Synthesis of novel schiff bases by microwave irradiation and their in vitro antibacterial activity

Article abstract of DOI:10.14233/ajchem.2013.14878

A series of thiophene-3-carbonitrile contaning schiff bases were synthesized, characterized by the reaction of 2-amino-4,5,6,7-tetrahydrobenzo[ b]thiophene-3-carbonitrile and corresponding active aldehyde under microwave irradiation and screened for their antibacterial activities. The structure of synthesized compounds were established by spectroscopic (FT-IR, ¹H NMR, ¹³C NMR, Mass) and elemental analyses. The antibacterial activity of these compounds were first tested in vitro by the disk diffusion assay against two Gram-positive and two Gram-negative bacteria and then the minimum inhibitory concentration was determined with the reference of standard drug chloramphenicol. The results showed that compound 6 is better at inhibiting the growth as compared to chloramphenicol against both types of the bacteria (gram-positive and gram-negative).

Full text of DOI:10.14233/ajchem.2013.14878

Asian Journal of Chemistry; Vol. 25, No. 15 (2013), 8643-8646
http://dx.doi.org/10.14233/ajchem.2013.14878
Synthesis of Novel Schiff Bases by Microwave Irradiation
and Their in vitro Antibacterial Activity
1,*
1,2
1,2
1
1
SALMAN A. KHAN , ABDULLAH M. ASIRI , AFTAB ASLAM PARWAZ KHAN , KHALID ALI KHAN and MOHIE A.M. ZAYED
1Department of Chemistry, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Kingdom of Saudi Arabia
2Center of Excellence for Advanced Materials Research, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Kingdom of Saudi Arabia
*Corresponding author: Fax: +966 2 6952292; E-mail: sahmad_phd@yahoo.co.in
(Received: 26 November 2012;
Accepted: 26 August 2013)
AJC-14016
A series of thiophene-3-carbonitrile contaning schiff bases were synthesized, characterized by the reaction of 2-amino-4,5,6,7-tetrahydro-
benzo[b]thiophene-3-carbonitrile and corresponding active aldehyde under microwave irradiation and screened for their antibacterial
activities. The structure of synthesized compounds were established by spectroscopic (FT-IR, 1H NMR, 13C NMR, Mass) and elemental
analyses. The antibacterial activity of these compounds were first tested in vitro by the disk diffusion assay against two Gram-positive and
two Gram-negative bacteria and then the minimum inhibitory concentration was determined with the reference of standard drug chloram-
phenicol. The results showed that compound 6 is better at inhibiting the growth as compared to chloramphenicol against both types of the
bacteria (gram-positive and gram-negative).
Key Words: Schiff bases, Microwave, Chloramphenicol, Antibacterial activity.
used organic compounds. They are used as pigments and dyes7,
INTRODUCTION
catalysts8, intermediates inorganic synthesis9 and polymer
stabilizers10. Schiff bases have also been shown to exhibit
Infectious diseases are the main cause of mortality in
abroad range of biological activities, including antifungal11,
the world and the resistance of pathogenic bacteria towards
antibacterial12, antimalarial13, antiproliferative14, antiinfla-
available antibiotics is rapidly becoming a major worldwide
mmatory15, antiviral16 and antipyretic properties17. Its also
problem, hence the design of new compounds to deal with
applicabile in materials fields such as non-linear optical18,
resistant bacteria has become one of the most important areas
optical limiting19, electrochemical sensing20, langmuir film
of antibacterial research today. Food poisoning, rheumatic,
and photoinitiated polymerization21. Five member heterocyclic
salmonellosis and diarrhoea are the second leading cause of
death from bacterial disease world-wide1. More than 50
compounds with sulphur and nitrogen containing are abun-
million people worldwide are infected and up to 1,50,000 die
every year due to these bacterial infections2. Moreover drug
resistance in food poisoning, rheumatic, salmonellosis and
diarrhea can be attributed to the use of drugs (amoxicillin,
norfloxacin, ciprofloxacin chloramphenicol) for treatment and
to the adaptation of the bacterial parasite by developing
alternate pathways for survival3,4. Hence, the present work is
aimed towards developing novel molecules with improved
potential for treating bacterial infections and with decreased
probability for developing drug resistance. Schiff bases, named
for Hugo Schiff, are formed when any primary amine reacts
with an aldehyde or acetone under specific conditions5. Struc-
turally, Schiff base (also known as imine or azomethine) is a
nitrogen analogue of an aldehyde or ketone in which the
carbonyl group(C=O) has been replaced by an imine or
azomethine group6. Schiff bases are some of the most widely
dant in nature and are of great significance to life because
their structural subunits exist in many natural products such
as vitamins, hormones, antibiotics etc. Compounds with a
pyrazoline structure are known to possess tranquilizing muscle
relaxing22, hypnotic23, ulcerogenic24, antidepressant25, anti-
bacterial26, antifungal27, analgesic and antiinflammatory prop-
erties28. Sulphur and nitrogen containing Schiff bases drama-
tically increase the biological activity such as antifungal,
antibacterial, antimalarial, antiproliferative, antiinflammatory,
antiviral and antipyreticproperties29,30. Lot of research has been
carried out on Schiff base derivatives as biological applicable
but no work has been done on this type heterocyclic containing
Schiff base products screening on bacteria. In this paper we
are reporting synthesis and characterizations novel hetero-
cyclic Schiff base under microwave irradiation as antibac terial
agent.

8644 Khan et al.
Asian J. Chem.
(s, CH), 6.47 (s, CH), 3.96 (s, OCH3), 3.94 (s, OCH3), 3.90 (s,
-OCH3), 2.69-1.83 (m, 8H, -CH2-cyclic); 13C NMR (CDCl3)
δ: 161.86, 156.16, 154.45, 15.27, 143.72, 134.68, 130.95,
115.52, 114.97, 108.97, 105.09, 95.83, 58.47, 56.32, 56.26,
56.10, 25.15, 28.47, 56.32, 56.26, 56.10, 25.15, 24.30, 23.12,
22.05, 18.43; EI-MS m/z (rel. int. %): 358(62) [M+1]+.; Anal.
calcd. for C19H20N2O3S: C, 64.02, H, 5.66, N, 7.86, Found: C,
63.98, H, 5.62, N, 7.83.
EXPERIMENTAL
Aldehydes have used fromAcros Organic and used with-
out further purification. Other solvents (A.R.) and reagents
were obtained commercially and used without further purifi-
cation except for dimethylformamide (DMF), ethanol and
methanol. Melting points were recorded on a Thomas Hoover
capillary melting apparatus without correction. IR spectra were
taken on KBr disks on a Nicolet Magna 520 FTIR spectro-
2-{[(E)-(3,4-dimethoxyphenyl)methylidene]amino}-
4,5,6,7-tetrahydro-1-benzothiophene-3-carbonitrile (4): IR
(KBr, νmax, cm-1): 2925(C-H), 1595 (C=C), 1566 (C=N), 1159
meter, H NMR and 13C NMR were recorded in CDCl3 on a
1
Brucker DPX 600 MHz spectrometer using TMS as internal
standard. Microanalyses were carried out using a Perkin Elmer
240B analyzer.
1
(C-N), 750 (C-S); H NMR (CDCl3) δ : 8.33 (s, 1H,
CHolefinic), 7.62 (s, CH), 7.36 (d, CH, J = 1.8 Hz), 6.93 (d,
CH, J = 3.8 Hz), 3.99 (s, -OCH3), 3.95 (s, -OCH3), 2.70-1.83
(m, -CH2-cyclic); 13C NMR (CDCl3) δ: 160.48, 158.66, 152.95,
149.50, 134.97, 131.17, 128.30, 125.51, 114.74, 110.48,
109.23, 105.78, 58.48, 56.08, 56.03, 25.17, 24.31, 23.08,
22.01, 18.43; EI-MS m/z (rel. int. %): 328 (72) [M+1]+.; Anal.
calcd. for C18H18N2O2S: C, 66.23, H, 5.56, N, 8.58, Found: C,
66.19, H, 5.52, N, 8.51.
Synthesis of Schiff bases: The Schiff base derivatives
were synthesized by using the literature procedure (Scheme-
I)31.A mixture of 2-amino-4,5,6,7-tetrahydro-benzo[b] thiophene-
3-carbonitrile and (5.8 mmol) and corresponding active alde-
hyde. (5.8 mmol) in anhydrous methanol (10 mL), in a beaker
(100 mL), in the presence of few drop of acetic acid and the
reaction mixture was heated inside a microwave oven for 2-5
min (at 210W, i.e. 30 % microwave power). Progress of reaction
was monitored by TLC. After completion of the reaction cool-
ing the reaction mixture, a good yield were obtained and
recrystallized from chloroform and ethanol (9:1), giving
crystals (1-6).
2-{[(E)-(9-ethyl-9H-carbazol-3-yl)methylidene]-
amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-
carbonitrile (5): IR (KBr, νmax cm-1): 2935 (C-H), 1586 (C=C),
1558 (HC=N), 1123 (C-N), 746 (C-S); 1H NMR (600 MHz,
CDCl3) δ : 8.55 (s, 1H, CH olefinic), 8.15 (d, CH, J = 7.8 Hz),
8.11 (d, CH, J = 8.4 Hz), 7.51 (dd, CH, J = 1.2 Hz), 7.42 (dd,
CH, J = 2.4 Hz), 7.30 (s, CH), 4.38 (q, N-CH2-CH3, Hz, J =
6.6 Hz), 1.25 (t, N-CH2-CH3, J = 7.2), 2.69-1.46 (m, 8H,
-CH2-,cyclic); 13C NMR (CDCl3) δ: 161.27, 159.93, 142.51,
140.44, 134.70, 130.94, 128.32, 127.12, 126.27, 123.21,
122.90, 120.81, 119.97, 115.06, 108.89, 105.89, 58.46, 37.81,
25.16, 24.30, 23.12, 22.04, 18.42, 13.87; EI-MS m/z (rel. int.
%): 385 (64) [M+1]+.; Anal. calcd. for C24H21N3S: C, 75.16,
H, 5.09, N, 10.92, Found: C, 75.12, H, 5.01, N,8.88.
N
N
O
Microwave radiation
H
N
R
+
H2N
S
H
EtOH, 2 to 5 min
S
R
Scheme-I: Synthesis of novel Schiff bases (1-6)
2-{[(E)-1,3-benzodioxol-5-ylmethylidene]amino}-
4,5,6,7-tetrahydro-1-benzothiophene-3-carbonitrile (1): IR
(KBr, νmax, cm-1): 2934 (C-H), 1573 (HC=N), 1137 (C-N), 771
(C-S); 1H NMR (600 MHz, CDCl3) (δ/ppm): 8.27 (s, CH ole-
finic), 7.50 (s, CH), 7.29 (d, CH, J = 8.4 Hz), 6.87 (d, CH, J =
8.4 Hz), 6.05 (s, -CH2), 2,69-1.23 (m, 8H, CH2-cyclic); 13C
NMR ( CDCl3) δ: 160.15, 158.10, 151.50, 148.57, 134.92,
131.78, 129.96, 127.00, 114.68, 108.32, 107.16, 106.18; EI-
MS m/z (rel. int.%): 312 (58) [M+1]+.; Anal. calcd. for
C17H14N2O2S: C, 65.79, H, 4.55, N, 9.03, Found: C, 65.75, H,
4.51, N, 8.98.
2-{[(E)-(4-chlorophenyl)methylidene]amino}-4,5,6,7-
tetrahydro-1-benzothiophene-3-carbonitrile (6): IR (KBr,
ν
max, cm-1): 2942 (C-H), 1592 (C=C), 1558 (C=N), 1133 (C-N),
1
756 (C-S); H NMR (CDCl3) δ: 8.36 ((s, 1H, CH olefinic),
7.86 (d, CHaromatic, J = 1.2 Hz), 7.86 (d, CH, J = 1.2 Hz),
7.45 (d, CHaromatic J = 1.8 Hz), 2.71-1.83 (m, 8H, -CH2-
cyclic); 13C NMR (CDCl3) δ: 159.25, 157.24, 138.37, 135.29,
133.50, 132.96, 130.50, 129.23, 114.43, 107.46, 25.23, 24.24,
23.01, 21.94. EI-MS m/z (rel. int.%): 302 (60) [M+1]+.; Anal.
calcd. for C16H13N2SCl: C, 63.89, H, 4.36, N, 9.31, Found: C,
63.85, H, 4.32, N, 9.28.
2-{[(E)-(4-methoxyphenyl)methylidene]amino}-
4,5,6,7-tetrahydro-1-benzothiophene-3-carbonitrile (2): IR
(KBr, νmax cm-1): 2936(C-H), 1594(C=C), 1558 (C=N),
In vitro screening: Disc -diffusion and micro dilution
assay: Antibacterial activity was done by the disk diffusion
method with minor modifications. S. aureus, S. pyogenes, S.
typhimurium and E. coli were sub-cultured in BHI medium
and incubated for 18 h at 37 ºC and then the bacterial cells
were suspended, according to the McFarland protocol in saline
solution to produce a suspension of about 10-5 CFU mL-1: 10
µL of this suspension was mixed with 10 mL of sterile nutrient
agar at 40 ºC and poured onto an agar plate in a laminar flow
cabinet. Five paper disks (6.0 mm diameter) were fixed onto
nutrient agar plate. One mg of each test compound was dis-
solved in 100 µL DMSO to prepare stock solution from stock
solution different concentration 10, 20, 25, 50 and 100 µg/µL
1
1135(C-N), 771(C-S); H NMR (CDCl3) δ: 8.34 (s, 1H, CH
olefinic), 7.89 (d, CH, J = 6.6 Hz), 7.88 (d, CH, J = 6.2 Hz),
6.98 (d, CH, J = 6.8 Hz), 1.899-1.82 (m, 8H -CH2-cyclic),
2.60 (s, -OCH3); 13C NMR (CDCl3) δ: 163.09, 160.61, 158.39,
134.84, 131.50, 131.39, 127.97, 114.78, 114.36, 105.88, 58.46,
55.51, 25.16, 24.28, 23.08, 22.01, 18.42; EI-MS m/z (rel.
int.%): 298 (65) [M+1]+.; Anal. calcd. for C17H16N2OS: C,
68.89, H, 5.44, N, 9.45, Found: C, 68.84, H, 5.41, N, 9.39.
2-{[(E)-(2,4,5-trimethoxyphenyl)methylidene]amino}-
4,5,6,7-tetrahydro-1-benzothiophene-3-carbonitrile (3): IR
(KBr, νmax cm-1: 2932(C-H), 1586(C=C), 1562 (C=N), 1127(C-
N), 759 (C-S); 1H NMR (CDCl3) δ: 8.77 (s, CH olefinic), 7.70

Vol. 25, No. 15 (2013)
Synthesis of Novel Schiff Bases by Microwave Irradiation and Their Antibacterial Activity 8645
TABLE-1
PHYSICOCHEMICAL DATA OF THE SYNTHESIZED COMPOUNDS (1-6)
Compound
Molecular formula
C17H14N2O2S
m.p. (oC)/ Crystallization
179/CHCl3
Yield (%)
85.2
Reaction time (min)
2.5 min
R
1
O
O
C17H16N2OS
C19H20N2O3S
132 /CH3OH
208 /CH2Cl2
85.00
83.5
2.0 min
3 min
2
3
O
O
O
O
O
O
C18H18N2O2S:
160/CHCl3
80.2
3.5 min
4 min
4
5
C24H21N3S
190.7/CH3OH
86.25
N
C16H13N2SCl
231/CHCl3
88.5
5 min
6
Cl
of each test compound were prepared. These compounds of
different concentration were poured over disk plate on to it.
Chloramphenicol (30 µg/disk) was used as standard drug
(positive control). DMSO poured disk was used as negative
control. The susceptibility of the bacteria to the test compounds
was determined by the formation of an inhibitory zone after
18 h of incubation at 36 ºC (Table-2) reports the inhibition
zones (mm) of each compound and the controls. The minimum
inhibitory concentration (MIC) was evaluated by the macro
dilution test using standard inoculums of 10-5 CFU mL-1.
Serial dilutions of the test compounds, dissolved in dimethyl
sulfoxide were prepared to final concentrations of 512, 256,
128, 64, 32, 16, 8, 4, 2 and 1 µg/mL to each tube was added
100 µL of a 24 h old inoculum. The MIC, defined as the lowest
concentration of the test compound, which inhibits the visible
growth after 18 h, was determined visually after incubation
for 18h, at 37 ºC and the results are presented in Table-3. Tests
using DMSO and chloramphenicol as negative and positive
controls.
showed intense bands at 1573-1558 cm-1 due to ν(C=N) stretch,
which confirmed the formation of donor accepter dyes
derivatives. Further evidence for the formation of Schiff base
1
derivative was obtained from the H NMR spectra, which
provide diagnostic tools for the positional elucidation of the
protons.Assignments of the signals are based on the chemical
shifts and intensity patterns. The aromatic protons of Schiff
base are shown as s,d and dd in the range (6.47-8.15) ppm for
the compounds. A Singlet due to 1H, CHolefinic, proton in
the compounds was observed at (8.27-8.77) ppm respectively.
13C NMR (CDCl3) spectra of Schiff base derivatives were
recorded in CDCl3 and spectral signals are in good agreement
with the probable structures details of 13C NMR spectra of all
compounds are given in the experimental section. Finally charac-
teristic peaks were observed in the mass spectra of Schiff base
by the molecular ion peak. The mass spectrum of compound
2 shows a molecular ion peak (M+.) m/z 298.
Antimicrobial activity: Disc.-diffusion and micro
dilution assay: The compounds (1-6) were tested for their
antibacterial activities by disc-diffusion method using nutrient
broth medium [contained (g/L): beef extract 3 g; peptone 5 g;
pH 7.0]32. The Gram-positive bacteria and Gram-negative
bacteria utilized in this study consisted of S. aureus, S.
pyogenes, S. typhimurium and E. coli. In the disc-diffusion
method, sterile paper discs (0.5 mm) impregnated with com-
pound dissolved in dimethyl sulfoxide at concentration 100
µg/mL were used. Then, the paper discs impregnated with the
solution of the compound tested were placed on the surface of
the media inoculated with the microorganism. The plates were
incubated at 35 ºC for 24 h.After incubation, the growth inhibi-
tion zones are shown in Table-2. The chalcone derivative was
further checked by MIC method. The results are presented in
Table-3.
RESULTS AND DISCUSSION
The synthesis of Schiff base derivatives is straight forward
and the compounds were isolated in good yield. The derivatives
were synthesized by using the literature procedure31. The
obtained compounds are stable in the solid state as well as in
the solution state. Physical data of the compounds (1-6) are
given in Table-1. The analytical data of these compounds are
in good agreement with their composition. The structure of
all the compounds presented in experimental section was
established by comparing spectral data (FT-IR, 1H NMR, 13C
NMR, Mass) and elemental analyses. Assignments of selects
characteristic IR band positions provide significant indication
for the formation of the Schiff base derivative. The compounds

8646 Khan et al.
Asian J. Chem.
TABLE-2
ANTIBACTERIAL ACTIVITY OF SCHIFF BASE DERIVATIVE, POSITIVE CONTROL CHLORAMPHENICOL
(CHLORA.) AND NEGATIVE CONTROL (DMSO) MEASURED BY THE HALO ZONE TEST (UNIT, mm)
Corresponding effect on microorganisms
Compounds
S. aureus
11.8 0.5
12.6 0.5
12.3 0.5
12.6 0.5
15.5 0.4
17.4 0.4
17.0 0.5
-
S. Pyogenes
11.2 0.4
11.6 0.4
12.8 0.5
13.2 0.5
15.6 0.5
18.8 0.5
18.2 0.4
-
S. typhimurium
10.8 0.2
10.6 0.4
11.4 0.4
11.8 0.5
16.6 0.4
18.6 0.4
17.2 0.8
-
E. coli
1
11.4 0.5
12.6 0.5
12.2 0.8
11.5 0.5
17.2 0.5
21.5 0.5
20.0 0.2
-
2
3
4
5
6
Chlora.
DMSO
4. S.A. Puerto, G.J. Fernandez, L.J. Castillo, M. Jose, S. Pinoa and P.G.
Anguloa, Diag. Microbiol. Infect. Dis., 42, 1513 (2006).
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TABLE-3
MINIMUM INHIBITION CONCENTRATION OF SCHIFF BASE
DERIVATIVE (1-6) PRODUCTS, POSITIVE CONTROL:
CHLORAMPHENICOL
Minimum inhibition concentration
Positive
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(µg mL-1) compound
Bacterial strain
1
2
3
4
5
6
Control
32
S. aureus
512 256 128 128
256 128 256 128
64
64
32
32
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S. pyogenes
32
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S. typhimurium 256 128 256 256 128 32
32
E. coli
512 256 128 512
32
32
32
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Conclusion
The novel Schiff bases thiophene containing nucleus were
synthesized by the reaction of 2-amino-4,5,6,7-tetrahydro-
benzo[b]thiophene-3-carbonitril and corresponding active
aldehyde and were studied for their antimicrobial activity. The
results of antibacterial screening reveal that among all the com-
pounds screened, compound 5 showed moderate antibacterial
activity while compound 6 displayed good antibacterial activity
when compared with chloramphenicol used as standard.
Particularly, compound 6 which is carrying chloro substituent
appears to exhibit the highest antibacterial activity. Our experi-
mental results were found in good corroboration with the theore-
tical results. Structure activity relationship studies revealed that
chloro substituted derivatives play important role in antimicrobial
activity. The present work suggests that there is need to develop
nonantibiotic drugs, which may overcome antibiotic resistance.
Such highly bioactive drugs preferably herbal preparations with
least toxicity.A little structure variation can cause immense diffe-
rence in the activity of the drug. This approach can open new
vistas in the chemotherapy of the infective disease. The field is
further open for pharmacokinetics and clinic studies to establish
these molecules as drugs in the market.
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ACKNOWLEDGEMENTS
27. B.S. Creaven, B. Duff, D.A. Egan, K. Kavanagh, G. Rosair, V.R.
Thangella and M. Walsh, Inorg. Chim. Acta, 363, 4048 (2010).
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S.Y. Abbas, Eur. J. Med. Chem., 45, 3365 (2010).
This Project was funded by SABIC and Deanship of Scien-
tific Research (DSR), King Abdulaziz University, Jeddah,
under Grant No. 13/258/1432. The authors, therefore, acknowl-
edge with thanks SABIC and DSR technical and financial support.
29. K.M. Amin, M.M. Kamel, M.M. Anwar, M. Khedr and Y.M. Syam,
Eur. J. Med. Chem., 45, 2117 (2010).
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45, 4215 (2010).
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