Microwave-assisted synthesis and antibacterial activity of unsymmetrical indolyl/aryl bis-thiosemicarbazones

Article abstract of DOI:10.3184/174751913X13688155249983

A series of nine novel unsymmetrical bis-thiosemicarbazones were prepared in high yield by condensation of aromatic aldehyde thiosemicarbazones with indole-3-carboxaldehyde using microwave irradiation. The structures of the new compounds were characterised. Six of the compounds displayed varying levels of antibacterial activity against Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa and Staphylococcus aureus.

Full text of DOI:10.3184/174751913X13688155249983

372 RESEARCH PAPER
JUNE, 372–374
JOURNAL OF CHEMICAL RESEARCH 2013
Microwave-assisted synthesis and antibacterial activity of unsymmetrical
indolyl/aryl bis-thiosemicarbazones
Lin Li, Yujia Jiang, Xingli Liu and Zhigang Zhao*
College of Chemistry and Environmental Protection Engineering, Southwest University for Nationalities, Chengdu 610041, P. R. China
A series of nine novel unsymmetrical bis-thiosemicarbazones were prepared in high yield by condensation of
aromatic aldehyde thiosemicarbazones with indole-3-carboxaldehyde using microwave irradiation. The structures of
the new compounds were characterised. Six of the compounds displayed varying levels of antibacterial activity
against Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa and Staphylococcus aureus.
Keywords: unsymmetrical bis-thiosemicarbazone, indole, microwave irradiation, antibacterial activity
Indole, as a basic subunit, plays a significant role in various
natural products and synthetic compounds,1 resulting from its
many-electron aromatic structure.2 Attention has focused on
the indole derivatives to identify potent therapeutic agents,3
specifically on five-membered heterocyclic ring,4–5 due to their
biological activity.6 Indole molecules with 3-position function-
ality are highly reactive in electrophilic substitution.7 Thus,
indole-3-carboxaldehyde is an attractive raw material for
producing 3-indole derivatives in medicinal chemistry.8
Thiosemicarbazones have been widely studied because of
their physiological activities, such as antibacterial, antifungal,
antiviral, antitumour and antimalarial properties.9–13 It has been
thought that superposition of two functional groups with dif-
ferent activities might create new compounds with improved
activities. Alhough there have been a large number of reports of
thiosemicarbazones and their pharmacological properties,14–15
few efforts have been made to study the indole-3-carboxalde-
hyde unsymmetrical bis-thiosemicarbazones and their relative
activities. Hence, we have considered the preparation and the
bacteriostatic activity of indole-3-carboxaldehyde unsymmet-
rical bis-thiosemicarbazone derivatives.
Microwave irradiation (MWI) has advantages in chemical
synthesis such as short-time, energy saving, higher yield,
higher reaction selectivity and low-waste.16–20 It thus also
conforms to the idea of green chemistry.21
We have already synthesised a sequence of compounds
containing Schiff-base structure using MWI.22–24 The targets
underwent antibacterial activity tests and mostly exhibited
promising results, leading to a promising theoretical basis for
indole-3-carboxaldehyde unsymmetrical bis-thiosemicarba-
zone synthesis.
Results and discussion
The synthetic route used is shown in Scheme 1. In the first
step, an aromatic aldehyde 1 is condensed with thiocarbohy-
drazide in EtOH–H2O to yield an aromatic aldehyde
semithiocarbohydrazone 2, as previously described.23,25–26 In
the second step, 2 is reacted with indole-3-carboxaldehyde 3 in
acetic acid, either at 80 °C or under MWI, to give the indolyl/
aryl bis-thiosemicarbazones 4.
As depicted in Table 1, we can see MWI largely reduced the
reaction time from 150–240 min to 3–5 min. However, the
yields were increased from 46–69% to 85–96%. Consequently,
microwave technology allows rapid and efficient procedures in
organic synthesis.
Compounds 4a–i were confirmed by IR, Mass, 1H NMR and
elementary analysis. Their mass spectra showed the expected
molecular peaks in high intensity. Their IR spectra exhibited
a characteristic strong absorption at 3058–3686 cm−1 due to
N–H stretching vibration. The disappearance of strong bands
in the region 1710–1725 cm−1 and appearance of strong absorp-
tion peak at 1604–1620 cm−1 indicated C=O of indole-3-car-
boxaldehyde had been replaced by C=N; The strong absorption
bands falling within the range of 1222–1247 cm−1 were
1
assigned to C=S. In the H NMR spectra, the singlet peaks
between δ 11.24 and 11.61 ppm should be assigned to indole-
NH protons, and singlet peaks due to the other two NH protons
were observed at δ 11.47–11.71 ppm and δ 11.56–11.93 ppm
respectively. In addition, the double peaks between δ 8.38 and
8.56 ppm were characteristic of the protons in =CH of indole
structure. The singlet peaks at δ 8.01–8.47 ppm and δ 8.62–
8.76 ppm were characteristic of the protons in the other two
=CH moieties.
Scheme 1 The synthetic route of indolyl/aryl thiosemicarbazones.
* Correspondent. E-mail: zzg63129@yahoo.com.cn

JOURNAL OF CHEMICAL RESEARCH 2013 373
Table 1 Comparison of microwave irradiation with conven-
tional heating for the efficiency of synthesis of indolyl/aryl
thiosemicarbazones 4a–i from aryl thiosemicarbazones 2a–i
(Scheme 1)
ciprofloxacin against S.aureus. The remaining compounds had
no effect on the bacteria. We can conclude that addition of
electron withdrawing group especially a halogen atom has the
potential for bacteria depression. More antibacterial activities
are under study.
In summary, we report the synthesis using MWI of new
novel indole bis-thiosemicarbazone derivatives and their anti-
bacterial activities. This method is efficient, environmental-
friendly, has a simple reaction set-up, and a high product yield.
The novel compounds might be useful for designing more
potent antibacterial agents for biological and pharmacological
uses.
a
Compd RCHO (R)
Conventional
method
Microwave tC /tMW
method
t/min Yield/%
t/min Yield/%
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
2-Cl-C6H4
4-Br-C6H4
200
160
220
59
66
69
46
58
57
61
65
62
5.0
3.0
5.0
5.0
3.5
3.0
4.0
4.5
4.0
88
90
92
87
96
95
85
91
90
40
53
44
48
46
50
50
51
45
4-MeO-C6H4 240
4-F-C6H4
2,4-2F-C6H3
3-Br-C6H4
160
150
200
Experimental
2,4-2(OH)-C6H3 230
4-N(CH3)2-C6H4 180
Melting points were determined on a micro-melting point apparatus
and the thermometer was uncorrected. IR spectra were obtained on
1700 PerkinElmer FTIR using KBr disks. 1H NMR spectra were
recorded on a Varian INOVA 400 MHz spectrometer using DMSO-d6
as solvent and TMS as internal standard. Mass spectra were deter-
mined on FinniganLCQDECA instrument. Elemental analysis was
performed on a Carlo-Erba-1106 auto analyser. All reactions were
performed in a commercial microwave reaction (XH-100A, 100-
1000W, Beijing XiangHu Science and Technology Development Co.
Ltd, Beijing, P.R. China). The disinfection of apparatus and reagents
used in vitro antimicrobial activity test was conducted in a portable
stainless steel pressure steam steriliser (YX280A, Shanghai Sanshen
Medical Instrument Co., Ltd, Shanghai, P. R. China). Sterile operation
was carried out on a super clean bench (DL-CJ-1N, Donglian
Elactronic & Technology Develepment Co.Ltd, Beijing, P.R. China).
Bacterial culture was grown in a biological constant temperature
incubator (ECA-9272, Beijing ECOA Science & Development Co.,
Ltd, Beijing, P.R. China). All the chemicals and solvents were dried
and purified before use.
tC = conventional method time; tMW = microwave method time.
In vitro antibacterial activity
The in vitro antibacterial activity of compounds 4a–i were
tested using cultures of E. coli, B. subtilis, P. aeruginosa and
S.aureus. Amoxicillin (2.56 mg) and ciprofloxacin (2.56 mg)
were used as the standard drugs. The MIC was evaluated by
the double dilution method in tubes employing standard inocu-
lums of 105 CFU mL−1. Successive dilutions of the test com-
pounds, dissolved in 1 mL DMSO beforehand were prepared
to final concentrations of 256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5
and 0.25 µg mL−1. 1 mL bacterial fluid of 0.5 McFarland stan-
dard was added to each tube. The MIC was determined by
inhibition of the visible bacteria growth after incubation for
16 h at 37°C. Meanwhile, the IC50 was evaluated by the inhibi-
tion zone test employing standard inoculums of 105 CFU mL−1.
Serial dilutions of the test compounds, previously dissolved in
2 mL DMSO were prepared to final concentrations of 640,
320, 160, 80, 40, 20, 10 and 5 µg mL−1. Bacteria fluid of 0.5
McFarland standard was grown on bouillon medium and then
filter papers (diameter of 6 mm) saturated with the compound
dilutions were placed on top of the growing bacteria. Incuba-
tion at 37°C for 16 h gave the diameter of the inhibition zone
which allowed us to evaluate theIC50 value. The results of MIC
and IC50 are presented in Table 2.
Synthesis of thiosemicarbazones 4a–i; general procedure
Conventional method: Indole-3-carboxaldehyde (3) (0.138 g, 0.95 mmol),
an aromatic aldehyde thiocarbohydrazone23,25–26 (2a–i) (1 mmol) was
dissolved in glacial acetic acid (5 mL). The mixture was stirred for
2.5–4h at 80 °C. The liquid phase was filtrated at a high temperature
immediately, and the pure product was recrystallised from a mixed
solvent of methanol and ethanol in 46–69% yields.
Microwave irradiation method: Indole-3-carboxaldehyde (3) (0.138 g,
0.95 mmol), aromatic aldehyde thiocarbohydrazones (2a–i) (1 mmol)
and glacial acetic acid (5 mL) were placed in a round-bottom flask
(25 mL). After being shaken, the flask was placed into a microwave
oven. The radiant power was set to 200–550W for 3–5 min. The output
was filtered while hot and the filtrate was reserved. The pure targets
was recrystallised from a mixed solvent of methanol and ethanol in
85–96% yields. The physical and spectra data of the compounds 2f
and 4a–i are as follows.
1-(2,4-Difluorobenzylidene)thiocarbonohydrazide (2f): White solid
(79%), m.p. 169–170 °C (EtOH). IR: 3409, 3356, 3265, 2930, 2791,
1615, 1564, 1507, 1429, 1283, 1253, 1141, 1077, 1018, 848, 611 cm−1;
1H NMR δ: 11.53 (s, 1H, NH), 9.96 (s, 1H, NH), 8.39–8.45 (m, 1H,
ArH), 8.17 (s, 1H, =CH), 7.27–7.33 (m, 1H, ArH), 7.15 (dd, J1 = 6.4,
J2 = 8.4 Hz, 1H, ArH), 4.88 (s, 2H, NH2); ESI-MS m/z (%): 231
([M+1]+, 100). Ana1. Calcd for C8H8F2N4S: C, 41.73; H, 3.50; N,
24.33; Found: C, 41.78; H, 3.48; N, 24.35%.
As shown in Table 2, 4b, 4c, 4e and 4f has better inhibitory
activities against E.coli than amoxicillin with 4f as the best;
4b, 4c, 4e, 4f, 4g and 4h could inhibit B.subtilis; 4b, 4c and 4e
had almost the same effect as that of amoxicillin; 4b, 4c, 4e
and 4f could suppress P.aeruginosa, 4c and 4e worked better
than amoxicillin while 4b and 4f had almost the same effect as
amoxicillin; 4b, 4c and 4e had a better effect on S.aureus than
did amoxicillin, and 4c had even better antimicrobial effects of
Table 2 Antibacterial activity of indolyl/aryl thiosemicar-
bazones 4a–i and two positive controls (ciprofloxacin and
amoxicillin)
2′-(Benzylidene)-2-[(1H-indol-3-yl)methylidene]hydrazine-1-thiocar-
bohydrazide (4a): Pale yellow solid (88%), m.p. 232–234 °C (MeOH
and EtOH); IR: 3422, 3281, 1610, 1535, 1483, 1222, 1104, 1059, 748,
Compd
E. coli
B. subtilis P. aeruginosa S. aureus
MIC IC50 MIC IC50 MIC
IC50 MIC IC50
1
663 cm−1; H NMR δ: 7.15–7.23 (m, 2H, ArH), 7.38–7.42 (dd, J1 =
5.6 Hz, J2 = 8.4 Hz, 3H, ArH), 7.78–7.79 (d, J = 6.4 Hz, 1H, ArH),
7.82–7.84 (d, J = 4.4 Hz, 1H, ArH), 7.85–7.88 (d, J = 12.0 Hz, 2H,
ArH), 8.13 (s, 1H, NCH), 8.44 (d, J = 7.2 Hz, 1H, indole-CH in
2-moiety), 8.75 (s, 1H, NCH), 11.41 (s, 1H, indole-NH), 11.58 (s, 1H,
NH), 11.72 (s, 1H, NH); ESI-MS m/z (%): 665 ([2M+Na]+, 100).
Ana1. Calcd for C17H15N5S: C, 63.53; H, 4.70; N, 21.79. Found: C,
63.50; H, 4.68; N, 21.81%.
2′-(2-Chlorobenzylidene)-2-[(1H-indol-3-yl)methylidene]hydra-
zine-1-thiocarbohydrazid-e 4b: bright yellow solid (90%), m.p. 198–
200 °C (MeOH and EtOH); IR: 3284, 3130, 1612, 1576, 1426, 1362,
1243, 747, 658 cm−1; 1H NMR δ: 7.16–7.23 (m, 2H, ArH), 7.44–7.46
(d, J = 8.0 Hz, 4H, ArH), 7.46–7.53 (m, 1H, ArH), 7.78–7. 82 (m, 1H,
Ciprofloxacin 0.25 0.18 0.125 0.1
0.5
4
–
4
2
–
2
4
–
0.41 3.12 1.82
Amoxicillin 16
7.3
–
2.66 2
1.48 2
–
1.92 2
1.43 8
–
–
–
2
1
2.5 16
6.4
–
2.53
1.65
–
1.72
–
4a
–
–
–
–
2.54
1.64
–
–
4b
4c
4d
4e
4f
4
2
1.48
1.60
–
4
2
–
–
–
4
2
1.55
3.52
12.35
10.18
–
1.69
2.32
–
4
–
4g
4h
4i
–
–
–
16
16
–
–
–
–
–
–
–
–
–
–
–
–, Not able to inhibit bacteria.

374 JOURNAL OF CHEMICAL RESEARCH 2013
ArH), 8.47 (s, 1H, NCH), 8.54(d, J = 7.2 Hz, 1H, indole-CH in
2-moiety), 8.75 (s, 1H, NCH), 11.48 (s, 1H, indole-NH), 11.59 (s, 1H,
NH), 11.90 (s, 1H, NH); ESI-MS m/z (%): 733 ([2M+Na]+, 100).
Ana1. Calcd for C17H14ClN5S: C, 57.38; H, 3.97; N, 19.68. Found: C,
57.42; H, 3.95; N, 19.65%.
2′-(4-Bromobenzylidene)-2-[(1H-indol-3-yl)methylidene]hydra-
zine-1-thiocarbohydrazid-e (4c): Pale yellow solid (92%), m.p. 208–
210 °C (MeOH and EtOH); IR: 3272, 3156, 3058, 1615, 1547, 1485,
1441, 1324, 1246, 1069, 819, 784 cm−1; 1H NMR δ: 7.16–7.23 (m, 2H,
ArH), 7.43 (d, J = 8.0 Hz, 1H, ArH), 7.65 (d, J = 8.4 Hz, 3H, ArH),
7.85(d, J = 7.2 Hz, 2H, ArH), 8.09 (s, 1H, NCH), 8.47 (d, J = 7.2 Hz,
1H, indole-CH in 2-moiety), 8.75 (s, 1H, NCH), 11.44 (s, 1H, indole-
NH), 11.59 (s, 1H, NH), 11.78 (s, 1H, NH); ESI-MS m/z (%): 823
([2M+Na]+, 100). Ana1. Calcd for C17H14BrN5S: C, 51.01; H, 3.53; N,
17.50. Found: C, 51.06; H, 3.50; N, 17.53%.
2′-(4-Dimethylaminobenzylidene)-2-[(1H-indol-3-yl)methylidene]hydra-
zine-1-thiocarbo-hydrazide (4i):Yellow solid (90%), m.p. 199–201 °C
(MeOH and EtOH); IR: 3394, 3277, 1604, 1526, 1437, 1364, 1226,
1
1175, 812 cm−1; H NMR δ: 2.99 (s, 6H, -N(CH3)2), 6.74 (d, J = 8.4
Hz, 2H, ArH), 7.16–7.23 (m, 3H, ArH), 7.43 (d, J = 8.0 Hz, 1H, ArH),
7.67 (d, J = 8.4 Hz, 2H, ArH), 8.01 (s, 1H, NCH), 8.48 (d, J = 7.2 Hz,
1H, indole-CH in 2-moiety), 8.73 (s, 1H, NCH), 11.24 (s, 1H, indole-
NH), 11.47 (s, 1H, NH), 11.56 (s, 1H, NH); ESI-MS m/z (%): 751
([2M+Na]+, 100). Ana1. Calcd for C19H20N6S: C, 62.61; H, 5.53; N,
23.06. Found: C, 62.64; H, 5.50; N, 23.03%.
We thank the Science and Technology Department of Sichuan
Province (Nos.2011JY0035, 2012JY0028) and the Post-
graduate Degree Construction Project of Southwest University
for Nationalities (No. 2013XWD-S0703) for financial support.
2′-(4-Methyloxybenzylidene)-2-[(1H-indol-3-yl)methylidene]hydra-
zine-1-thiocarbohydr-azide (4d): Pale yellow solid (87%), m.p. 204–
206 °C (MeOH and EtOH); IR: 3292, 3248, 1606, 1535, 1498, 1387,
Received 16 February 2013; accepted 4 April 2013
Paper 1301795 doi: 10.3184/174751913X13688155249983
Published online: 12 June 2013
1
1247, 831, 799 cm−1; H NMR δ: 3.82 (s, 3H, –OCH3), 7.01 (d, J =
8.0 Hz, 2H, ArH), 7.17–7.24 (m, 2H, ArH), 7.44 (d, J = 8.0 Hz, 1H,
ArH), 7.81 (d, J = 8.8 Hz, 3H, ArH), 8.09 (s, 1H, NCH), 8.50 (d,
J = 7.2 Hz, 1H, indole-CH in 2-moiety), 8.76 (s, 1H, NCH), 11.34 (s,
1H, indole-NH), 11.58 (s, 1H, NH), 11.62 (s, 1H, NH); ESI-MS m/z
(%): 725 ([2M+Na]+, 100). Ana1. Calcd for C18H17N5OS: C, 61.52; H,
4.88; N, 19.93. Found: C, 61.49; H, 4.89; N, 19.95%.
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1118, 1076, 835 cm−1; H NMR δ: 7.16–7.24 (m, 2H, ArH), 7.44 (d,
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(MeOH and EtOH); IR: 3275, 3244, 3170, 1612, 1539, 1236, 1124,
896, 842, 752 cm−1; 1H NMR δ: 7.16 (d, J = 7.2 Hz, 1H, ArH), 7.20–
7.26 (m, 3H, ArH), 7.35–7.39 (dd, J1 = 10.0 Hz, J2 = 9.2 Hz, 1H, ArH),
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57.13; H, 3.67; N, 19.60. Found: C, 57.18; H, 3.64; N, 19.62%.
2′-(3-Bromobenzylidene)-2-[(1H-indol-3-yl)methylidene]hydra-
zine-1-thiocarbohydrazide (4g): Pale yellow solid (85%), m.p. 203–
205 °C (MeOH and EtOH); IR: 3437, 3265, 3145, 1610, 1518, 1470,
1246, 1055, 787, 748, 681 cm−1; 1H NMR δ: 7.16–7.22 (m, 3H, ArH),
7.44–7.46 (d, J = 7.6 Hz, 1H, ArH), 7.73 (t, J = 7.6 Hz, 1H, ArH), 8.25
(d, J = 9.2 Hz, 2H, ArH), 8.33 (s, 1H, NCH), 8.49 (d, J = 7.2 Hz, 1H,
indole-CH in 2-moiety), 8.73 (s, 1H, NCH), 8.78 (s, 1H, ArH), 11.61
(s, 1H, indole-NH), 11.64 (s, 1H, NH), 11.93 (s, 1H, NH); ESI-MS
m/z (%): 823 ([2M+Na]+, 100). Ana1. Calcd for C17H14BrN5S: C,
51.01; H, 3.53; N, 17.50. Found: C, 51.09; H, 3.50; N, 17.48%.
2′-(2,4-Dihydroxybenzylidene)-2-[(1H-indol-3-yl)methylidene]hydra-
zine-1-thiocarbohy-drazide (4h): White solid (91%), m.p. 198–200 °C
(MeOH and EtOH); IR: 3686, 3413, 3290, 1620, 1503, 1232, 1165,
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23 Z.C. Shi, Z.G. Zhao, X.L. Liu and L.L. Wu, J. Chem. Res., 2011, 35, 198.
24 Y. Shi,Y.L. Peng, Z.G. Zhao, G.H. Li and H.R. Li, J. Chem. Res., 2011, 35,
15.
1
882, 741, 658 cm−1; H NMR δ: 6.28–6.38 (m, 2H, ArH), 7.19–7.25
(m, 3H, ArH), 7.44 (d, J = 7.6 Hz, 1H, ArH), 7.90 (s, 1H, ArH), 8.34
(s, 1H, NCH), 8.38 (d, J = 7.2 Hz, 1H, indole-CH in 2-moiety), 8.62
(s, 1H, NCH), 9.94 (s, 2H, OH), 11.36 (s, 1H, indole-NH), 11.71 (s,
1H, NH), 11.84 (s, 1H, NH); ESI-MS m/z (%): 729 ([2M+Na]+, 100).
Ana1. Calcd for C17H15N5O2S: C, 57.78; H, 4.28; N, 19.82. Found: C,
57.75; H, 4.30; N, 19.83%.
25 X.J. Yang, Z.C. Shi and Z.G. Zhao, Chin. J. Synth. Chem. (in Chinese),
2011, 3, 352.
26 F. Han, Y.H. Bao, Z.G. Yang, T.M. Fyles, J.Z. Zhao, X.J. Peng, J.L. Fan,
Y.K. Wu and S.G. Sun, Chem. Eur. J., 2007, 13, 2880.

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