Derivatives of benzimidazole pharmacophore: Synthesis, anticonvulsant, antidiabetic and DNA cleavage studies

Article abstract of DOI:10.1016/j.ejmech.2010.01.007

In seeking broad spectrum pharmacological activities of benzimidazole derivatives, a group of 4-thiazolidinones 5(a-j) and 1,3,4-oxadiazoles 6(a-j) containing 2-mercapto benzimidazole moiety were synthesized and screened for in vivo anticonvulsant activit

Full text of DOI:10.1016/j.ejmech.2010.01.007

European Journal of Medicinal Chemistry 45 (2010) 1753–1759
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Derivatives of benzimidazole pharmacophore: Synthesis, anticonvulsant,
antidiabetic and DNA cleavage studies
*
Ramya V. Shingalapur, Kallappa M. Hosamani , Rangappa S. Keri, Mallinath H. Hugar
P.G. Department of Studies in Chemistry, Karnatak University, Pavate Nagar, Dharwad – 580 003, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In seeking broad spectrum pharmacological activities of benzimidazole derivatives, a group of 4-thia-
zolidinones 5(a–j) and 1,3,4-oxadiazoles 6(a–j) containing 2-mercapto benzimidazole moiety were
synthesized and screened for in vivo anticonvulsant activity by Maximal Electroshock (MES) model and
antidiabetic activity using Oral Glucose Tolerance Test (OGTT). Compounds (5c), (5d), (5g) and (5i)
exhibited potent anticonvulsant results and (6c), (6d), (6h) and (6i) showed excellent antidiabetic
activities and also pharmacophore derived from active molecules suggested that presence of –OH group
was a common feature in all active compounds. In DNA cleavage studies, compound (5d) cleaved DNA
completely as no trace of DNA was found. On the other hand, a sharp streak was found for compounds
(5c), (6a) and (6d).
Received 30 September 2009
Received in revised form
4 January 2010
Accepted 6 January 2010
Available online 14 January 2010
Keywords:
4-Thiazolidinones
1,3,4-Oxadiazoles
2-Mercapto benzimidazole
Anticonvulsant
Antidiabetic
Ó 2010 Elsevier Masson SAS. All rights reserved.
DNA cleavage
1. Introduction
end-stage renal disease [4], followed by neuropathy, cataracts and
retinopathy, which practically are not controlled by insulin. Sulfo-
Epilepsy, being one of the most common and serious neuro-
logical disorders is characterized by recurrent seizures which
results from a temporary electrical disturbance of the brain due to
an imbalance between excitory and inhibitory neurotransmitters.
The mechanisms of action of the antiepileptic drugs (AEDs) consist
in the blockade of voltage-dependent Naþ channels or T-type Caþþ
channels, inhibition of glutamatergic transmission and facilitation
nylureas are the most widely used antidiabetic agents. These agents
are acting on pancreatic -cells stimulating insulin secretion. Next
b
to these are thiazolidinediones which enhance insulin action.
Glibenclamide, Ciglitazone and Troglitazone belong to this group
which is effective towards enhancing insulin in a large number of
Type-2 patients. Metformin which belongs to the third class of
oral-lowering agents i.e., Biguanides, enhances insulin action at the
postreceptor level in peripheral tissues such as muscle [5].
DNA is a helical polyanion built by the union of two linear
polymeric strands that are composed of sugars (deoxyribose)
linked by phosphates. It is an important target of antitumoral drugs
because it plays a central role in replication, transcription, and
regulation of genes. Substantial progress has been made during the
past few decades to develop metal-based small molecules as DNA
foot-printing as well as therapeutic agents that are capable of
binding and cleaving DNA under physiological conditions [6–8].
DNA cleavage can occur by a nucleophilic attack to a phosphate in
nucleic acid backbone [9,10]. The design of DNA and RNA-specific
agents capable of controlled chemical cleavage are of paramount
importance due to their potential use as drugs, regulators of gene
expression and tools for molecular biology. The ability to selectively
target and cleave DNA with high affinity and to report on the
binding event by changes in luminescence is of great current
interest [11,12].
of
g-aminobutyric acid (GABA) inhibitory neurotransmission.
About one third of patients do not respond well to current multiple
drugs therapy [1,2]. Phenytoin, Carbamazepine and Sulfamate
topiramate (TPM) are recent antiepileptic drugs which have been
clinically effective against different types of seizures [3].
Diabetes mellitus (DM) is a non-communicable disease and the
most daunting challenges posed by chronic, complex and a multi-
farious group of disorders that disturbs the metabolism of carbo-
hydrates, fats and proteins resulting from insulin deficiency or
insulin resistance. Insulin resistance is associated with a deficit in
protein tyrosine phosphorylation in insulin signal transduction
cascade. Diabetic nephropathy, a serious chronic diabetic micro-
vascular complication has become most important cause of
* Corresponding author. Tel.: þ91 836 2215286; fax: þ91 836 2747884/þ91 836
2771275.
E-mail address: dr_hosamani@yahoo.com (K.M. Hosamani).
0223-5234/$ – see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.01.007

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R.V. Shingalapur et al. / European Journal of Medicinal Chemistry 45 (2010) 1753–1759
The target thiazolidinone and oxadiazole pharmacophores are
2. Chemistry
being introduced to 2-mercapto benzimidazole in search of potent
drugs. The introduction of sulphur was expected to bring in a bulky
polarisable atom for potent pharmacological activities, thus
altering its geometry, polarisability, stability, lipophilicity, steric
and electronic characteristics of the molecule. It was also antici-
pated that, thiazolidinone ring along with sulphur atom improves
the activity of lead molecules. Wherein, 4-thiazolidinones have
many interesting activity profiles [13,14]. Similarly, 1,3,4-oxadia-
zoles [15] are thermally stable and neutral heteroaromatic mole-
cules which exhibit one of the active class of compounds possessing
various pharmacological properties such as antimicrobial [16],
antiinflammatory [17], antimalarial [18], antimycobacterial [19]
and anti HIV [20] activities.
Considering extensive applications of benzimidazole moiety in
medicinal chemistry and in continuation of our ongoing project
biologically active heterocycles [21–25], an attempt has been made
to synthesize 4-thiazolidinone and 1,3,4-oxadiazole derivatives
containing 2-mercapto benzimidazole and evaluate for their in vivo
bioassays.
2-Mercapto benzimidazole (1) was prepared according to
reported method [26]. The synthetic routes to compounds 5(a–j)
and 6(a–j) are illustrated in Scheme 1. The appearance of signals at
d
1.32 ppm due to –CH3 and d 4.33 ppm due to –CH2 in
–COOCH2CH3 in 1H NMR confirms the formation of ester (2). This
was also confirmed by IR spectra which shows a band at 1720 cmꢀ1
because of C]O of ester. Compound (3) was confirmed by signals at
d
8.02 ppm and d 4.13 ppm due to –CONH and –NH2 respectively.
The pC]O band for amide in IR appears at 1641 cmꢀ1 and –NHNH2
around 3207 and 3346 cmꢀ1 confirms the formation of (3). A signal
at
the formation of thiazolidinone ring. In the 1H NMR spectra of
4(a–j), the proton of –N]CH appears at about 4.02–4.10 ppm. But,
d 3.70 ppm and 3.65 ppm due to pCH–Ar– and –S–CH2– confirms
d
in the spectra of 5(a–j), this proton signal is shifted slightly
downfield in contrast with compounds 4(a–j). The reason being the
deshielding affected by heterocycles, which shifted the resonances
to about
a multiplet in the region
d 3.70–3.95 ppm. The aromatic protons appeared as
d
6.98–8.01 ppm. In 13C NMR, signals of
NH2
NH2
N
N
(ii)
(i)
SH
SCH2COOC2H5
+ ClCH2COOC2H5
N
H
N
H
(1)
(2)
(iii)
N
O
SCH2
N
(iv)
SCH2CONHN CH
R
S
NHNH2
N
H
N
H
4 (a-j)
(3)
(vi)
N
(v)
O
N
N
N
SCH2
SCH2CONH
N
O
R
R1
N
H
N
H
6 (a-j)
5 (a-j)
(iii) EtOH , NH2NH2.H2O
(vi) R1-COOH , POCl3
(ii) EtOH
(v)
(i) CS2, NaOH, EtOH
(iv) R-CHO
SHCH2COOH, DMF, ZnCl2
OH
d)
R = a)
c)
b)
g)
e)
Cl
OH
OH
CH3
NH2
OH
h)
f)
i)
j)
O
OMe
OMe
R1 = a)
b)
c)
e)
HO
d)
i)
OH
OH
Cl
OH
Cl
f)
HO
g)
h)
j)
OH
N
OH
NH2
NO2
NO2
Scheme 1. Synthetic pathway to generate benzimidazole derivatives.

R.V. Shingalapur et al. / European Journal of Medicinal Chemistry 45 (2010) 1753–1759
1755
ring S–CH2 and ring pC]O appeared at about
172.35 ppm respectively. The appearance of (C–O–C) signal at
1267.7 cmꢀ1 confirms the formation of the oxadiazole moiety.
d
31.63 and
compounds showed better reduction in blood–glucose levels on
9th day compared with glibenclamide. They were considered as
significant compared to diabetic control group. Therefore, the best
potent activity was found to be associated with (6c), (6d), (6h) and
(6i). Several other compounds (6a), (6b), (6c), (6f), (6h) and (6i)
were significant compared to normal control group during Oral
Glucose Tolerance Test at 90th min.
3. Pharmacology
All the compounds prepared herein were screened for their
potential in vivo biological activities such as anticonvulsant, anti-
diabetic and DNA cleavage studies. The anticonvulsant activities of
the synthesized compounds were tested through an in vivo rodent
model of convulsions (Maxima ElectroShock, MES test) [27]. Eval-
uation of antidiabetic activity was done by blood–glucose test and
oral glucose tolerance test (OGTT) [28,29]. Male Wister albino rats
(150–200 g) of either sex were selected. DNA cleavage of selected
compounds is also studied by electrophoresis method.
4.1.3. DNA cleavage study
The results of DNA cleavage for compounds 5(a–f) and 6(a–f)
studied by agarose gel electrophoresis method. The gel after
electrophoresis clearly revealed that, compound (5d) did cleave
the DNA completely, as no traces of DNA were found. (5c) was
also found to be significant than other compounds. In case of
6(a–f), a sharp streak was found for compounds (6a) and (6d).
Other compounds were seen to be nearly completely inactive to
cleave DNA.
4. Results and discussion
5. Conclusion
4.1. Pharmacology
By choosing proper experimental conditions we have been able
to synthesize thiazolidinone and oxadiazole containing 2-mercapto
benzimidazole derivatives and investigate for various bioassays
with the hope of discovering new structure leads serving as
potential broad spectrum pharmacological agents. SAR studies
revealed the critical role of –OH function in the target compounds
that showed very promising activities. Compounds (5c), (5d), (5g)
and (5i) were considered significant compared to control group for
anticonvulsant activity. Meanwhile compounds (6c), (6d), (6h) and
(6i) showed excellent activity against Glibenclamide and were
considered significant compared to diabetic control group.
Compound (5d) cleaved DNA completely as no traces of DNA were
found. Other compounds were seen to be nearly completely inac-
tive to cleave DNA.
4.1.1. Anticonvulsant activity
Results of anticonvulsant activity with standard drug phenytoin
are discussed in Table 1. The existence of a hydrophobic unit in
benzimidazole ring, an electron donor group and hydrogen-
bonding domain was essential for anticonvulsant activity as
depicted by the models and also evidenced by active drug
phenytoin and carbamazepine.
A study of structure–activity
relationship revealed that compounds (5c), (5d), (5g) and (5i)
exhibited their ability to diminish tonic-extensor seizures. The
presence of a hydroxyl –OH function at 2 and 4 position of the
phenyl ring as seen with compounds (5c), (5d), (5g) and (5i) was
found to be the main structural requirement for maintaining
anticonvulsant activity. The extensor phase time was remarkably
reduced for these compounds. This requirement was further
evidenced by compounds (5b) and (5e) where –OH function was
replaced by a –Cl, –CH3 function, which resulted in complete loss of
activity due to the disappearance of this function and can be
explained in terms of interaction at the binding site by the phar-
macophoric models. From the present study, four compounds have
emerged as lead moieties. Further structural modifications might
lead to the discovery of more potent anticonvulsant agents.
6. Experimental section
6.1. Chemistry
All reagents and solvents were used as obtained from the
supplier or recrystallized/redistilled unless otherwise noted.
Melting points were determined in open capillaries and are
uncorrected. Infrared spectra were recorded using KBr pellets on
Nicolet 5700 FT-IR instrument. The 1H NMR and 13C NMR spectra
were recorded on Brucker Avanace-300 (300 MHz) model
4.1.2. Antidiabetic study
In vivo efficacy of compounds 6(a–j) was evaluated for antidia-
betic activity and the results are discussed in Table 2. Four
Table 1
Anticonvulsant activity of 4-thiazolidinones 5(a–j) using Maximal Electroshock (MES) Model.
S. No treatment (dose)
Time (s) in various phases of convulsion (mean ꢁ SEM)
Flexion
Extensor
Clonus
Stupor
Recovery/Death
Control Gumacacia
Phenytoin (Std. drug)
1% w/w
3.12 ꢁ 0.31
11 ꢁ 0.57
0 ꢁ 0.00**
16.80 ꢁ 2.50
4.90 ꢁ 4.20ns
1.20 ꢁ 1.20*
1.36 ꢁ 1.32*
15.62 ꢁ 2.10*
1.02 ꢁ 1.20*
14.62 ꢁ 2.10ns
218.33 ꢁ 5.80
158.6 ꢁ 20.51ns
192.5 ꢁ 13.20ns
215.5 ꢁ 20.54ns
209.3 ꢁ 4.96*
202.1 ꢁ 20.54ns
207.3 ꢁ 4.96ns
208.0 ꢁ 5.66ns
213.80 ꢁ 5.68*
208.6 ꢁ 4.80ns
172.5 ꢁ 13.40ns
210.5 ꢁ 4.85*
–
20 mg/kg
80 mg/kg
75 mg/kg
85 mg/kg
70 mg/kg
70 mg/kg
75 mg/kg
82 mg/kg
65 mg/kg
60 mg/kg
60 mg/kg
2.87 ꢁ 0.31ns
3.20 ꢁ 0.25ns
4.56 ꢁ 1.02ns
3.14 ꢁ 0.30ns
3.96 ꢁ 1.16ns
3.12 ꢁ 0.30ns
3.02 ꢁ 0.27ns
3.30 ꢁ 0.36ns
4.20 ꢁ 1.08ns
3.08 ꢁ 0.28*
3.15 ꢁ 0.25*
Recovery
Death
Death
Death
Death
Death
Death
Death
Death
Death
Death
5a
5b
5c
5d
5e
5f
5g
5h
5i
9.20 ꢁ 0.70*
12.1 ꢁ 0.57*
4.33 ꢁ 0.42**
3.73 ꢁ 0.42**
11.0 ꢁ 0.57ns
9.50 ꢁ 0.57*
4.21 ꢁ 0.39**
5.30 ꢁ 0.31
3.98 ꢁ 0.44**
5.66 ꢁ 0.21**
ns
12.62 ꢁ 2.10
16.20 ꢁ 2.14**
1.00 ꢁ 1.20*
1.80 ꢁ 1.20*
15.40 ꢁ 2.15*
5j
The active compounds are marked in bold letters.
P > 0.05 is considered as non-significant (ns).
P < 0.05 is considered as significant.
**P < 0.001 as compared to normal control group.
***P < 0.001 as compared to diabetic control group.

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R.V. Shingalapur et al. / European Journal of Medicinal Chemistry 45 (2010) 1753–1759
Table 2
Antidiabetic activity of 1,3,4-oxadiazoles 6(a–j) using Oral Glucose Tolerance Test (OGTT) test.
Treatment & Groups
Blood glucose level in mg/dl
Basal
Oral Glucose Tolerance Test (OGTT) in non-diabetic rats
9th day
Fasting
30 min
90 min
Control Normal saline
Diabetic control (Alloxan)
Glibenclamide (Std drug)
74.67 ꢁ 1.38
336.6 ꢁ 2.651þþþ
332.3 ꢁ 4.349
320.2 ꢁ 7.58
352.0 ꢁ 12.53
353.0 ꢁ 6.74
327.3 ꢁ 5.00
320.0 ꢁ 7.58
352.0 ꢁ 12.53
320.0 ꢁ 7.58
322.2 ꢁ 1.80
327.4 ꢁ 5.00
325.5 ꢁ 7.58
79.17 ꢁ 0.48
83.33 ꢁ 1.54
–
183.2 ꢁ 3.68
–
135.7 ꢁ 2.9
339.8 ꢁ 1.815þþþ
139.2 ꢁ 2.52***
337.2 ꢁ 13.08
386.7 ꢁ 25.68
181.2 ꢁ 17.49***
166.2 ꢁ 15.20***
337.2 ꢁ 13.08
386.4 ꢁ 25.60
335.5 ꢁ 12.42
158.7 ꢁ 4.76***
187.7 ꢁ 29.4***
343.3 ꢁ 14.40
–
79.17 ꢁ 3.15
76.33 ꢁ 2.98
74.83 ꢁ 1.62
80.33 ꢁ 2.55
80.83 ꢁ 3.33
81.50 ꢁ 2.14
73.33 ꢁ 3.72
80.85 ꢁ 2.55
78.33 ꢁ 2.30
77.17 ꢁ 2.57
81.34 ꢁ 2.92
176.8 ꢁ 3.04
180.2 ꢁ 6.40
173.2 ꢁ 5.50
162.8 ꢁ 6.60
167.5 ꢁ 3.05
155.7 ꢁ 2.20
174.2 ꢁ 3.38
155.5 ꢁ 2.20
154.5 ꢁ 5.77
155.3 ꢁ 10.38
181.8 ꢁ 3.09
105.7 ꢁ 2.20**
107.7 ꢁ 3.30**
120.0 ꢁ 4.50**
107.3 ꢁ 2.81**
125.0 ꢁ 2.70
106.5 ꢁ 2.10
110.0 ꢁ 3.70**
106.5 ꢁ 2.15
110.0 ꢁ 4.11**
121.7 ꢁ 10.6**
122.8 ꢁ 2.85
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
The active compounds are marked in bold letters.
One way ANOVA followed by Dunnets‘t’ test. Values are expressed as ꢁ SEM.
P > 0.05 is considered as non-significant.
P < 0.05 is considered as significant.
þþþP < 0.001 as compared to normal control group.
**P < 0.001 as compared to normal control group.
***P < 0.001 as compared to diabetic control group.
spectrophotometer in CDCl3 and DMSO as a solvent and TMSi as
internal standard with 1H resonant frequency of 300 MHz and 13C
resonant frequency of 75 MHz D2O exchange was applied to
confirm the assignment of the signals of NH protons. The chemical
–CONH–), 10.25 (s, 1H, –NH–benzimidazole). Anal. Calcd for
C9H10N4OS: C, 48.64; H, 4.80; N, 25.22%. Found: C, 48.67; H, 4.83; N,
25.26%.
shifts were measured in ppm downfield from internal TMSi at
d
¼ 0.
6.1.4. Synthesis of (1H-benzimidazol-2-ylsulfanyl)-acetic acid
hydrazide (4)
The mass spectra were recorded on Schimadzu GCMS-QP2010S at
70 eV. All reactions were monitored by thin layer chromatography
(TLC) using E. Merck 60F254 procoated silica gel plates detected by
UV light (254 nm) or iodine vapours. The elemental analysis was
carried out by using Heraus CHN rapid analyzer. All the compounds
gave C, H and N analysis within ꢁ0.5% of the theoretical values. The
biological activities were carried out at Luqman Pharmacy College,
Gulbraga, Rajiv Gandhi University, India.
A mixture of compound (3) (2.22 g, 0.01 mol), respective alde-
hyde (1.06 mL, 0.01 mol) and 2–3 drops of glacial acetic acid in
ethanol (20 mL) was refluxed on a water bath for about 6 h. The
solvent was removed and the residue recrystallized from chloro-
form–methanol mixture to yield the required compound. The other
compounds 4(a–j) were prepared similarly by treating with
corresponding aldehydes.
6.1.1. General method for the synthesis of 2-mercapto
benzimidazole (1)
6.1.5. Synthesis of (1H-benzimidazol-2-ylsulfanyl)-thiazolidin-4-
one 5(a–j)
Compound (1) was prepared according to the reported
procedure [26].
To a solution of (4) (0.01 mol) in DMF (30 mL) was added
mercapto acetic acid (0.9 mL, 0.01 mol) and ZnCl2 (1 g) and the
reaction mixture was refluxed for 8 h, cooled and poured onto
crushed ice, the separated solid was filtered and washed with 10%
NaHCO3. The crude product was dried and recrystallized from DMF
to obtain the desired compound.
6.1.2. Synthesis of ethyl 2-(benzimidazolyl-thio) acetate (2)
An equimolar solution of 2-mercapto benzimidazole (1) (1.50 g,
0.01 mol) and ethylchloroacetate (1.22 mL, 0.01 mol) in dry acetone
(4 mL) in presence of anhydrous K2CO3 (1 g) was refluxed on
a water bath for 6 h. The solvent was removed by vacuum distil-
lation and the residue was dried and recrystallized to furnish
compound (2). White solid, yield: 70%; m.p. 60–62 ꢂC; IR (KBr): ymax
in cmꢀ1: 3042 (aromatic ring), 638 (C–S), 1719 (pC]O of ester),
1684 (–C]N–), 1320 and 1234 (C–O–C), 830 (C–S–C), 2955, 2889,
6.1.5.1. 3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-phenyl-thiazoli-
din-4-one (5a). Pale yellow crystals, yield: 75.66%; m.p. 230–
232 ꢂC; IR (KBr) ymax in cmꢀ1: 3212.4, 1378 (–NH–), 1522.9 (–C]N),
1593.7 (–CONH), 1640.0 (ring pC]O); 1H NMR (CDCl3, 300 MHz)
d
ppm: 3.60 (s, 2H, –CH2, ring), 3.65 (s, 2H, S–CH2), 3.70 (d, 1H,
1443, 714, (–CH2 and –CH3); 1H NMR (CDCl3, 300MHz)
(t, 3H, Hz, –COOCH2CH3), 3.85 (q, 2H,
–COOCH2CH3), 4.20 (s, 2H, S–CH2–), 6.90–7.85 (m, 4H, Ar–H), 10.9
(s, 1H, –NH–benzimidazole); Anal. Calcd for C11H12N2O2S: C, 55.93;
H, 5.10; N, 11.86%. Found: C, 55.90; H, 5.12; N, 11.85%.
d
ppm: 1.40
6.5 Hz,
J ¼ 15.8 Hz, CH–Ar), 7.0–7.94 (m, 9H, Ar–H), 8.08 (s, 1H, –CONH–),
J
¼
7
J
¼
11.9 (b, 1H, –NH–benzimidazole, D2O exchangeable); 13C NMR
(CDCl3, 75 MHz) d ppm: 31.63 (ring S–CH2), 36.63 (S–CH2), 54.98
(–CH), 121.50, 122.4, 127.53, 129.21, 129.46, 130.05, 135.52, 143.15
(heteroaromatics), 163.18 (Amide pC]O), 172.35 (ring pC]O);
EIMS m/z: 384 [Mþ], 385 (M þ 1), 386 (M þ 2),197,195,191,180,174,
164, 163, 150, 149, 117, 105, 28; Anal. Calcd for C18H16N4O2S2: C,
56.23; H, 4.19; N, 14.57%. Found: C, 56.27; H, 4.22; N, 14.56%.
6.1.3. Synthesis of [(2-benzimidazolylthio)-acetyl]-hydrazine (3)
Compound (2) (2.36 g, 0.01 mol) and hydrazine hydrate (0.9 mL,
0.02 mol) in ethanol (20 mL) were refluxed for about 5 h on a steam
bath. After cooling the resulting solid was filtered, dried and
recrystallized to obtain compound (3). Pinkish white solid, yield:
75%; m.p. 195 ꢂC; IR (KBr) ymax in cmꢀ1: 3311, 3369 (–NHNH2), 1680
6.1.5.2. 3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-(4-chloro-phenyl)-
thiazolidin-4-one (5b). Yellow crystals, yield: 78.24%; m.p. 235–
237 ꢂC; IR (KBr) ymax in cmꢀ1: 3206.3, 1377.0 (–NH–), 1531.3 (C]N),
1595.8 (–CONH), 1639.1 (ring pC]O), Ar–Cl (825.6); 1H NMR
(pC]O of amide); 1H NMR (CDCl3, 300MHz)
–NH2), 4.35 (s, 2H, S–CH2), 6.95–7.90 (m, 4H, Ar–H), 7.55 (s, 1H,
d ppm: 3.90 (s, 2H,
(CDCl3, 300 MHz)
d ppm: 3.50 (s, 2H, S–CH2), 3.58 (s, 2H, –CH2,

R.V. Shingalapur et al. / European Journal of Medicinal Chemistry 45 (2010) 1753–1759
1757
ring), 3.72 (d, 1H, J ¼ 15.6 Hz, CH–Ar), 6.98–7.90 (m, 9H, Ar–H), 8.12
6.1.5.7. 3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-(2-hydroxy-3-
methoxy-phenyl)-thiazolidin-4-one (5g). Yellow crystals, yield:
776.35%; m.p. 220–222 ꢂC; IR (KBr) ymax in cmꢀ1: 3280.9, 1382.7
(–NH–), 1585.0 (C]N), 1637.1 (–CONH), 1670.1 (ring pC]O), 3410.9
(s, 1H, –CONH–), 11.78 (b, 1H, –NH–benzimidazole, D2O exchange-
able); 13C NMR (CDCl3, 75 MHz)
d ppm: 31.11 (ring S–CH2), 36.79
(S–CH2), 55.15 (–CH), 112.82, 120.0, 122.42, 129.23, 129.45, 130.28,
132.9, 134.28, 135.3, 145.85 (heteroaromatics), 164.72 (pC]O),
173.87 (ring pC]O); EIMS m/z: 418 [Mþ], 419 (M þ 1), 420 (M þ 2),
231, 215, 202, 200, 191, 194, 187, 170, 149, 117, 28; Anal. Calcd for
C18H15N4O2S2Cl: C, 51.61; H, 3.61; N, 13.37%. Found: C, 51.59; H,
3.65; N, 13.34%.
(–OH), 2812 (Ar–OCH3); 1H NMR (CDCl3, 300 MHz)
d ppm: 3.60 (s,
2H, S–CH2), 3.65 (s, 2H, –CH2, ring), 3.82 (d, 1H, J ¼ 15.8 Hz, CH–Ar),
7.55–8.01 (m, 9H, Ar–H), 8.08 (s, 1H, –CONH–), 11.9 (b, 1H, –NH–
benzimidazole, D2O exchangeable); 13C NMR (CDCl3, 75 MHz)
d
ppm: 31.55 (ring S–CH2), 36.85 (S–CH2), 55.26 (–CH), 115.4, 121.0,
129.31, 129.80, 129.84, 130.45, 135.32, 142.45 (heteroaromatics),
163.17 (pC]O), 174.29 (ring pC]O); EIMS m/z: 430 [Mþ], 431
(M þ 1), 432 (M þ 1), 240, 228, 224, 215, 191, 163, 150, 118, 105, 58,
14; Anal. Calcd for C19H18N4O4S2: C, 53.01; H, 4.21; N, 13.01%.
Found: C, 53.05; H, 4.24; N, 12.99%.
6.1.5.3. 3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-(2-hydroxy-phenyl)-
thiazolidin-4-one (5c). Brown crystals, yield: 69.84%; m.p. 135–
137 ꢂC; IR (KBr) ymax in cmꢀ1: 3235, 1355 (–NH–), 1586.4 (C]N),
1620.5 (–CONH), 1657.5 (ring pC]O); 1H NMR (CDCl3, 300 MHz)
d
ppm: 3.58 (s, 2H, –CH2, ring), 3.62 (s, 2H, S–CH2), 3.75 (d, 1H,
J ¼ 14.6 Hz, CH–Ar), 7.0–7.85 (m, 9H, Ar–H), 8.25 (s, 1H, –CONH–),
6.1.5.8. 3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-furan-2-yl-thia-
zolidin-4-one (5h). Brown crystals, yield: 76.5%; m.p.155–157 ꢂC; IR
(KBr) ymax in cmꢀ1: 3225.2, 1384.3 (–NH–), 1590.5 (C]N), 1685.0
(–CONH), 1697.3 (ring pC]O), 1256.2 (C–O–C); 1H NMR (CDCl3,
11.54 (b, 1H, –NH–benzimidazole, D2O exchangeable); 13C NMR
(CDCl3, 75 MHz)
d ppm: 32.5 (ring S–CH2), 35.4 (S–CH2), 58.10
(–CH), 112.0, 121.0, 127.9, 128.85, 129.21, 129.58, 130.54, 136.9,
146.85, 156.5 (heteroaromatics), 164.53 (pC]O), 172.98 (ring
pC]O); EIMS m/z: 400 [Mþ], 401 (M þ 1), 402 (M þ 2), 213, 194,
190, 169, 152, 106, 89, 44, 15; Anal. Calcd for C18H16N4O3S2: C, 53.98;
H, 4.03; N, 13.99%. Found: C, 53.95; H, 4.00; N, 14.03%.
300 MHz)
d ppm: 3.62 (s, 2H, –CH2, ring), 3.65 (s, 2H, S–CH2), 3.70
(d, 1H, J ¼ 15.80 Hz, CH–Ar), 7.0–7.94 (m, 9H, Ar–H), 8.21 (s, 1H,
–CONH–), 11.54 (b, 1H, –NH–benzimidazole, D2O exchangeable);
13C NMR (CDCl3, 75 MHz)
d ppm: 32.55 (ring S–CH2), 36.85 (S–CH2),
54.99 (–CH), 102.8, 114.8, 122.99, 140.22, 141.2, 150.5 (hetero-
aromatics), 165.81 (pC]O), 174.2 (ring pC]O); EIMS m/z: 374 [Mþ],
375 (M þ 1), 377 (M þ 2), 194, 183, 167, 155, 149, 119, 107, 92, 68, 39,
29; Anal. Calcd for C16H14N4O3S2: C, 51.32; H, 3.77; N, 14.96%.
Found: C, 51.28; H, 3.80; N, 14.99%.
6.1.5.4. 3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-(4-hydroxy-phenyl)-
thiazolidin-4-one (5d). Yellow powder, yield: 74.29%; m.p. 140–
142 ꢂC; IR (KBr) ymax in cmꢀ1: 3207.6, 1380.9 (–NH–), 1515.0 (C]N),
1604.3 (–CONH), 1641.7 (ring pC]O), 3448.8 (–OH); 1H NMR
(CDCl3, 300 MHz) d ppm: 3.62 (s, 2H, ring –CH2), 3.69 (s, 2H, S–CH2),
3.72 (d, 1H, J ¼ 14.6 Hz, CH–Ar), 7.0–7.99 (m, 9H, Ar–H), 8.06 (s, 1H,
6.1.5.9. 3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-(3-hydroxy-
naphthalen-2-yl)-thiazolidin-4-one (5i). Pale yellow crystals, yield:
68.65%; m.p. 240–242 ꢂC; IR (KBr) ymax in cmꢀ1: 3202.6, 1383.0
(–NH–), 1585.0 (C]N), 1624.6 (–CONH), 1678.8 (ring pC]O),
–CONH–), 12.06 (b, 1H, –NH–benzimidazole, D2O exchangeable);
13C NMR (CDCl3, 75 MHz)
d ppm: 31.94 (ring S–CH2), 36.26 (S–CH2),
55.42 (–CH), 120.55, 128.21, 129.11, 129.81, 129.99, 139.88, 142.55,
154.9 (heteroaromatics), 164.53 (pC]O), 172.58 (ring pC]O); EIMS
m/z: 400 [Mþ], 401 (M þ 1), 402 (M þ 2), 213, 209,194, 169,152,119,
115, 106, 94, 92, 28; Anal. Calcd for C18H16N4O3S2: C, 53.98; H, 4.03;
N, 13.99%. Found: C, 54.02; H, 4.00; N, 13.97%.
3450.5 (–OH); 1H NMR (CDCl3, 300 MHz)
d ppm: 3.55 (s, 2H,
S–CH2), 3.62 (s, 2H, –CH2, ring), 3.72 (d, 1H, J ¼ 15.5 Hz, CH–Ar),
7.52–7.99 (m, 9H, Ar–H), 8.20 (s, 1H, –CONH–), 11.62 (b, 1H,
–NH–benzimidazole, D2O exchangeable); 13C NMR (CDCl3,
75 MHz)
d ppm: 32.5 (ring S–CH2), 37.82 (S–CH2), 56.28 (–CH),
6.1.5.5. 3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-p-tolyl-thiazolidin-
4-one (5e). Pale white crystals, yield: 78.54%; m.p. 238–240 ꢂC; IR
(KBr) ymax in cmꢀ1: 3224, 1346.3 (–NH–), 1590.6 (C]N), 1639.9
121.18, 122.4, 125.29, 127.92, 129.19, 129.87, 129.95, 130.11,
135.98, 143.45 (heteroaromatics), 164.05 (pC]O), 172.90 (ring
pC]O). EIMS m/z: 450 [Mþ], 451 (M þ 1), 453 (M þ 2), 262, 259,
245, 230, 216, 164, 144, 115, 105, 58, 32, 28, 14; Anal. Calcd for
C22H18N4O3S2: C, 58.65; H, 4.03; N, 12.44%. Found: C, 58.66; H,
4.02; N, 12.41%.
(–CONH), 1680.5 (ring pC]O); 1H NMR (CDCl3, 300 MHz)
d ppm:
3.60 (s, 2H, S–CH2), 3.62 (s, 2H, –CH2, ring), 3.81 (d, 1H, J ¼ 15.3 Hz,
CH–Ar), 7.08–8.01. (m, 9H, Ar–H), 8.28 (s, 1H, –CONH–), 11.55 (b, 1H,
–NH–benzimidazole, D2O exchangeable); 13C NMR (CDCl3, 75 MHz)
d
ppm: 21.89 (–CH3), 32.54 (ring S–CH2), 37.83 (S–CH2), 55.42
6.1.5.10. 3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-(4-amine-phenyl)-
thiazolidin-4-one (5j). Yellow crystals, yield: 70.25%; m.p. 218–
220 ꢂC; IR (KBr) ymax in cmꢀ1: 3346.6, 1376.6 (–NH–), 1575.0 (C]N),
1620.6 (–CONH),1675.2 (ring pC]O), 3450.5 (–OH); 1H NMR (CDCl3,
(–CH), 121.5, 128.5, 129.58, 129.82, 129.88, 138.25, 145.28 (hetero-
aromatics), 168.8 (pC]O), 173.52 (ring pC]O); EIMS m/z: 398
[Mþ], 399 (M þ 1), 400 (M þ 2), 210, 195, 181, 165, 149, 105, 91, 58,
44, 15; Anal. Calcd for C19H18N4O2S2: C, 57.26; H, 4.55; N, 14.06%.
Found: C, 57.25; H, 4.57; N, 14.10%.
300 MHz) d ppm: 3.52 (s, 2H, S–CH2), 3.64 (s, 2H, –CH2, ring), 3.75 (d,
1H, J ¼ 15.6 Hz, CH–Ar), 7.50–7.85 (m, 9H, Ar–H), 8.20 (s,1H, –CONH–
), 11.60 (b, 1H, –NH–benzimidazole, D2O exchangeable); 13C NMR
6.1.5.6. 3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-(4-methoxy-phenyl)-
thiazolidin-4-one (5f). White crystals, yield: 75.54%; m.p. 219–
220 ꢂC; IR (KBr) ymax in cmꢀ1: 3208.0, 1378.9 (–NH–)1513.8
(C]N),1606.0 (–CONH), 1637.6 (ring pC]O), 2831.8 (Ar–OCH3); 1H
(CDCl3, 75 MHz) d ppm: 32.9 (ring S–CH2), 37.75 (S–CH2), 56.15
(–CH), 121.18, 122.9, 125.29, 127.92, 129.19, 129.8, 129.95, 130.11,
135.98, 141.9, 145.9 (heteroaromatics), 171.05 (pC]O), 167.90 (ring
pC]O); EIMS m/z: 399 [Mþ], 400 (M þ 1), 401 (M þ 2), 262, 259, 245,
230, 216,164,115,105, 58, 28; Anal. Calcd for C22H18N4O3S2: C, 54.12;
H, 4.29; N, 17.53%. Found: C, 54.10; H, 4.26; N, 17.57%.
NMR (CDCl3, 300 MHz)
d ppm: 3.65 (s, 2H, S–CH2), 3.66 (s, 2H,
–CH2, ring), 3.94 (d, 1H, J ¼ 15.5 Hz, CH–Ar), 7.54–7.91 (m, 9H, Ar–
H), 8.28 (s, 1H, –CONH–), 11.52 (b, 1H, –NH– benzimidazole, D2O
exchangeable); 13C NMR (CDCl3, 75 MHz)
d
ppm: 31.12 (ring S–CH2),
6.1.6. Synthesis of 2-(5-phenyl-[1, 3, 4]-oxadiazole-2-
36.55 (S–CH2), 55.98 (–CH), 112.12, 121.77, 129.0, 129.51, 129.82,
130.55, 135.81, 142.42 (heteroaromatics), 163.14 (pC]O), 174.31
(ring pC]O); EIMS m/z: 414 [Mþ], 415 (M þ 1), 416 (M þ 2), 226,
211, 195, 180, 167, 119, 108, 92; Anal. Calcd for C19H18N4O3S2: C,
55.05; H, 4.38; N, 13.52%. Found C, 55.08; H, 4.34; N, 13.49%.
ylmethylsulfanyl)-1H-benzimidazole 6(a–j)
A solution of hydrazide (3) (2.22 g, 0.01 mol) and corresponding
acid (0.01 mol) in POCl3 (30 mL) was refluxed for 18–20 h. Excess
solvent was removed by vacuum distillation and the solution was
poured onto crushed ice with stirring and the precipitated product

1758
R.V. Shingalapur et al. / European Journal of Medicinal Chemistry 45 (2010) 1753–1759
was neutralized with ammonia, filtered, washed with water and
recrystallized from chloroform to get respective oxadiazole.
300 MHz)
(b, 1H, –NH–benzimidazole, D2O exchangeable), 12.05 (s, 1H, –OH,
D2O exchangeable); 13C NMR (CDCl3, 75 MHz)
ppm: 35.44 (S–
d ppm: 3.29 (s, 2H, S–CH2), 7.18–8.53 (m, 6H, Ar–H),10.42
d
6.1.6.1. 2-(5-Phenyl-[1,3,4]-oxadiazole-2-ylmethylsulfanyl)-1H-benz-
imidazole (6a). Dark brown powder, yield: 65.42%; m.p. 198–
200 ꢂC; IR (KBr) ymax in cmꢀ1: 3237.6,13387 (–NH–),1267.1 (C–O–C),
CH2), 122.90, 133.83, 137.25, 140.56, 145.2, 145.8 (heteroaromatics),
155.0 (C2, oxa), 172.11 (C5, oxa); EIMS m/z: 356 [Mþ], 357 (M þ 1),
357 (M þ 2), 163, 149, 128, 105, 70, 28; Anal. Calcd for C16H12N4O4S:
C, 53.93; H, 3.39; N, 15.72%. Found: C, 53.95; H, 3.43; N, 15.70%.
1654.7 (C]N); 1H NMR (CDCl3, 300 MHz)
d
ppm: 3.39 (s, 2H, S–CH2),
7.17–8.53 (m, 9H, Ar–H), 11.45 (b, 1H, –NH–benzimidazole, D2O
exchangeable); 13C NMR (CDCl3, 75 MHz)
ppm: 37.23 (S–CH2),
d
6.1.6.7. 4-[5-(1H-Benzimidazol-2-ylsulfanylmethyl)-[1,3,4]-oxadia-
zole-2-yl]-phenylamine (6g). Light brown crystals, yield: 68.65%;
m.p. 228–230 ꢂC; IR (KBr) ymax in cmꢀ1: 3346.6, 1376.6 (–NH–),
117.2, 120.9, 129.5, 135.0, 136.8, 140.0 (heteroaromatics), 155.8 (C2,
oxa), 172.6 (C5, oxa); EIMS m/z: 308 [Mþ], 309 (M þ 1), 310 (M þ 2),
163, 150, 145, 119, 105, 91, 78, 70, 44; Anal. Calcd for C16H12N4OS: C,
62.32; H, 3.92; N, 18.17%. Found: C, 61.30; H, 3.89; N, 18.20%.
1269.5 (C–O–C), 1603.8 (C]N); 1H NMR (CDCl3, 300 MHz)
d ppm:
3.29 (s, 2H, S–CH2), 7.17–8.55 (m, 8H, Ar–H), 10.92 (b, 1H, –NH–
benzimidazole, D2O exchangeable); 13C NMR (CDCl3, 75 MHz)
6.1.6.2. 2-(5-Chloro-phenyl-[1,3,4]-oxadiazole-2-ylmethylsulfanyl)-
1H-benzimidazole (6b). Dark brown powder, yield: 68.42%; m.p.
202–204 ꢂC; IR (KBr) ymax in cmꢀ1: 3322.4,1340.1 (–NH–),1275.8 (C–
d ppm: 36.82 (S–CH2), 155.21 (C2, oxa), 171.73 (C5, oxa), 145.42,
141.8, 137.2, 127.54, 122.3 (heteroaromatics); EIMS m/z: 326 [Mþ],
327 (M þ 1), 328 (M þ 2), 149, 70, 93, 77, 16; Anal. Calcd for
C16H13N5OS: C, 59.43; H, 4.05; N, 21.66%. Found: C, 59.47; H, 4.08; N,
21.69%.
O–C),1618.4 (C]N), 3412.3 (–OH); 1H NMR (CDCl3, 300 MHz)
d
ppm:
3.86 (s, 2H, S–CH2), 7.57–8.13 (m, 8H, Ar–H), 11.02 (b, 1H, –NH–
benzimidazole, D2O exchangeable); 13C NMR (CDCl3, 75 MHz)
ppm:
d
36.65 (S–CH2),122.7, 129.6, 136.25,145.25, (heteroaromatics),155.54
(C2, oxa), 172.81 (C5, oxa); EIMS m/z: 342 [Mþ], 343 (M þ 1), 344
(M þ 2), 163, 108, 91, 70, 111, 51, 35; Anal. Calcd for C16H11N4O3Cl: C,
56.06; H, 3.23; N, 16.34%. Found: C, 56.10; H, 3.28; N, 16.30%.
6.1.6.8. 2-[5-(4-Nitro-phenyl)-[1, 3, 4]-oxadiazole-2-ylmethylsulfanyl]-
1H-benzimidazole (6h). Brown crystals, yield: 68.75%; m.p.
164–166 ꢂC; IR (KBr) ymax in cmꢀ1: 3348.1, 1380.1 (–NH–), 1269.2
(C–O–C), 1618.7 (C]N); 1H NMR (CDCl3, 300 MHz)
d
ppm: 3.11 (s,
2H, S–CH2), 7.28–8.21 (m, 8H, Ar–H), 10.85 (b, 1H, –NH–benz-
imidazole, D2O exchangeable); 13C NMR (CDCl3, 75 MHz)
ppm:
6.1.6.3. 3-[5-(1H-Benzimidazol-2-ylsulfanylmethyl)-[1,3,4]-oxadiazole-
2-yl]-naphthalene-2-ol (6c). Pale yellow crystals, yield: 69.54%;
m.p. 205–207 ꢂC; IR (KBr) ymax in cmꢀ1: 3386.5, 1388.5 (–NH–),
d
36.14 (S–CH2), 122.82, 124.34, 133.82, 149.79 (heteroaromatics),
156.73 (C2, oxa), 172.6 (C5, oxa); EIMS m/z: 356 [Mþ], 357
(M þ 1), 358 (M þ 2), 105, 117, 122, 46, 15; Anal. Calcd for
C16H11N5O3S: C, 54.38; H, 3.14; N, 19.82%. Found: C 54.42; H, 3.12;
N, 19.80%.
1241.1 (C–O–C), 1636.4 (C]N); 1H NMR (CDCl3, 300 MHz)
d ppm:
3.42 (s, 2H, S–CH2), 7.18–8.11 (m, 10H, Ar–H), 11.09 (b, 1H, –NH–
benzimidazole, D2O exchangeable), 12.41 (s, 1H, –OH, D2O
exchangeable); 13C NMR (CDCl3, 75 MHz)
d ppm: 37.26 (S–CH2),
122.85, 129.89, 136.85, 145.28 (heteroaromatics), 155.2 (C2, oxa),
172.65 (C5, oxa); EIMS m/z: 374 [Mþ], 375 (M þ 1), 376 (M þ 2), 149,
91, 117, 143, 32, 28. Anal. Calcd for C20H14N4O2S: C, 64.16; H, 3.77; N,
14.96%. Found: C, 64.14; H, 3.80; N, 14.95%.
6.1.6.9. 2-[5-(2-Chloro-4-nitro-phenyl)-[1,3,4]-oxadiazole-2-ylme-
thylsulfanyl]-1H-benzimidazole (6i). Light brown crystals, yield:
64.25%; m.p. 208–210 ꢂC; IR (KBr) ymax in cmꢀ1: 3409.8, 1390.6
(–NH–), 1251.1 (C–O–C), 1657.4 (C]N), 890.8 (C–Cl); 1H NMR
(CDCl3, 300 MHz)
H), 11.25 (b, 1H, –NH–benzimidazole, D2O exchangeable); 13C NMR
(CDCl3, 75 MHz) ppm: 33.52 (S–CH2), 121.42,122.58, 133.85, 138.9,
140.0, 145.57 (heteroaromatics), 154.99 (C2, oxa), 171.42 (C5, oxa);
EIMS m/z: 387 [Mþ], 388 (M þ 1), 391 (M þ 2), 163, 157, 149, 112,
105, 32; Anal. Calcd for C16H10ClN5O3S: C, 49.55; H, 2.60; N, 18.06%.
Found: C, 49.58; H, 2.58; N, 18.02%.
d ppm: 3.12 (s, 2H, S–CH2), 7.65–8.11 (m, 7H, Ar–
6.1.6.4. 4-[5-(1H-Benzimidazol-2-ylsulfanylmethyl)-[1,3,4]-oxadia-
zole-2-yl]-phenol (6d). Yellow powder, yield: 69.55%; m.p. 215–
217 ꢂC; IR (KBr) ymax in cmꢀ1: 3320.9,1342.5 (–NH),1280.4 (C–O–C),
d
1621.4 (C]N); 1H NMR (CDCl3, 300 MHz)
d ppm: 3.38 (s, 2H, S–
CH2), 7.07–7.95 (m, 8H, Ar–H), 11.15 (b, 1H, –NH–benzimidazole,
D2O exchangeable), 12.38 (s, 1H, –OH, D2O exchangeable); 13C NMR
(CDCl3, 75 MHz)
d ppm: 35.82 (S–CH2), 122.10, 129.43, 135.87,
145.69 (heteroaromatics), 155.62 (C2, oxa), 172.87 (C5, oxa). EIMS m/
z: 324 [Mþ], 325 (M þ 1), 326 (M þ 2), 165, 149, 106, 94, 70,15; Anal.
Calcd for C16H12N4O2S: C, 59.25; H, 3.73; N, 17.27%. Found: C, 59.28;
H, 3.71; N, 17.29%.
6.1.6.10. 2-(5-Pyridin-3-yl-[1,3,4]
oxadiazole-2-ylmethylsulfanyl)-
1H-benzimidazole (6j). Light brown crystals, yield: 69.86%; m.p.
201–202 ꢂC; IR (KBr) ymax in cmꢀ1: 3348.5, 1354 (–NH–), 1275.1 (C–
O–C), 1610 (C]N); 1H NMR (CDCl3, 300 MHz)
d
ppm: 3.15 (s, 2H, S–
CH2), 7.46–8.28 (m, 8H, Ar–H), 11.45 (b, 1H, –NH–benzimidazole,
D2O exchangeable); 13C NMR (CDCl3, 75 MHz)
ppm: 36.42 (S–
6.1.6.5. 6-[5-(1H-Benzimidazol-2-ylsulfanylmethyl)-[1,3,4]-
oxadiazole-2-yl]-naphthalene ꢀ1,7-diol (6e). Brown crystals, yield:
64.22%; m.p. 187–189 ꢂC; IR (KBr) ymax in cmꢀ1: 3322.4, 1340.1
(–NH–), 1275.8 (C–O–C), 1618.4 (C]N), 3412.3 (–OH); 1H NMR
d
CH2), 122.0, 134.2, 138.2, 142.9, 148.15, 149.82, (heteroaromatics),
156.2 (C2, oxa), 172.64 (C5, oxa). EIMS m/z: 309 [Mþ], 310 (M þ 1),
311 (M þ 2), 161, 149, 70, 52, 27; Anal. Calcd for C15H11N5OS: C,
58.24; H, 3.58; N, 22.64%. Found: C, 58.27; H, 3.59; N, 22.63%.
(CDCl3, 300 MHz)
H), 11.42 (b, 1H, –NH–benzimidazole, D2O exchangeable), (s, 1H,
–OH, D2O exchangeable); 13C NMR (CDCl3, 75 MHz)
ppm: 35.93
d ppm: 3.60 (s, 2H, S–CH2), 6.92–8.52 (m, 9H, Ar–
d
6.2. Pharmacology
(S–CH2), 123.45, 128.65, 136.85, 146.73, 148.0 (heteroaromatics),
154.73 (C2, oxa), 171.96 (C5, oxa); EIMS m/z: 390 [Mþ], 391 (M þ 1),
392 (M þ 2), 163, 150, 105, 160, 71, 28; Anal. Calcd for C20H14N4O3S:
C, 61.53; H, 3.61; N, 14.35%. Found: C, 61.57; H, 3.65; N, 14.32%.
6.2.1. Anticonvulsant activity
The anticonvulsant activities of the synthesized compounds
were tested through an in vivo rodent model of convulsions (the
Maxima ElectroShock, MES test) [27]. In MES-convulsions electro-
shock is applied through the corneal electrode. Through optic
stimulation cortical excitation is produced. The MES-convulsions
are divided into five phases such as (a) tonic flexion, (b) tonic
extensor, (c) clonic convulsions, (d) stupor and (e) recovery or
6.1.6.6. 5-[5-(1H-Benzimidazol-2-ylsulfanylmethyl)-[1,3,4]-oxadia-
zole-2-yl]-benzene-1,2,3-triol (6f). Brown crystals, yield: 69.54%;
m.p. 196–198 ꢂC; IR (KBr) ymax in cmꢀ1: 3166.1, 1387.8 (–NH–),
1269.5 (C–O–C), 1642.7 (C]N), 3499.0 (–OH); 1H NMR (CDCl3,

R.V. Shingalapur et al. / European Journal of Medicinal Chemistry 45 (2010) 1753–1759
1759
death. The time (s) spent by the animal in each phase of the
convulsions is noted down. A substance is known to possess
anticonvulsant property if it reduces or abolishes the extensor
phase of MES-convulsions.
30 min. Removing the gel and being stained with 10.0 mg/mL
ethidium bromide for 10–15 min, the bands were observed under
Vilberlourmate Gel documentation system and then photographed
to determine the extent of DNA cleavage. Henceforth the results
were compared with standard DNA marker.
6.2.2. Antidiabetic activity
Evaluation of antidiabetic activity was done by blood–glucose
test and oral glucose tolerance test (OGTT) [28,29]. Male wistar
albino rats (150–200 g) of either sex were selected. Diabetes was
induced by single intraperitonial injection of freshly prepared
aqueous solution of alloxan monohydrate (150 mg/kg) to overnight
fasted rats. After 48hrs of alloxan injection, the animals which did
not develop hyperglycemia i.e. glucose level >200 mg/dL were
rejected/replaced with new animals. Treatment was continued for
9 days. Before the treatment (0 day) and at the end of 9th day, blood
samples were collected by retro orbital puncture of each rat under
mild anesthesia in 1 mL Ependorff’s tubes containing 50 mL of
anticoagulant heparin. And serum separated by centrifugation
of blood at 4000 rpm for 10 min was subjected for estimation of
glucose by Glucose oxidase method [30].
Acknowledgments
This research work is financially supported by the University
Grants Commission, (UGC), New Delhi 110 012. (Ref: No. 33-296/
2007 (SR) dated 28-02-2008).
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