Indol–H),
4
-Amino-5-(1H-indol-3-yl)-4H-[1,2,4]triazole-3-thiol (8)
0.1 mmol), 1,2-dibromoethane (9) (0.1 mmol), the 2-mer-
capto-5-substituted-1,3,4-oxadiazoles (5a–m) (0.1 mmol),
CO (0.2 mmol), and acetonitrile (10 mL) were placed in a
5-mL round-bottom flask. The mixture was sonicated
25 kHz, constant frequency) at 30 8C for 15–35 min.
7.34–7.41 (m, 2H, ArH), 7.45 (d, J = 7.6 Hz, 2H, ArH), 7.91 (d,
J = 8.0 Hz, 1H, Indol–H), 8.21 (d, J = 8.4 Hz, 1H, Indol–H),
(
1
3
8.24 (d, J = 2.0 Hz, 1H, Indol–H), 11.62 (s, 1H, NH). C NMR
(100 MHz, DMSO-d ): 21.90, 31.36, 32.57, 102.08,
K
2
(
2
3
6
d
C
112.10, 121.76, 120.58, 122.61, 122.67, 125.78, 126.14,
126.95, 129.24, 131.85, 132.11, 136.07, 137.89, 150.86,
+
The progress of the reaction was monitored using TLC.
When the reaction was complete, the precipitation was
filtered, subsequently washed with 5 mL of acetonitrile,
and concentrated in vacuo to get the crude solid products.
The product was recrystallized from ethanol with 82–93%
yields. The physical and spectra data of the compounds
152.37, 163.24, 165.86. ESI–MS m/z (%): 450 ([M+1] , 100).
19 7 2
Anal. calcd. for C21H N OS : C, 56.11; H, 4.26; N,
21.81. Found C, 56.24; H, 4.25; N, 21.78.
4.3.3. Compound 10c
3-(1H-indol-3-yl)-5-[[2-[[5-(3-methylphenyl)-1,3,4-
oxadiazol-2-yl]thio]ethyl]thio]-4H-1,2,4-triazol-4-
1
0a–m are as follows.
amine: white solid, yield 87%, mp 171–172 8C (ethanol). IR
À1
4
.3.1. Compound 10a
-(1H-indol-3-yl)-5-[[2-[(5-phenyl-1,3,4-oxadiazol-
-yl)thio]ethyl]thio]-4H-1,2,4-triazol-4-amine: yellow
(KBr, cm ):
v
3434, 3250, 3155, 2923, 2852, 1623, 1591,
3
1561, 1480, 1413, 1239, 1215, 1178, 1066, 1013, 983, 793,
1
2
755, 717. H NMR (400 MHz, DMSO-d
CH ), 3.87 (t, J = 5.6 and 6.4 Hz, 2H, CH
6.0 Hz, 2H, CH ), 5.92 (s, 2H, NH ), 7.11 (t, J = 7.2 and 7.6 Hz,
6 H
d 2.38 (s, 3H, Ar–
):
solid, yield 83%, mp 113–114 8C (ethanol). IR (KBr,
cm ):
3
2
), 4.70 (t, J = 6.4 and
À1
v
3423, 3041, 2998, 2953, 2925, 2852, 1609,
2
2
1
7
7
559, 1493, 1468, 1411, 1201, 1198, 1078, 1064, 922, 768,
1H, Indol–H), 7.21 (t, J = 7.6 and 7.2 Hz, 1H, Indol-H),
7.42–7.45 (m, 2H, ArH), 7.50 (d, J = 7.6 Hz, 1H, Indol–H),
7.72–7.77 (m, 2H, ArH), 8.12 (d, J = 8.0 Hz, 1H, Indol–H),
1
01. H NMR (400 MHz, DMSO-d
.6 Hz, 2H, CH ), 3.81 (t, J = 6.8 and 7.2 Hz, 2H, CH
), 7.21 (t, J = 7.2 and 7.6 Hz, 1H, Indol–H), 7.27
t, J = 7.6 and 6.8 Hz, 1H, Indol–H), 7.55 (d, J = 8.0 Hz, 2H,
6
):
d
H
3.67 (t, J = 6.4 and
2
2
), 6.19
1
3
(
(
s, 2H, NH
2
8.42 (d, J = 2.4 Hz, 1H, Indol–H), 11.79 (s, 1H, NH). C NMR
(100 MHz, DMSO-d ): 21.22, 30.43, 30.80, 100.36,
6
d
C
ArH), 7.62–7.68 (m, 3H, Indol–H and ArH), 8.09 (d,
J = 7.2 Hz, 1H, ArH), 8.32 (d, J = 9.6 Hz, 1H, Indol–H), 8.24
112.44, 121.02, 121.28, 122.93, 123.33, 123.96, 125.07,
127.11, 128.96, 129.63, 132.99, 136.13, 139.26, 147.10,
163.34, 165.63, 165.93. ESI–MS m/z (%): 450 ([M+1] , 100).
1
3
+
(
s, 1H, Indol–H), 11.72 (s, 1H, NH). C NMR (100 MHz,
DMSO-d ): 31.38, 32.59, 102.10, 112.11, 120.57, 121.76,
22.61, 123.53, 125.79, 126.15, 126.95, 129.81, 132.76,
36.08, 150.88, 152.38, 163.65, 165.71. ESI–MS m/z (%):
6
d
C
19 7 2
Anal. calcd. for C21H N OS : C, 56.11; H, 4.26; N,
1
1
4
21.81. Found C, 56.01; H, 4.25; N, 21.88.
+
36 ([M+1] , 100). Anal. calcd. for C20
H
17
N
7
OS
2
: C, 55.16;
4.3.4. Compound 10d
H, 3.93; N, 22.51. Found C, 55.27; H, 3.92; N, 22.53.
3-(1H-indol-3-yl)-5-[[2-[[5-(4-methylphenyl)-1,3,4-
oxadiazol-2-yl]thio]ethyl]thio]-4H-1,2,4-triazol-4-
4
.3.2. Compound 10b
amine: white solid, yield 92%, mp 247–248 8C (ethanol). IR
À1
3
-(1H-indol-3-yl)-5-[[2-[[5-(2-methylphenyl)-1,3,4-
(KBr, cm ):
v
3352, 3282, 3136, 3052, 2922, 1614, 1587,
oxadiazol-2-yl]thio]ethyl]thio]-4H-1,2,4-triazol-4-
1500, 1245, 1200, 1182, 1145, 1074, 1008, 936, 743, 723.
1
amine: white solid, yield 82%, mp 196–197 8C (ethanol). IR
H NMR (400 MHz, DMSO-d
(t, J = 6.4 and 7.6 Hz, 2H, CH
CH ), 6.11 (s, 2H, NH ), 7.15 (t, J = 6.8 and 7.6 Hz, 1H,
6 H 3
d 2.35 (s, 3H, Ar–CH ), 3.60
):
À1
(
KBr, cm ):
v
3354, 3171, 3112, 3077, 2969, 2927, 1624,
2
), 3.74 (t, J = 8.0 and 6.4 Hz, 2H,
1
6
3
585, 1474, 1454, 1246, 1206, 1142, 1041, 1006, 944, 730,
2
2
1
99. H NMR (400 MHz, DMSO-d
6
):
d
H
2.58 (s, 3H, Ar–CH
), 3.71 (t, J = 7.6 and
3
),
Indol–H), 7.21 (t, J = 7.6 and 6.8 Hz, 1H, Indol–H), 7.36
(d, J = 7.6 Hz, 2H, ArH), 7.49 (d, J = 7.6 Hz, 1H, Indol–H), 7.90
.58 (t, J = 6.0 and 8.0 Hz, 2H, CH
2
Please cite this article in press as: Shi Z, et al. Ultrasound-assisted, one-pot, three-component synthesis and
antibacterial activities of novel indole derivatives containing 1,3,4-oxadiazole and 1,2,4-triazole moieties. C. R. Chimie
(2015), http://dx.doi.org/10.1016/j.crci.2015.09.005

G Model
CRAS2C-4141; No. of Pages 8
6
Z. Shi et al. / C. R. Chimie xxx (2015) xxx–xxx
1
3
(
d, J = 8.0 Hz, 2H, ArH), 8.27 (s, 1H, Indol–H), 8.28 (d,
6 C
11.64 (s, 1H, NH). C NMR (100 MHz, DMSO-d ): d 14.94,
13
J = 2.8 Hz, 1H, Indol–H), 11.65 (s, 1H, NH).
C NMR
31.37, 32.53, 64.63, 102.09, 112.10, 112.62, 114.02, 120.58,
121.14, 121.76, 122.61, 125.79, 126.15, 130.54, 133.93,
(100 MHz, DMSO-d
6
):
C
d 21.54, 31.49, 32.55, 102.13,
1
1
1
C
4
12.10, 120.55, 120.76, 121.80, 122.61, 125.80, 126.15,
136.09, 150.80, 152.38, 157.01, 163.29, 164.65. ESI–MS
+
26.89, 130.35, 136.09, 142.48, 150.84, 152.39, 163.624,
m/z (%): 480 ([M+1] , 100). Anal. calcd. for C22
H
21
N
7
O
2
S
2
:
+
65.78. ESI–MS m/z (%): 900 ([M+1] , 100). Anal. calcd. for
C, 55.10; H, 4.41; N, 20.44. Found C, 55.25; H, 4.40;
N, 20.39.
21
H
19
N
7
2
OS : C, 56.11; H, 4.26; N, 21.81. Found C, 56.25; H,
.27; N, 21.70.
4.3.8. Compound 10 h
4.3.5. Compound 10e
3-(1H-indol-3-yl)-5-[[2-[[5-(4-fluorophenyl)-1,3,4-
3
-(1H-indol-3-yl)-5-[[2-[[5-(2-methoxyphenyl)-
oxadiazol-2-yl]thio]ethyl]thio]-4H-1,2,4-triazol-4-
1
4
,3,4-oxadiazol-2-yl]thio]ethyl]thio]-4H-1,2,4-triazol-
amine: yellow solid, yield 82%, mp 244–245 8C (ethanol).
À1
-amine: white solid, yield 86%, mp 157–158 8C (ethanol).
IR (KBr, cm ):
v
3301, 3193, 3089, 2967, 2914, 1615, 1540,
À1
1
IR (KBr, cm ):
2
9
v
3434, 3353, 3208, 3172, 3107, 3080,
1500, 1487, 1264, 1189, 1081, 1030, 964, 789, 705. H NMR
(400 MHz, DMSO-d ): 3.62 (t, J = 6.4 and 8.0 Hz, 2H,
CH ), 3.75 (t, J = 7.6 and 6.8 Hz, 2H, CH ), 6.12 (s, 2H, NH ),
926, 1624, 1586, 1471, 1268, 1250, 1123, 1044, 1017,
6
d
H
1
24, 745, 700. H NMR (400 MHz, DMSO-d
), 3.73 (t, J = 7.6 and 6.4 Hz, 2H,
), 6.13 (s, 2H, NH ), 7.10–7.23
6
):
d
H
3.62
2
2
2
(
t, J =7.2 and 6.8 Hz, 2H, CH
2
7.15 (t, J = 7.2 and 7.6 Hz, 1H, Indol–H), 7.21 (t, J = 7.6 and
6.8 Hz, 1H, Indol–H), 7.49 (d, J = 8.0 Hz, 1H, Indol–H),
7.56–7.64 (m, 2H, ArH), 8.03 (d, J = 6.8 Hz, 2H, ArH), 8.26 (d,
J = 10.8 Hz, 1H, Indol–H), 8.27 (s, 1H, Indol–H), 11.65 (s, 1H,
CH
2
), 3.89 (s, 3H, Ar–OCH
3
2
(
(
(
m, 3H, Indol–H and ArH), 7.25 (d, J = 8.8 Hz, 1H, ArH), 7.49
d, J = 8.0 Hz, 1H, Indol–H), 7.57–7.62 (m, 1H, ArH), 7.86
d, J = 7.2 Hz, 1H, ArH), 8.26 (d, J = 7.6 Hz, 1H, Indol–H),
1
3
NH).
6 C
C NMR (100 MHz, DMSO-d ): d 31.39, 32.59,
1
3
8
.28 (s, 1H, Indol–H), 11.66 (s, 1H, NH).
C NMR
102.10, 112.10, 120.58, 121.76, 122.61, 123.52, 125.79,
126.15, 126.95, 129.81, 132.37, 136.08, 150.88, 152.38,
(
100 MHz, DMSO-d
6
): 31.30, 32.55, 56.43, 102.08,
d
C
+
1
1
1
12.10, 112.35, 113.06, 120.59, 121.20, 121.76, 122.61,
25.78, 126.16, 130.56, 133.99, 136.08, 150.84, 152.37,
163.65, 165.71. ESI–MS m/z (%): 454 ([M+1] , 100). Anal.
7 2
calcd. for C20H16FN OS : C, 52.97; H, 3.56; N, 21.62. Found
+
57.70, 163.37, 164.45. ESI–MS m/z (%): 466 ([M+1] , 100).
C, 52.85; H, 3.57; N, 21.67.
Anal. calcd. for C21
19 7 2 2
H N O S : C, 54.18; H, 4.11; N,
2
1.06. Found C, 54.02; H, 4.12; N, 21.13.
4.3.9. Compound 10i
3-(1H-indol-3-yl)-5-[[2-[[5-(4-chlorophenyl)-1,3,4-
4.3.6. Compound 10f
oxadiazol-2-yl]thio]ethyl]thio]-4H-1,2,4-triazol-4-
3
-(1H-indol-3-yl)-5-[[2-[[5-(4-methoxyphenyl)-
amine: yellow solid, yield 88%, mp 233–234 8C (ethanol).
À1
1
4
,3,4-oxadiazol-2-yl]thio]ethyl]thio]-4H-1,2,4-triazol-
-amine: white solid, yield 93%, mp 213–214 8C (ethanol).
IR (KBr, cm ):
243, 1246, 1162, 1038, 933, 793, 702. H NMR (400 MHz,
IR (KBr, cm ):
v
3363, 3176, 3071, 3054, 2928, 1605, 1469,
1
1407, 1247, 1198, 1090, 1071, 1009, 842, 747, 722. H NMR
(400 MHz, DMSO-d ): 3.61 (t, J = 6.0 and 8.0 Hz, 2H,
CH ), 3.75 (t, J = 7.6 and 6.8 Hz, 2H, CH ), 6.11 (s, 2H, NH ),
À1
v
3358, 3145, 3092, 2928, 1619, 1588, 1482,
6
d
H
1
1
2
2
2
DMSO-d
J = 6.8 and 8.0 Hz, 2H, CH
6
):
d
H
3.60 (t, J = 8.0 and 6.4 Hz, 2H, CH
), 3.78 (s, 3H, Ar–OCH
2
), 3.74 (t,
), 6.12 (s,
7.15 (t, J = 7.2 and 7.6 Hz, 1H, Indol–H), 7.21 (t, J = 7.6 and
6.8 Hz, 1H, Indol–H), 7.49 (d, J = 7.6 Hz, 1H, Indol–H), 7.63
(d, J = 8.4 Hz, 2H, ArH), 8.05 (d, J = 8.4 Hz, 2H, ArH), 8.25 (d,
J = 8.4 Hz, 1H, Indol–H), 8.26 (s, 1H, Indol–H), 11.65 (s, 1H,
2
3
2
H, NH
2
), 7.08 (d, J = 8.4 Hz, 2H, ArH), 7.15 (t, J = 7.6 and
7
.2 Hz, 1H, Indol–H), 7.21 (t, J = 7.2 and 8.0 Hz, 1H, Indol–
1
3
H), 7.49 (d, J = 8.0 Hz, 1H, Indol–H), 7.94 (d, J = 8.8 Hz, 2H,
ArH), 8.28 (s, 1H, Indol–H), 8.29 (d, J = 3.6 Hz, 1H, Indol–H),
NH).
6 C
C NMR (100 MHz, DMSO-d ): d 31.41, 32.57,
102.08, 112.12, 120.56, 121.73, 122.42, 122.62, 125.77,
126.14, 128.79, 129.96, 136.09, 137.04, 150.91, 152.39,
13
1
3
1
1
6 C
1.65 (s, 1H, NH). C NMR (100 MHz, DMSO-d ): d 31.53,
2.54, 55.83, 102.13, 112.11, 115.22, 115.87, 120.57,
21.78, 122.61, 125.79, 126.17, 128.81, 136.10, 150.88,
+
163.90, 164.94. ESI–MS m/z (%): 471 ([M+1] , 100). Anal.
7 2
calcd. for C20H16ClN OS : C, 51.11; H, 3.43; N, 20.86. Found
52.39, 162.40, 162.79, 165.62. ESI–MS m/z (%): 466
C, 51.22; H, 3.43; N, 20.81.
+
([M+1] , 100). Anal. calcd. for C21
H
19
N
7
O
2
S
2
: C, 54.18; H,
4
.11; N, 21.06. Found C, 54.02; H, 4.11; N, 21.14.
4.3.10. Compound 10j
3-(1H-indol-3-yl)-5-[[2-[[5-(4-bromophenyl)-1,3,4-
4.3.7. Compound 10 g
oxadiazol-2-yl]thio]ethyl]thio]-4H-1,2,4-triazol-4-
3
-(1H-indol-3-yl)-5-[[2-[[5-(2-ethoxyphenyl)-1,3,4-
amine: yellow solid, yield 86%, mp 211–212 8C (ethanol).
À1
oxadiazol-2-yl]thio]ethyl]thio]-4H-1,2,4-triazol-4-
amine: white solid, yield 86%, mp 244–245 8C (ethanol). IR
KBr, cm ): 3332, 3141, 3105, 2976, 2926, 2880, 1603,
IR (KBr, cm ):
v
3352, 3125, 3011, 2976, 1607, 1453, 1406,
1
1252, 1173, 1096, 1012, 962, 847, 743, 708. H NMR
(400 MHz, DMSO-d ): 3.60 (t, J = 6.4 and 8.0 Hz, 2H,
CH ), 3.74 (t, J = 8.0 and 6.4 Hz, 2H, CH ), 6.12 (s, 2H, NH ),
À1
(
1
(
6
d
H
1
585, 1495, 1452, 1245, 1190, 1039, 940, 745, 704. H NMR
400 MHz, DMSO-d ): 1.35 (t, J = 6.8 Hz, 3H, Ar–
), 3.60–3.63 (m, 2H, CH ), 3.70–3.74 (m, 2H,
CH ), 6.11 (s, 2H,
), 7.08–7.18 (m, 2H, Indol–H), 7.22 (t, J = 8.4 and 7.2 Hz,
H, ArH), 7.48 (d, J = 8.0 Hz, 1H, Indol–H), 7.54–7.59 (m, 1H,
2
2
2
6
d
H
7.15 (t, J = 7.2 and 7.6 Hz, 1H, Indol–H), 7.21 (t, J = 7.2 and
6.8 Hz, 1H, Indol–H), 7.49 (d, J = 7.6 Hz, 1H, Indol–H), 7.78
(d, J = 8.4 Hz, 2H, ArH), 7.99 (d, J = 8.4 Hz, 2H, ArH), 8.26 (d,
J = 10.4 Hz, 1H, Indol–H), 8.27 (s, 1H, Indol–H), 11.66 (s, 1H,
OCH
2
CH
3
2
CH
NH
2
), 4.17 (q, J = 6.8 Hz, 2H, Ar–OCH
2
3
2
1
3
2
NH).
6 C
C NMR (400 MHz, DMSO-d ): d 31.39, 32.55,
ArH), 7.86 (dd, J = 2.0 and 1.6 Hz, 1H, ArH), 8.24 (d,
J = 8.0 Hz, 1H, Indol–H), 8.26 (d, J = 2.4 Hz, 1H, Indol–H),
102.08, 112.14, 120.58, 121.74, 122.64, 122.74, 125.77,
125.94, 126.14, 128.91, 132.89, 136.09, 150.94, 152.40,
Please cite this article in press as: Shi Z, et al. Ultrasound-assisted, one-pot, three-component synthesis and
antibacterial activities of novel indole derivatives containing 1,3,4-oxadiazole and 1,2,4-triazole moieties. C. R. Chimie
(2015), http://dx.doi.org/10.1016/j.crci.2015.09.005

G Model
CRAS2C-4141; No. of Pages 8
Z. Shi et al. / C. R. Chimie xxx (2015) xxx–xxx
7
+
1
63.92, 165.05. ESI–MS m/z (%): 516 ([M+2] , 100). Anal.
Anal. calcd. for C24
H
19
N
7
OS
2
: C, 59.36; H, 3.94; N,
calcd. for C20
H
16BrN
7
OS
2
: C, 46.70; H, 3.14; N, 19.06. Found
20.19. Found C, 59.42; H, 3.93; N, 20.22.
C, 46.79; H, 3.14; N, 19.03.
4.4. Conventional procedure for the preparation of
4.3.11. Compound 10k
compounds (10a–m)
3
-(1H-indol-3-yl)-5-[[2-[[5-(3,5-dimethylphenyl)-
1
4
,3,4-oxadiazol-2-yl]thio]ethyl]thio]-4H-1,2,4-triazol-
4-Amino-5-(1H-indol-3-yl)-4H-[1,2,4]triazole-3-thiol (8)
(0.1 mmol), 1,2-dibromoethane (9) (0.1 mmol), the 2-mer-
capto-5-substituted-1,3,4-oxadiazoles (5a–m) (0.1 mmol),
-amine: yellow solid, yield 85%, mp 189–190 8C (etha-
À1
nol). IR (KBr, cm ):
v 3427, 3355, 3113, 2973, 2922, 1625,
1
1
(
(
587, 1471, 1246, 1179, 1026 1007, 940, 744, 724. H NMR
400 MHz, DMSO-d ): 2.31 (s, 6H, Ar–CH ), 3.59
t, J = 6.4 and 6.8 Hz, 2H, CH ), 3.71 (t, J = 7.6 and 6.0 Hz,
H, CH ), 6.09 (s, 2H, NH ), 7.10 (t, J = 7.2 and 7.6 Hz, 1H,
Indol–H), 7.17 (t, J = 7.6 and 8.4 Hz, 1H, Indol–H), 7.19 (s,
2 3
K CO (0.2 mmol), and acetonitrile (10 mL) were placed in a
6
d
H
3
25-mL round-bottom flask. Afterthe mixturewascompletely
dissolved, it was stirred for 540–900 min at 82 8C. The
progress of the reaction was monitored using TLC. When
the reaction was complete, the precipitate was filtered,
subsequently washed with 5 mL of acetonitrile, and
concentrated in vacuo to get the crude solid products.
The products were purified through column chromatog-
raphy using ethyl acetate: petroleum ether (1:3) as an
eluent with 40–68% yield.
2
2
2
2
1
8
H, ArH), 7.45 (d, J = 8.0 Hz, 1H, Indol–H), 7.59 (s, 2H, ArH),
.21 (d, J = 7.6 Hz, 1H, Indol–H), 8.24 (s, 1H, Indol–H), 11.62
13
6 C
(s, 1H, NH). C NMR (100 MHz, DMSO-d d 21.14, 31.36,
):
3
1
1
2.57, 102.10, 112.08, 120.54, 121.76, 122.60, 123.32,
24.45, 125.79, 126.14, 133.81, 136.08, 139.20, 150.88,
+
52.36, 163.44, 165.89. ESI–MS m/z (%): 464 ([M+1] , 100).
Anal. calcd. for C22
H
21
N
7
OS
2
: C, 57.00; H, 4.57; N,
4.5. Microwave procedure for the preparation of compounds
2
1.15. Found C, 57.12; H, 4.58; N, 21.20.
(10a–m)
4
.3.12. Compound 10l
4-Amino-5-(1H-indol-3-yl)-4H-[1,2,4]triazole-3-thiol
(8) (0.1 mmol), 1,2-dibromoethane (9) (0.1 mmol), the 2-
3
-(1H-indol-3-yl)-5-[[2-[[5-(4-aminophenyl)-1,3,4-
oxadiazol-2-yl]thio]ethyl]thio]-4H-1,2,4-triazol-4-
mercapto-5-substituted-1,3,4-oxadiazoles
(5a-m)
amine: brown solid, yield 86%, mp 251–252 8C. IR (KBr,
(0.1 mmol), K CO (0.2 mmol), and acetonitrile (10 mL)
2
3
À1
cm ):
v
3452, 3346, 3215, 3051, 2922, 2854, 1609, 1585,
were placed in a vessel, which was then shaken to
homogenize the mixture. The mixture was then irradiated
in a microwave oven for 10–22 min at 350 W. The progress
of the reaction was monitored using TLC. When the
reaction was complete, the precipitate was filtered,
subsequently washed with 5 mL of acetonitrile, and
concentrated in vacuo to get the crude solid products.
The products were purified through column chromatogra-
phy using ethyl acetate: petroleum ether (1:3) as an eluent
with 62–86% yield.
1
505, 1479, 1454, 1247, 1177, 1107, 1070, 942, 740, 700.
1
H NMR (400 MHz, DMSO-d
H, CH ), 3.69 (t, J = 8.0 and 6.0 Hz, 2H, CH
Ar–NH ), 6.12 (s, 2H, NH ), 6.67 (d, J = 8.4 Hz, 2H, ArH), 7.16
t, J = 7.2 and 8.0 Hz, 1H, Indol–H), 7.21 (t, J = 8.0 and 6.8 Hz,
H, Indol–H), 7.49 (d, J = 7.6 Hz, 1H, Indol–H), 7.66 (d,
J = 8.4 Hz, 2H, ArH), 8.26 (d, J = 8.8 Hz, 1H, Indol–H), 8.27 (s,
6
):
d
H
3.59 (t, J = 6.4 and 7.2 Hz,
2
2
2
), 5.94 (s, 2H,
2
2
(
1
13
1
H, Indol–H), 11.65 (s, 1H, NH). C NMR (100 MHz, DMSO-
d
1
1
6 C
): d 31.41, 32.59, 102.10, 109.81, 112.09, 113.98, 120.62,
21.78, 122.60, 125.80, 126.16, 128.46, 136.08, 150.87,
52.37, 152.79, 161.33, 165.55. ESI–MS m/z (%): 451
4.6. Bioactivity
+
([M+1] , 100). Anal. calcd. for C20
H
18
N
8
OS
2
: C, 53.32; H,
4
.03; N, 24.87. Found C, 53.41; H, 4.02; N, 24.91.
The in vitro antimicrobial activity of the structurally
promising 10a–m against Gram-positive (B. subtilis and S.
aureus) and Gram-negative (E. coli and P. aeruginosa)
bacteria were investigated using disc diffusion and
microdilution assays along with reference drugs amoxicil-
lin and ciprofloxacin for comparison. Dimethylformamide
was used as a negative control.
4.3.13. Compound 10m
3
-(1H-indol-3-yl)-5-[[2-[[5-(naphthalen-1-yl)-1,3,4-
oxadiazol-2-yl]thio]ethyl]thio]-4H-1,2,4-triazol-4-
amine: yellow solid, yield 82%, mp 175–176 8C (ethanol).
IR (KBr, cm ):
À1
v
3418, 3278, 3174, 3056, 2923, 2852, 1624,
1
7
6
2
590, 1538, 1513, 1331, 1291, 1181, 1122, 1067, 963, 773,
1
50. H NMR (400 MHz, DMSO-d
.4 Hz, 2H, CH ), 4.76 (t, J = 6.4 and 6.0 Hz, 2H, CH
H, Ar–NH ), 7.09 (t, J = 7.2 and 7.6 Hz, 1H, Indol–H), 7.20
6
):
d
H
3.94 (t, J = 6.0 and
4.6.1. Disc diffusion assay
2
2
), 5.93 (s,
The compounds were tested for their antibacterial
activities through disc diffusion using a nutrient agar
medium [31,32]. Serial dilutions of the test compounds
were prepared in DMSO to final concentrations of 40, 20,
2
(t, J = 7.2 and 7.6 Hz, 1H, Indol–H), 7.49 (d, J = 8.0 Hz, 1H,
Indol–H), 7.60–7.74 (m, 3H, ArH), 8.08 (d, J = 7.6 Hz, 1H,
ArH), 8.14–8.20 (m, 3H, Indol–H and ArH), 8.41 (d,
J = 2.8 Hz, 1H, Indol–H), 9.03 (d, J = 8.0 Hz, 1H, ArH),
10, 5 and 0
mg/mL. Sterile paper discs (diameter = 6 mm)
were then placed on the nutrient agar medium, and 20
m
L
13
1
3
1
1
1
1.77 (s, 1H, NH). C NMR (100 MHz, DMSO-d
6
):
d
C
of the compounds were added to each disc in five
replications. Then, the paper discs impregnated with the
compounds were placed on the surface of the media
inoculated with the microorganism. The plates were
incubated at 37 8C for 16–18 h (Table 2). The IC50 was
0.87, 47.89, 100.36, 112.43, 119.75, 121.01, 121.28,
22.92, 125.08, 125.69, 125.82, 127.23, 128.61, 128.93,
28.96, 129.28, 129.42, 132.99, 133.80, 136.13, 147.13,
+
63.33, 165.41, 165.99. ESI–MS m/z (%): 486 ([M+1] , 100).
Please cite this article in press as: Shi Z, et al. Ultrasound-assisted, one-pot, three-component synthesis and
antibacterial activities of novel indole derivatives containing 1,3,4-oxadiazole and 1,2,4-triazole moieties. C. R. Chimie
(2015), http://dx.doi.org/10.1016/j.crci.2015.09.005

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Please cite this article in press as: Shi Z, et al. Ultrasound-assisted, one-pot, three-component synthesis and
antibacterial activities of novel indole derivatives containing 1,3,4-oxadiazole and 1,2,4-triazole moieties. C. R. Chimie
(2015), http://dx.doi.org/10.1016/j.crci.2015.09.005