Microwave-assisted synthesis and antibacterial activity of derivatives of 3-[1-(4-fluorobenzyl)-1H-indol-3-yl]-5-(4-fluorobenzylthio)-4H-1,2, 4-triazol-4-amine

Article abstract of DOI:10.2478/s11696-013-0461-2

Herein, an excellent method for the synthesis of twelve novel Schiff base derivatives containing indole and triazole assisted by microwave irradiation is reported. Compared with the conventional method, the yields increased from 59-84 % to 85-96 % and the

Full text of DOI:10.2478/s11696-013-0461-2

Chemical Papers 68 (3) 401–408 (2014)
DOI: 10.2478/s11696-013-0461-2
ORIGINAL PAPER
Microwave-assisted synthesis and antibacterial activity
of derivatives of 3-[1-(4-fluorobenzyl)-1 -indol-3-yl]-
5-(4-fluorobenzylthio)-4 -1,2,4-triazol-4-amine
Yong-Le Peng, Xing-Li Liu, Xiao-Hong Wang, Zhi-Gang Zhao*
College of Chemistry and Environmental Protection Engineering, Southwest University for Nationalities, 610041 Chengdu, China
Received 27 February 2013; Revised 14 June 2013; Accepted 16 June 2013
Herein, an excellent method for the synthesis of twelve novel Schiff base derivatives containing
indole and triazole assisted by microwave irradiation is reported. Compared with the conventional
method, the yields increased from 59–84 % to 85–96 % and the reaction time was reduced from 24–
30 h to 4–8 min. Moreover, all series of the newly synthesized Schiff bases were evaluated for their
antibacterial activity. The values of minimum inhibitory concentration (MIC) and IC50 indicated
that many target compounds possessed excellent antibacterial activity against Escherichia coli,
Staphylococcus aureus, Pseudomonas aeruginosa, and Bacillus subtilis.
c
ꢀ 2013 Institute of Chemistry, Slovak Academy of Sciences
Keywords: microwave synthesis, indole, triazole, Schiff base, antibacterial activity
Introduction
2010), and sulfonamide-1,2,4-triazoles (Zoumpoulakis
et al., 2012) were confirmed to have good antimicro-
bial activity against S. aureus, E. coli, and B. subtilis,
etc.
Due to the universality and resistance of patho-
genic bacteria, the contest between human and patho-
genic bacteria exists along the whole course of hu-
man development (Giske & Cornaglia, 2010). Unfor-
tunately, billions of people are infected by pathogenic
bacteria every year, which brings great pain and loss
to mankind. Therefore, the research of antibacterial
drugs has become an urgent task for our existence.
In recent years, indole has attracted significant
attention because of its good antimicrobial activ-
ity. Many derivatives of indole-2-ones were reported
to possess good antimicrobial activity against Es-
cherichia coli, Staphylococcus aureus, and Bacillus
subtilis, etc. (Reddy et al., 2011; Akhaja & Raval,
2011, 2012). Some derivatives of 1-(1H-indol-3-yl)
ethanamine were found to strongly inhibit the growth
of Staphylococcus strains (Burchak et al., 2011).
1,2,4-Triazole derivatives are reported frequently
for their good antimicrobial activity (Patil et al.,
2010; Pardeshi & Bobade, 2011). Quinoline derivatives
carrying 1,2,4-triazole (Eswaran et al., 2009), 1,2,4-
triazole fused macrocyclic crown compounds (Khalil,
Schiff bases have also received attention owing
to their good antimicrobial activity (da Silva et al.,
2011). Many Schiff bases with good inhibition activity
against both Gram-positive and Gram-negative bac-
terial strains were explored (Bharti et al., 2010; Negm
et al., 2010); e.g. pyrazole based Schiff bases (Singh
et al., 2012) and Schiff bases containing the thiourea
structure (Zhang et al., 2011) were reported to pos-
sess good inhibition activity against E. coli, and B.
subtilis, etc.
From the above facts results that indole, 1,2,4-
triazole and Schiff bases possess good antimicrobial
activity. However, to our knowledge, Schiff bases con-
taining both 1,2,4-triazole and indole have been re-
ported only rarely.
In addition, due to the environmental pollution
and waste of resources, traditional chemical indus-
try processes have also brought serious harm to the
environment (Nadal et al., 2011). To improve chem-
ical processes and reduce environmental pollution
*Corresponding author, e-mail: zzg63129@163.com

402
Y. L. Peng et al./Chemical Papers 68 (3) 401–408 (2014)
Fig. 1. Reagents and conditions: i) K2CO3; ii) NH2NH2 · H2O, microwave irradiation; iii) CS2, KOH, ethanol; iv) NH2NH2
H2O, microwave irradiation; v) K2CO3; vi) ArCHO, AcOH, microwave irradiation.
·
has become an urgent task for chemical researchers.
Microwave-assisted synthesis as a novel green chemical
process shows distinct advantages over the traditional
process, such as energy conservation, short reaction
times, good conversions, and solvent-free mechanism
(Appukkuttan et al., 2009). Further study is required
to broaden its range of application.
Based on the above research information and our
efforts on pharmaceutical synthesis (Zhao et al., 2010;
Shi et al., 2011), a series of novel Schiff bases contain-
ing indole, triazole structures was designed and syn-
thesized under microwave irradiation for the purpose
of broadening the application range of microwave-
assisted synthesis and discovering new antibacterial
compounds. The synthetic route is shown in Fig. 1.
Experimental
General
Melting point was measured on a WRS-1B micro-
melting point apparatus (China) without thermome-
ter correction. Infrared spectra were determined on
a 1700 Perkin–Elmer FTIR (USA) using KBr disks.
1H NMR (400 MHz) and 13C NMR (100 MHz) spec-
tra were taken on a Varian INOVA (USA) spectrom-
eter with TMS as the internal standard, DMSO-d6
or CDCl3 as the solvent. Chemical shift is given in
δ relative to TMS. Mass spectra were obtained at
70 eV on a Finnigan LCQDECA (USA) instrument.
Elemental analyses were carried out on a Carlo Erba-

Y. L. Peng et al./Chemical Papers 68 (3) 401–408 (2014)
403
1106 autoanalyzer (USA). All microwave-assisted re-
actions were run in a commercial microwave reac-
tor (XH-100A, 100–1000 W, Beijing Xianghu Science
and Technology Development, China). Sterilization of
equipment and reagents used in the in vitro antimicro-
bial activity tests was carried out in a portable stain-
less steel pressure steam sterilizer (YX280A, Shanghai
Sanshen Medical Instrument, China). Aseptic opera-
tion was carried out in a super clean bench (DL-CJ-
1N, Donglian Elactronic & Technology Develepment,
China). Bacterial culture was processed in a biological
constant temperature incubator (ECA-9272, Beijing
ECOA Science & Development, China). All solvents
(Beijing Chemical Reagent Factory, China) were pu-
rified before use. Petroleum ether, boiling point range
30–60◦C was used. Intermediates II, III, IV, and V
were prepared by the reported procedure (Farghaly,
2004; Shi et al., 2011).
reaction was completed. Then, the solvent was re-
moved by reduced pressure distillation. The mixture
was purified by silica gel column chromatography us-
ing a mixture of ethyl acetate/petroleum ether (ϕr =
1 : 1; Rf = 0.4) to get pure compound VI.
Conventional method for the preparation of
compounds VIIa–VIIl
Compound VI (0.045 g, 0.1 mmol), aromatic alde-
hyde (0.1 mmol), and acetic acid (100 %, 4 mL)
were placed in a round bottom flask assembled with
a condenser pipe, and heated to reflux for 24–30 h.
The reaction was monitored by TLC (ethyl ac-
etate/petroleum ether; ϕr = 1 : 1) until it was com-
pleted. Acetic acid was removed by reduced pres-
sure distillation and co-evaporated with toluene. The
residue was purified by silica gel column chromatogra-
phy using a mixture of ethyl acetate/petroleum ether
(ϕr = 1 : 1) (Rf = 0.5–0.7) to get pure compounds
VIIa–VIIl.
Synthesis of compound VI
Compound V (2 g, 5.89 mmol), 1-(bromomethyl)-
4-fluorobenzene (1.1 g, 5.89 mmol), K2CO3 (0.81 g,
11.78 mmol), and N,N-dimethylformamide (DMF;
20 mL) were stirred in a 50 mL round bottom
flask at room temperature for 2 h. TLC (ethyl ac-
etate/petroleum ether; ϕr = 1 : 1) indicated that the
Microwave method for the preparation of com-
pounds VIIa–VIIl
Compound VI (0.045 g, 0.1 mmol), aromatic alde-
hyde (0.1 mmol), and one drop of acetic acid (100 %,
Table 1. Characterization data of newly prepared compounds
wi(calc.)/%
wi(found)/%
Yield
M.p.
Compound
Formula
Mr
C
H
N
%
91
85
85
91
89
86
95
87
88
86
87
84
85
◦C
VI
C24H19F2N5S
C31H23F2N5OS
C31H22BrF2N5S
C31H22BrF2N5S
C31H22ClF2N5S
C31H22F3N5S
447.50
551.61
614.51
614.51
570.05
553.60
535.61
565.64
580.61
551.61
570.05
525.57
551.61
64.41
64.44
67.50
67.57
60.59
60.64
60.59
60.66
65.32
65.36
67.26
67.29
69.52
69.59
67.95
67.89
64.13
64.20
67.50
67.58
65.32
65.38
66.27
66.35
67.50
67.57
4.28
4.31
4.20
4.15
3.61
3.65
3.61
3.64
3.89
3.85
4.01
4.08
4.33
4.38
4.45
4.42
3.82
3.84
4.20
4.24
3.89
3.95
4.03
4.09
4.20
4.22
15.65
15.63
12.70
12.56
11.40
11.44
11.40
11.38
12.29
12.33
12.65
12.64
13.08
13.04
12.38
12.42
14.47
14.44
12.70
12.68
12.29
12.23
13.33
13.23
12.70
12.68
173–175
199–201
137–139
132–134
175–177
156–158
147–149
110–112
108–110
210–212
148–150
149–151
234–236
VIIa
VIIb
VIIc
VIId
VIIe
VIIf
VIIg
VIIh
VIIi
VIIj
VIIk
VIIl
C31H23F2N5S
C32H25F2N5OS
C31H22F2N6O2S
C31H23F2N5S
C31H22ClF2N5S
C29H21F2N5OS
C31H23F2N5OS

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Y. L. Peng et al./Chemical Papers 68 (3) 401–408 (2014)
Table 2. Spectral data of newly prepared compounds
Compound
Spectral data
IR, ν˜/cm−1: 1221 (C—S), 1447 (C—N), 1597 (C N), 3353 (NH2)
—
—
VI
1H NMR (CDCl3), δ: 4.24 (s, 2H, ArCH2S), 4.32 (s, 2H, ArCH2N), 5.28 (s, 2H, NH2), 6.94–7.00 (m, 4H, ArH),
7.09–7.10 (m, 2H, ArH), 7.28–7.31 (m, 5H, ArH), 7.97 (s, 1H, ArH), 8.48–8.50 (m, 1H, ArH)
13C NMR (DMSO-d6), δ: 34.8, 49.1, 102.2, 110.9, 111.1, 115.7, 121.0, 122.3, 122.9, 126.4, 129.6, 131.5, 134.3, 134.5,
134.6, 135.9, 151.2, 152.0, 160.6, 160.8, 163.2
ESI–MS, m/z (Ir/%): 448.14 (100) (M + 1)+
IR, ν˜/cm−1: 1226 (C—S), 1438 (C—N), 1575 (C N), 3419 (PhOH)
—
VIIa
—
1H NMR (DMSO-d6), δ: 4.40 (s, 2H, ArCH2S), 5.47 (s, 2H, ArCH2N), 7.06–7.32 (m, 11H, ArH), 7.37–7.40 (m, 3H,
—
ArH), 7.61 (d, 1H, J = 8.0 Hz, ArH), 7.88 (s, 1H, ArH), 8.26 (d, 1H, J = 8.0 Hz, ArH), 8.74 (s, 1H, N CHAr),
—
10.02 (s, 1H, ArOH)
13C NMR (DMSO-d6), δ: 36.9, 49.0, 101.7, 111.0, 111.3, 115.2, 115.7, 115.9, 121.0, 121.5, 122.0, 123.0, 123.3, 126.1,
129.7, 129.9, 130.1, 130.7, 130.9, 131.3, 131.6, 133.3, 133.9, 136.1, 144.4, 148.9, 158.4, 160.8, 163.1, 168.4
ESI–MS, m/z (Ir/%): 552.15 (100) (M + 1)+
—
VIIb
VIIc
VIId
VIIe
VIIf
VIIg
VIIh
IR, ν˜/cm−1: 1226 (C—S), 1428 (C—N), 1590 (C N)
—
1H NMR (CDCl3), δ: 4.46 (s, 2H, ArCH2S), 5.28 (s, 2H, ArCH2N), 6.95–6.97 (m, 4H, ArH), 7.26–7.34 (m, 7H,
—
—
ArH), 7.53 (d, 3H, J = 7.2 Hz, ArH), 7.62 (d, 2H, J = 6.8 Hz, ArH), 8.36 (s, 1H, N CHAr), 8.49–8.51 (m, 1H,
ArH)
13C NMR (DMSO-d6), δ: 37.2, 48.9, 101.6, 111.0, 111.3, 115.7, 115.9, 121.2, 121.5, 122.0, 123.0, 123.3, 126.1, 127.5,
129.8, 130.0, 130.2, 131.2, 131.6, 132.7, 132.9, 133.8, 136.2, 144.3, 149.0, 160.7, 163.1, 166.6, 166.9
ESI–MS, m/z (Ir/%): 616.01 (100) (M + 1)+
IR, ν˜/cm−1: 1229 (C—S), 1438 (C—N), 1587 (C N)
—
—
1H NMR (CDCl3), δ: 4.50 (s, 2H, ArCH2S), 5.30 (s, 2H, ArCH2N), 6.95–6.99 (m, 4H, ArH), 7.13–7.14 (m, 2H,
ArH), 7.29–7.38 (m, 7H, ArH), 7.58 (s, 1H, ArH), 7.63 (d, 1H, J = 7.2 Hz, ArH), 7.90 (d, 1H, J = 6.4 Hz, ArH),
—
—
8.41 (d, 1H, J = 6.4 Hz, ArH), 8.94 (s, 1H, N CHAr)
13C NMR (DMSO-d6), δ: 37.2, 49.0, 101.6, 111.1, 111.3, 115.7, 115.9, 121.2, 121.5, 121.9, 123.3, 126.1, 129.0, 130.0,
130.2, 131.0, 131.3, 131.6, 133.7, 134.0, 134.9, 135.1, 136.2, 144.4, 149.2, 160.8, 163.2, 163.7, 163.9
ESI–MS, m/z (Ir/%): 614.09 (100) (M + 1)+
IR, ν˜/cm−1: 1215 (C—S), 1430 (C—N), 1575 (C N)
—
—
1H NMR (CDCl3), δ: 4.50 (s, 2H, ArCH2S), 5.30 (s, 2H, ArCH2N), 6.94–6.99 (m, 4H, ArH), 7.12–7.13 (m, 2H,
ArH), 7.29–7.37 (m, 7H, ArH), 7.59 (s, 1H, ArH), 7.91 (d, 1H, J = 7.6 Hz, ArH), 7.99 (d, 1H, J = 7.6 Hz, ArH),
—
—
8.39 (d, 1H, J = 7.6 Hz, ArH), 8.97 (s, 1H, N CHAr)
13C NMR (DMSO-d6), δ: 37.3, 49.0, 101.6, 111.1, 115.8, 121.4, 121.9, 123.2, 126.1, 127.7, 128.5, 128.7, 130.0, 131.3,
131.9, 132.0, 133.0, 133.8, 134.0, 134.8, 135.7, 136.2, 144.3, 149.2, 160.7, 161.8, 161.9, 163.1, 163.2, 167.2
ESI–MS, m/z (Ir/%): 570.05 (100) (M + 1)+
IR, ν˜/cm−1: 1221 (C—S), 1437 (C—N), 1577 (C N)
—
—
1H NMR (CDCl3), δ: 4.47 (s, 2H, ArCH2S), 5.29 (s, 2H, ArCH2N), 6.93–6.99 (m, 4H, ArH), 7.12–7.15 (m, 2H,
—
—
ArH), 7.29–7.34 (m, 6H, ArH), 7.41–7.46 (m, 3H, ArH), 7.54 (s, 1H, ArH), 8.40 (s, 1H, N CHAr), 8.50–8.51 (m,
1H, ArH)
13C NMR (DMSO-d6), δ: 37.3, 48.9, 101.5, 111.1, 111.2, 115.1, 115.4, 115.7, 120.6, 121.4, 122.0, 123.2, 126.1, 126.3,
130.0, 131.5, 131.9, 133.8, 133.9, 134.3, 134.4, 136.2, 144.3, 149.1, 160.8, 161.5, 163.1, 164.0, 166.4
ESI–MS, m/z (Ir/%): 554.22 (100) (M + 1)+
IR, ν˜/cm−1: 1222 (C—S), 1434 (C—N), 1585 (C N)
—
—
1H NMR (CDCl3), δ: 4.45 (s, 2H, ArCH2S), 5.28 (s, 2H, ArCH2N), 6.95–6.97 (m, 4H, ArH), 7.12–7.15 (m, 2H,
ArH), 7.31–7.33 (m, 5H, ArH), 7.49–7.50 (m, 2H, ArH), 7.57–7.58 (m, 2H, ArH), 7.69 (d, 2H, J = 7.6 Hz, ArH),
—
—
8.40 (s, 1H, N CHAr), 8.54 (d, 1H, J = 7.2 Hz, ArH)
13C NMR (DMSO-d6), δ: 37.1, 48.9, 101.7, 111.1, 115.6, 115.8, 116.0, 121.3, 122.0, 123.2, 126.1, 129.5, 129.8, 130.1,
131.5, 132.0, 133.6, 133.9, 136.2, 144.3, 149.0, 160.7, 160.8, 163.1, 163.2, 167.9
ESI–MS, m/z (Ir/%): 536.15 (100) (M + 1)+
IR, ν˜/cm−1: 1226 (C—S), 1427 (C—N), 1596 (C N)
—
—
1H NMR (CDCl3), δ: 3.91 (s, 3H, OCH3), 4.43 (s, 2H, ArCH2S), 5.26 (s, 2H, ArCH2N), 6.92–6.97 (m, 6H, ArH),
7.10–7.12 (m, 2H, ArH), 7.30–7.34 (m, 5H, ArH), 7.53 (s, 1H, ArH), 7.63 (d, 2H, J = 7.2 Hz, ArH), 8.28 (s, 1H,
—
—
N
CHAr), 8.55 (d, 1H, J = 6.4 Hz, ArH)
13C NMR (DMSO-d6), δ: 36.9, 48.9, 56.1, 101.8, 111.2, 115.1, 115.3, 115.7, 115.9, 116.1, 121.2, 121.4, 122.1, 123.0,
123.3, 124.5, 126.1, 129.5, 129.7, 130.2, 131.5, 131.7, 133.8, 136.2, 144.4, 148.9, 160.8, 163.1, 163.8, 167.9
ESI–MS, m/z (Ir/%): 1130.25 (100) (2M + 1)+
IR, ν˜/cm−1: 1222 (C—S), 1430 (C—N), 1589 (C N)
—
—
1H NMR (CDCl3), δ: 4.50 (s, 2H, ArCH2S), 5.30 (s, 2H, ArCH2N), 6.96–6.99 (m, 4H, ArH), 7.13–7.14 (m, 2H,
ArH), 7.29–7.34 (m, 5H, ArH), 7.53 (s, 1H, ArH), 7.80 (d, 2H, J = 8.4 Hz, ArH), 8.30–8.32 (m, 2H, ArH), 8.42 (d,
—
J = 7.2 Hz, 1H, ArH), 8.54 (s, 1H, N CHAr)
—
13C NMR (DMSO-d6), δ: 37.5, 49.0, 101.4, 111.1, 111.3, 115.7, 115.9, 121.6, 122.1, 123.1, 123.3, 124.8, 126.1, 130.0,
130.2, 130.6, 131.3, 131.6, 132.1, 133.7, 136.2, 137.7, 144.3, 149.3, 150.2, 160.7, 163.1, 164.8, 165.0, 167.4
ESI–MS, m/z (Ir/%): 581.08 (100) (M + 1)+

Y. L. Peng et al./Chemical Papers 68 (3) 401–408 (2014)
405
Table 2. (continued)
Compound
Spectral data
VIIi
VIIj
VIIk
VIIl
IR, ν˜/cm−1: 1223 (C—S), 1435 (C—N), 1594 (C N), 3427 (PhOH)
—
—
1H NMR (CDCl3), δ: 4.42 (s, 2H, ArCH2S), 5.25 (s, 2H, ArCH2N), 6.89–6.95 (m, 4H, ArH), 6.97–7.01 (m, 1H,
ArH), 7.05–7.11 (m, 3H, ArH), 7.17–7.19 (m, 1H, ArH), 7.29–7.32 (m, 5H, ArH), 7.39 (s, 1H, ArH), 7.49–7.52 (m,
—
2H, ArH), 8.41 (s, 1H, N CHAr), 10.26 (s, 1H, ArOH)
—
13C NMR (DMSO-d6), δ: 36.8, 49.0, 101.8, 111.1, 115.5, 115.8, 115.9, 117.1, 118.3, 120.2, 121.3, 122.0, 123.1, 126.1,
127.9, 129.1, 130.0, 131.5, 132.0, 132.1, 133.7, 133.9, 135.3, 136.2, 144.2, 149.1, 159.1, 160.7, 163.3, 167.4
ESI–MS, m/z (Ir/%): 552.15 (100) (M + 1)+
IR, ν˜/cm−1: 1219 (C—S), 1418 (C—N), 1589 (C N)
—
—
1H NMR (CDCl3), δ: 4.45 (s, 2H, ArCH2S), 5.28 (s, 2H, ArCH2N), 6.92–6.99 (m, 4H, ArH), 7.10–7.13 (m, 2H,
ArH), 7.27–7.33 (m, 5H, ArH), 7.46 (d, 2H, J = 6.8 Hz, ArH), 7.51 (s, 1H, ArH), 7.60–7.61 (m, 2H, ArH), 8.37 (s,
—
1H, N CHAr), 8.49 (d, 1H, J = 8.0 Hz, ArH)
—
13C NMR (DMSO-d6), δ: 37.3, 49.0, 101.6, 111.1, 111.3, 115.7, 115.9, 121.5, 121.9, 123.2, 126.1, 128.3, 128.6, 129.5,
130.0, 130.2, 130.3, 130.7, 130.9, 131.3, 131.5, 133.8, 134.0, 134.8, 135.7, 136.2
ESI–MS, m/z (Ir/%): 570.07 (100) (M + 1)+
IR, ν˜/cm−1: 1221 (C—S), 1431 (C—N), 1586 (C N)
—
—
1H NMR (CDCl3), δ: 4.47 (s, 2H, ArCH2S), 5.31 (s, 2H, ArCH2N), 6.63 (s, 1H, ArH), 7.00–6.94 (m, 6H, ArH),
7.12–7.15 (m, 2H, ArH), 7.28–7.29 (m, 3H, ArH), 7.36–7.33 (m, 1H, ArH), 7.68–7.70 (m, 2H, ArH), 8.24 (s, 1H,
—
—
N
CHAr), 8.54–8.55 (m, 1H, ArH)
13C NMR (DMSO-d6), δ: 36.9, 49.0, 101.6, 111.2, 113.6, 115.7, 115.9, 121.2, 121.5, 121.8, 122.1, 123.2, 126.1, 129.7,
130.1, 131.3, 131.6, 133.8, 133.9, 136.2, 144.4, 147.6, 148.9, 149.2, 155.8, 155.9, 160.7, 163.2
ESI–MS, m/z (Ir/%): 526.08 (100) (M + 1)+
IR, ν˜/cm−1: 1226 (C—S), 1429 (C—N), 1595 (C N), 3440 (PhOH)
—
—
1H NMR (DMSO-d6), δ: 4.38 (s, 2H, ArCH2S), 5.46 (s, 2H, ArCH2N), 6.88–6.90 (d, 2H, J = 7.6 Hz, ArH), 7.05–7.13
(m, 4H, ArH), 7.20–7.26 (m, 4H, ArH), 7.37–7.39 (m, 2H, ArH), 7.59 (d, 1H, J = 8.0 Hz, ArH), 7.72 (d, 2H, J =
—
8.0 Hz, ArH), 7.86 (s, 1H, ArH), 8.29 (d, 1H, J = 7.6 Hz, ArH), 8.57 (s, 1H, N CHAr), 10.02 (s, 1H, ArOH)
—
13C NMR (DMSO-d6), δ: 36.7, 48.9, 101.9, 111.1, 115.7, 116.9, 121.2, 122.1, 123.1, 126.1, 129.5, 130.0, 131.4, 132.0,
133.9, 134.9, 136.1, 140.5, 144.4, 148.9, 160.7, 163.2, 164.0, 168.3
ESI–MS, m/z (Ir/%): 552.10 (100) (M + 1)+
catalyst) were mixed thoroughly by grinding in a
porcelain mortar. The mixture was transferred into
a 10 mL specialized tube placed in a microwave oven
and irradiated with the MW power of 300 W at 125◦C
and the pressure of 413–552 kPa for 4–6 min. The reac-
tion was monitored by TLC (ethyl acetate/petroleum
ether; ϕr = 1 : 1) until it was completed. The mixture
was extracted with DMF (3 × 5 mL). Then, ethanol
(10 mL) was added to the DMF mixture. Solid was
formed and collected by filtration, it was purified by
silica gel column chromatography using a mixture of
ethyl acetate/petroleum ether (ϕr = 1 : 1) (Rf = 0.5–
0.7) to get pure compounds VIIa–VIIl. The opera-
tional procedure was referred to a published article
(Ju & Varma, 2005).
nique described by NCCLS (National Committee for
Clinical Laboratory Standards, 2000).
Results and discussion
Spectral characterization
Purity of the compounds was checked by the phys-
ical properties and elemental analyses (Table 1), and
the structures of compounds were identified using
spectral data (Table 2). The elemental analysis results
were within
0.4 % of the theoretical values. The
mass spectra showed the expected molecular peaks at
high intensity. In the IR spectra of V, the absorption
band at about 2640 cm−1 assigned to the SH group
which was absent in the IR spectra of VI can be ob-
served. The strong bands at about 3353 cm−1 ascribed
to the NH2 group disappeared in IR spectra of VIIa–
Biological activity test for MIC and IC val-
ues
VIIl. The strong bands at 1596–1575 cm−1 were at-
1
—
Two Gram-positive bacteria (S. aureus ATCC6538,
B. subtilis ATCC 6633) and two Gram-negative bac-
teria (E. coli ATCC 35218, Pseudomonas aerugi-
nosa ATCC 27853; Agricultural University of Sichuan,
China) were used in the biological activity tests
(in vitro). Amoxicillin (Shanghai medical company,
China) was used as positive control and DMF was
used as negative control. The experimental procedure
was referred to the standard broth microdilution tech-
tributed to the absorption of C N. In the H NMR
—
spectra, compound V showed a singlet peak at δ 13.72
due to the SH group which was not observed in the
spectra of compound VI. The singlet peak at δ 5.28
(VI ) was assigned to the NH2 group and that at δ
—
8.96–8.28 was assigned to N CHAr. Protons of ArH
—
appeared at δ 8.56–6.88. The singlet peak in VIIa–
VIIl at δ 5.26–5.45 was assigned to ArCH2N and that
at δ 4.38–4.50 (VI and VIIa–VIIl) was attributed to

406
Y. L. Peng et al./Chemical Papers 68 (3) 401–408 (2014)
Table 3. Comparison of syntheses under microwave irradiation and conventional heating
Traditional method Microwave method
Compounds
Time ratioa
Time/h
Yield/%
Time/min
Yield/%
III
V
21
25
30
26
28
27
26
24
25
28
26
26.5
28.5
24.5
75
43
65
59
72
73
68
70
64
67
66
75
84
68
6
8
4
5
5
6
5
4
6
6
5
4
4
5
93
86
85
88
89
91
86
95
87
88
86
87
96
85
210
188
450
312
336
270
312
360
250
280
312
398
428
294
VIIa
VIIb
VIIc
VIId
VIIe
VIIf
VIIg
VIIh
VIIi
VIIj
VIIk
VIIl
a) Ratio between time needed for the conventional and microwave method.
Table 4. MIC and IC50 values of Schiff bases VIIa–VIIl and Amoxicillin
Inhibitory concentration/( g mL−1
Gram-negative bacteria
B. subtilis E. coli P. aeruginosa
)
Gram-positive bacteria
Compounds
S. aureus
MIC
IC50
MIC
IC50
MIC
IC50
MIC
IC50
VIIa
VIIb
VIIc
VIId
VIIe
> 128
8
16
32
8
> 64
5.3
7.5
14.9
4.1
> 128
2
32
8
4
> 64
1.4
14.6
5.7
> 128
8
16
8
8
> 64
7
9.8
6.2
5.2
> 128
2
16
4
8
> 64
1.5
8.3
3.1
3.9
2.8
VIIf
VIIg
VIIh
> 128
32
8
> 64
26.9
4.9
> 128
> 128
4
> 64
> 64
2.4
> 128
> 128
4
> 64
> 64
2.8
> 128
> 128
8
> 64
> 64
5.2
VIIi
VIIj
> 128
8
> 64
6.4
> 128
8
> 64
4.6
> 128
4
> 64
3.3
> 128
4
> 64
3.3
VIIk
VIIl
Amoxicillin
32
> 128
16
25.4
> 64
6.4
> 128
> 128
8
> 64
> 64
2.7
64
> 128
16
33.3
> 64
7.3
> 128
> 128
8
> 64
> 64
2.5
SCH2Ar. In the 13C NMR spectra, the peak at δ 34.8–
37.4 (VI and VIIa–VIIl) was assigned to SCH2Ar, that
at δ 48.9–49.1 (VI and VIIa–VIIl) to ArCH2N, and
the traditional method.
In the synthesis of III, the reaction time decreased
from 21 h to 6 min and the yield increased from 75 %
to 93 % in the microwave method. In the synthesis of
V, the reaction time was decreased from 25 h to 8 min,
and the yield was increased from 43 % to 86 %. More-
over, VIIa–VIIl were synthesized without using any
solvent under microwave radiation. A typical aromatic
aldehyde (VI ) and a drop of acetic acid were thor-
oughly mixed together and irradiated by microwave
radiation for a few minutes. To our amazement, the
reaction time decreased from 24–30 h to 4–6 min and
the yield increased from 59 % (84 %) to 84 % (96 %).
—
that at δ 163.2–168.4 (VIIa–VIIl) to N CHAr. Car-
—
bon atoms of the aromatic ring in VI and VIIa–VIIl
showed their peaks at δ 101.4–166.6.
Comparison of syntheses under microwave ir-
radiation and conventional heating
Using methyl 1H-indole-3-carboxylate as the ini-
tial material, the target Schiff bases were synthe-
sized in six steps, three of which were completed via
microwave radiation. Compared with the traditional
heating method, microwave synthesis showed many
advantages (Table 3). From Table 3, it can be seen
that the microwave synthesis has significantly shorter
reaction time and visibly higher yields compared to
Biological screening
MIC and IC50 values of these newly synthesized
target compounds to four tested microorganisms are

Y. L. Peng et al./Chemical Papers 68 (3) 401–408 (2014)
407
presented in Table 4. According to the data in Table 4
it can be concluded that compounds VIIb, VIIe, VIIh,
and VIIj possess antibacterial activity equivalent to or
even higher than Amoxicillin. Compared with Amox-
icillin, VIIc and VIId are a little weaker in the inhibi-
tion of Gram-positive bacteria and a little stronger in
the inhibition of Gram-negative bacteria. Compounds
VIIg and VIIk showed poor antibacterial activity, and
VIIa, VIIf, VIIi, and VIIl no antibacterial activity at
all.
Burchak, O. N., Le Pihive, E., Maigre, L., Guinchard, X.,
Bouhours, P., Jolivalt, C., Schneider, D., Maurin, M.,
Giglione, C., Meinnel, T., Paris, J. M., & Denis, J. N. (2011).
Synthesis and evaluation of 1-(1H-indol-3-yl)ethanamine
derivatives as new antibacterial agents. Bioorganic & Medic-
inal Chemistry, 19, 3204–3215. DOI: 10.1016/j.bmc.2011.03.
060.
da Silva, C. M., da Silva, D. L., Modolo, L. V., Alves, R.
B., de Resende, M. A., Martins, C. V. B., & de Fátima,
ˆ
A. (2011). Schiff bases: A short review of their antimicro-
bial activities. Journal of Advanced Research, 2, 1–8. DOI:
10.1016/j.jare.2010.05.004.
It can thus be concluded that the aromatic sub-
stituent of these Schiff bases plays an important
part in their antibacterial activity. Halogen and nitro
groups enhance the antibacterial activity significantly
while hydroxy and methoxy groups have no such func-
tion.
Eswaran, S., Adhikari, A. V., & Shetty, N. S. (2009). Synthesis
and antimicrobial activities of novel quinoline derivatives car-
rying 1,2,4-triazole moiety. European Journal of Medicinal
Chemistry, 44, 4637–4647. DOI: 10.1016/j.ejmech.2009.06.
031.
Farghaly, A. R. A. H. (2004). Synthesis, reactions and antimi-
crobial activity of some new indolyl-1,3,4-oxadiazole, triazole
and pyrazole derivatives. Journal of the Chinese Chemical
Society, 51, 147–156.
Giske, C. G., & Cornaglia, G. (2010). Supranational surveillance
of antimicrobial resistance: The legacy of the last decade and
proposals for the future. Drug Resistance Updates, 13, 93–98.
DOI: 10.1016/j.drup.2010.08.002.
Ju, Y. H., & Varma, R. S. (2005). Microwave-assisted cyclo-
condensation of hydrazine derivatives with alkyl dihalides or
ditosylates in aqueous media: syntheses of pyrazole, pyrazo-
lidine and phthalazine derivatives. Tetrahedron Letters, 46,
6011–6014. DOI: 10.1016/j.tetlet.2005.07.018.
Khalil, N. S. A. M. (2010). Efficient synthesis of novel 1,2,4-
triazole fused acyclic and 21–28 membered macrocyclic
and/or lariat macrocyclic oxaazathia crown compounds with
potential antimicrobial activity. European Journal of Medic-
inal Chemistry, 45, 5265–5277. DOI: 10.1016/j.ejmech.2010.
08.046.
Nadal, M., Schuhmacher, M., & Domingo, J. L. (2011). Long-
term environmental monitoring of persistent organic pollu-
tants and metals in a chemical/petrochemical area: Human
health risks. Environmental Pollution, 159, 1769–1777. DOI:
10.1016/j.envpol.2011.04.007.
National Committee for Clinical Laboratory Standards (2000).
U.S. standard: Methods for dilution antimicrobial suscepti-
bility tests for bacteria that grow aerobically. Approved stan-
dard, 5th ed. M7–A5. Villanova, PA, USA.
Negm, N. A., Aiad, I. A., & Tawfik, S. M. (2010). Screen-
ing for potential antimicrobial activities of some cationic
uracil biocides against wide-spreading bacterial strains.
Journal of Surfactants and Detergents, 13, 503–511. DOI:
10.1007/s11743-010-1229-0.
Conclusions
In summary, a facile, efficient and eco-friendly
method for the synthesis of twelve novel Schiff bases
via microwave irradiation has been introduced. The
presented method has some distinct advantages com-
pared with the conventional method, such as shorter
reaction times, good conversions, and it also meets the
requirements of the green chemistry protocols. An-
tibacterial activity of these newly synthesized com-
pounds was evaluated by biological activity tests in
vitro. Based on the activity data, compounds VIIb,
VIIe, VIIh, and VIIj were proved to possess strong
antibacterial activity which can be possibly used in an-
tibacterial drugs. Studies on their efficiency and safety
in vitro are planned.
Acknowledgements. This work was financially supported
by the Science and Technology Department of the Sichuan
Province (Nos. 2012JY0028, 2011JY0035) and the postgrad-
uate Degree Construction Project of the Southwest University
for Nationalities of P.R. China (No. 2013XWD-S0703). We
are grateful to the Southwest University for Nationalities for
their support and facilities.
References
Akhaja, T. N., & Raval, J. P. (2011). 1,3-Dihydro-2H-indol-
2-ones derivatives: Design, synthesis, in vitro antibacterial,
antifungal and antitubercular study. European Journal of
Medicinal Chemistry, 46, 5573–5579. DOI: 10.1016/j.ejmech.
2011.09.023.
Akhaja, T. N., & Raval, J. P. (2012). Design, synthesis, in vitro
evaluation of tetrahydropyrimidine–isatin hybrids as poten-
tial antibacterial, antifungal and anti-tubercular agents. Chi-
nese Chemical Letters, 23, 446–449. DOI: 10.1016/j.cclet.
2012.01.040.
Appukkuttan, P., Mehta, V. P., & Van der Eycken, E. V. (2009).
Microwave-assisted cycloaddition reactions. Chemical Soci-
ety Reviews, 39, 1467–1477. DOI: 10.1039/b815717k.
Bharti, S. K., Nath, G., Tilak, R., & Singh, S. K. (2010). Syn-
thesis, anti-bacterial and anti-fungal activities of some novel
Schiff bases containing 2,4-disubstituted thiazole ring. Eu-
ropean Journal of Medicinal Chemistry, 45, 651–660. DOI:
10.1016/j.ejmech.2009.11.008.
Pardeshi, S., & Bobade, V. D. (2011). Synthesis and biologi-
cal evaluation of some novel triazol-3-ones as antimicrobial
agents. Bioorganic & Medicinal Chemistry Letters, 21, 6559–
6562. DOI: 10.1016/j.bmcl.2011.08.049.
Patil, B. S., Krishnamurthy, G., Naik, H. S. B., Latthe, P.
R., & Ghate, M. (2010). Synthesis, characterization and
antimicrobial studies of 2-(4-methoxy-phenyl)-5-methyl-4-
(2-arylsulfanyl-ethyl)-2,4-dihydro-[1,2,4]triaz olo-3-ones and
their corresponding sulfones. European Journal of Medicinal
Chemistry, 45, 3329–3334. DOI: 10.1016/j.ejmech.2010.04.
016.
Reddy, B. V. S., Rajeswari, N., Sarangapani, M., Reddy,
G. R., Madan, C., Kumar, K. P., & Rao, M. S. (2011).
Iodine-catalyzed conjugate addition of indoles onto en-
1,4-dione: A novel synthesis of 3-(1-(1H-indol-3-yl)-2-oxo-
2-phenylethyl)indolin-2-ones as antibacterial and antifungal
agents. Bioorganic & Medicinal Chemistry Letters, 21, 6510–
6514. DOI: 10.1016/j.bmcl.2011.08.075.

408
Y. L. Peng et al./Chemical Papers 68 (3) 401–408 (2014)
Shi, Y., Peng, Y. L., Zhao, Z. G., Li, G. H., & Li, H. R.
(2011). Synthesis of new Schiff bases derived from dimers of
4-amino-3-(1-naphthyl)-5-thiomethyl-1,2,4-triazole using mi-
crowave irradiation. Journal of Chemical Research, 35, 15–
17. DOI: 10.3184/174751911x12964930076647.
Zhao, Z. G., Liu, X. L., Liu, L. L., & Li, G. H. (2010).
Microwave-assisted synthesis of new steroidal thiosemicar-
bazones derived from methyl 3-oxocholanate under solvent-
free conditions. Journal of Chemical Research, 34, 455–458.
DOI: 10.3184/030823410x12798092457988.
Singh, K., Kumar, Y., Puri, P., Kumar, M., & Sharma, C.
(2012). Cobalt, nickel, copper and zinc complexes with 1,3-
diphenyl-1H-pyrazole-4-carboxaldehyde Schiff bases: Antimi-
crobial, spectroscopic, thermal and fluorescence studies. Eu-
ropean Journal of Medicinal Chemistry, 52, 313–321. DOI:
10.1016/j.ejmech.2012.02.053.
Zhang, H. J., Qin, X., Liu, K., Zhu, D. D., Wang, X.
M., & Zhu, H. L. (2011). Synthesis, antibacterial activ-
ities and molecular docking studies of Schiff bases de-
rived from N-(2/4-benzaldehyde-amino) phenyl-N-phenyl-
thiourea. Bioorganic & Medicinal Chemistry, 19, 5708–5715.
DOI: 10.1016/j.bmc.2011.06.077.
Zoumpoulakis, P., Camoutsis, C., Pairas, G., Sokovi´c, M.,
Glamočlija, J., Potamitis, C., & Pitsas, A. (2012). Syn-
thesis of novel sulfonamide-1,2,4-triazoles, 1,3,4-thiadiazoles
and 1,3,4-oxadiazoles, as potential antibacterial and antifun-
gal agents. Biological evaluation and conformational analysis
studies. Bioorganic & Medicinal Chemistry, 20, 1569–1583.
DOI: 10.1016/j.bmc.2011.12.031.