Synthesis of 2-mercaptobenzimidazole derivatives as potential anti-microbial and cytotoxic agents

Article abstract of DOI:10.1002/ardp.200900291

A series of novel 2-(1H-benzimidazol-2-ylsulfanyl)-N-(4-oxo-2-phenyl- thiazolidin-3yl)-acetamide 5a-j have been synthesized from various aldehydes and 2-(5-phenyl-[1,3,4]-oxadiazol-2-ylmethylsulfanyl)-1H-benzimidazole 6a-j from various benzoic acids. Thes

Full text of DOI:10.1002/ardp.200900291

Arch. Pharm. Chem. Life Sci. 2011, 11, 311–319
311
Full Paper
Synthesis of 2-Mercaptobenzimidazole Derivatives as
Potential Anti-microbial and Cytotoxic Agents
Kallappa M. Hosamani and Ramya V. Shingalapur
P. G. Department of Studies in Chemistry, Karnatak University, Pavate Nagar, Dharwad, India
A series of novel 2-(1H-benzimidazol-2-ylsulfanyl)-N-(4-oxo-2-phenyl-thiazolidin-3yl)-acetamide 5a–j
have been synthesized from various aldehydes and 2-(5-phenyl-[1,3,4]-oxadiazol-2-ylmethylsulfanyl)-
1H-benzimidazole 6a–j from various benzoic acids. These compounds were screened for their in-vitro
anti-bacterial activity against Staphylococcus aureus and Enterococcus faecalis as Gram positive, Klebsiella
pneumoniae and Escherichia coli as Gram negative bacterial strains and for in-vitro anti-fungal activity
against Asperigillus fumigatus and Candida albicans. The in vitro cytotoxic properties were studied using
brine shrimp bioassay. Results revealed that, compounds 5b, 5d, 5g, 5i, 6b, 6e, 6f, and 6i showed
excellent activity against a panel of microorganisms. The cytotoxic activities of 5b, 5g, 5i, 6b, 6f, 6h,
and 6i were found to be good. All the newly synthesized compounds were characterized by elemental
1
analysis, IR, H-NMR, 13C-NMR and MS.
Keywords: Antibacterial / Antifungal / Cytotoxicity / 1,3,4-Oxadiazole / 4-Thiazolidinone
Received: November 28, 2009; Revised: February 16, 2010; Accepted: March 3, 2010
DOI 10.1002/ardp.200900291
Introduction
most potential 4-thiazolidinone and 1,3,4-oxadiazole deriva-
tives, their biological impact, and also the future potential of
this protocol [4, 5]. Interest in the biological and industrial
potentialities of 4-thiazolidinone [6] and 1,3,4-oxadiazole [7]
derivatives has resulted in the development of various syn-
thetic procedures for the introduction of such heterocyclic
moieties into 2-mercapto benzimidazole. Because of signifi-
cant potential therapeutic properties and industrial appli-
cations, a prominent place and much interest is generated in
the synthesis of new class of heterocyclic systems such as 4-
thiazolidinone [8] and 1,3,4-oxadiazole [9] derivatives,
thereby to explore their biological properties and industrial
applications.
Research and development of potent and effective anti-
microbial agents represents one of the most important
advances in therapeutics, not only in the control of serious
infections, but also in the prevention and treatment of some
infectious complications of other therapeutic modalities
such as cancer chemotherapy and surgery. However, in
recent years, much attention has been focused on addressing
the problem of multi-drug resistant (MDR) bacteria and fungi
resulting from the widespread use and misuse of classical
anti-microbial agents [1]. Recent observations suggested that
substituted benzimidazoles, benzoxazoles, and related het-
erocycles, which are the structural isosters of nucleotides
owing to the fused heterocyclic nuclei in their structures,
interact easily with biopolymers and possess potential
activity with lower toxicities in the chemotherapeutic
approach in man [2, 3].
It is well-known that a number of heterocyclic compounds
containing nitrogen and sulphur exhibit a wide variety of
biological activities. 2-Mercapto benzimidazole derivatives
are known to possess broad spectrum of activities and clinical
applications [10]. Benzimidazoles are
a component of
The aim of this research article is to explore the impor-
tance of heterocyclic compounds, trends in novel synthesis of
Vitamin B12 and are related to the DNA base purine and
the stimulant caffeine. Several five membered aromatic sys-
tems having three heteroatoms at symmetrical positions
have been studied because of their interesting physiological
properties. Hence our study involves the synthesis of 4-thia-
zolidinones and 1,3,4-oxadiazoles.
Correspondence: Kallappa M. Hosamani, P. G. Department of Studies in
Chemistry, Karnatak University, Pavate Nagar, Dharwad-580 003, India.
E-mail: dr_hosamani@yahoo.com
Fax: þ91-836-2747884 and þ91-836-2771275
4-Thiazolidinones are the derivatives of thiazolidine with a
carbonyl group at 4-position. Introduction of sulphur was
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312
K. M. Hosamani et al.
Arch. Pharm. Chem. Life Sci. 2011, 11, 311–319
–
expected to bring in a bulky polarizable atom, thus altering
geometry, polarizability, stability, lipophilicity, steric and
electronic characteristics of the molecule. It was anticipated
that the thiazolidine ring improves the activity of the
lead molecules. 4-Thiazolidinones have many interesting
activity profiles namely anti-bacterial, anti-fungal [11], anti-
inflammatory [12], anti-convulsant [13], COX-1 inhibitors [14],
inhibitors of the bacterial enzyme MurB [15], non-nucleoside
inhibitors of HIV-RT [16], and anti-histamine agents [17].
Recently, they have also been utilized as hypolipidemics
and hypocholesteremics [18]. Besides this they are used as
Maillard reaction inhibitors and for treatment of diabetes
complications [19].
respectively. In IR, the >C O band for amide appears at
–
1641 cmꢀ1 and –NHNH2 around 3207 and 3346 cmꢀ1 also
confirms the formation of 3. 3 on treatment with aromatic
aldehydes in ethanol gave {1H-benzimidazol-2-ylsulfanyl}-(N-
2-substituted phenyl) hydrazide 4a–j. The hydrazone was
–
–
confirmed by a signal at d 4.02 ppm due to the –N CH– in
1H-NMR and the signal at 65.8 ppm due to >CH-N< in 13C-
NMR and 1640 cmꢀ1 due to –N CH– in IR also confirms this.
–
–
In the process of synthesis of compounds 4a–j, it was found
that the substituted aromatic aldehyde having an electron
withdrawing group Ex: –Cl ends up the reaction quickly with
high yield in the absence of catalyst. When there is an
electron releasing group Ex: -OCH3 in the benzene ring,
the reaction could be finished just in the presence of glacial
acetic acid as catalyst.
1,3,4-Oxadiazoles are thermally stable and neutral hetero-
aromatic molecules which exhibit one of the active class of
compounds possessing various pharmacological properties
such as anti-inflammatory [20, 21], anti-viral [22], anti-
bacterial [23, 24] activities. The substituted oxadiazoles are
heterocyclic compounds, which serve both as biomimetic
and reactive pharmacophores and many are key elements
with potential biological activities. Additionally substituted
1,3,4-oxadiazole derivatives are becoming an important
member in the heterocyclic family because of their wide
usage as dyes, photosensitive electrical materials, liquid
crystals and organic light emitting diodes. The incorporation
of 4-thiazolidinone and 1,3,4-oxadiazole moiety into 2-
mercapto benzimidazole scaffold enhances its activity.
The present work has been designed considering the exten-
sive applications of 4-thiazolidinone and 1,3,4-oxadiazole
derivatives as industrial and biological products and benzi-
midazole moiety as an important pharmacophore and priv-
ileged structure in medicinal chemistry [25, 26]. Here, an
attempt has been made to synthesize 4-thiazolidinone and
1,3,4-oxadiazole derivatives containing 2-mercapto benzim-
idazole in good yield without microwave irradiation [27, 28].
Compounds 4a–j when treated with thioglycolic acid in
presence of anhydrous ZnCl2 afforded 2-(1H-bezimidazol-2-
ylsulfanyl)-N-(4-oxo-2-phenyl-thiazolidin-3-yl)-acetamide 5a–j.
A signal at d 3.70 ppm and 3.65 ppm due to >CH-Ar- and
-S–CH2- confirms the formation of thiazolidinone ring. In the
1
H-NMR spectra of 4a–j, the proton of –N CH appears at
–
–
about d 4.02–4.10 ppm. But, in the spectrum of 5a–j this
proton signal is shifted slightly downfield in contrast with
compound 4a–j. The reason was due to the deshielding
affected by heterocycles which shifted the resonances to
about d 3.70–3.95 ppm. In 13C-NMR, signals of ring S–CH2
–
and ring >C O appeared at about d 31.63 ppm and
–
172.35 ppm, respectively.
Treatment of a suspension of 2-sulfanyl acid hydrazide (3)
with equimolar amount of various acids in the presence of
phosphorous oxytrichloride at room temperature and then
refluxing for 18–20 h gave 1,3,4-oxadiazoles 6a–j in yields
ranging from 70–75%. The appearance of (C–O–C) signal at
1267.7 cmꢀ1 confirms the formation of the oxadiazole
moiety.
Results and discussion
Biological Evaluation
All the compounds prepared herein were screened for their
potential biological activities such as anti-bacterial, anti-fun-
gal and cytotoxic activities. Bacterial strains Staphylococcus
aureus [ATCC-25923] and Enterococcus faecalis [ATCC-29212] as
Gram positive, Klebsiella pneumoniae [ATCC-13883] and
Escherichia coli [ATCC-25922] as Gram negative and Candida
albicans [ATCC-10145], Asperigillus fumigatus [36607] as fungal
strains are used for the in-vitro study. The in-vitro anti-
microbial activity of the compounds was tested by tube
dilution technique. Each of the test compounds and stan-
dards ciprofloxacin and fluconazole were dissolved in DMSO
at an initial concentration of 250 mg/mL and then were
serially diluted in culture medium as follows: 125, 62.5,
31.250, 16, 8, 4, 2, and 1 mg/mL concentrations. The mini-
mum inhibitory concentrations (MIC) were defined as the
Chemistry
We synthesized the target title compounds according to
Scheme 1. 2-Mercapto benzimidazole (1) was prepared accord-
ing to the reported method [16]. Condensation of 1 with
ethylchloroacetate in presence of anhydrous K2CO3 yielded
ethyl-2-(benzimidazolyl thio)-acetate 2. The appearance of the
signal at d 1.32 ppm due to –CH3 and d 4.33 ppm due to –CH2
in –COOCH2CH3 in 1H-NMR confirmed the formation of ester.
This was also confirmed by IR due to a band at 1720 cmꢀ1
which appeared because of C ¼ O of ester. Using ethanol as
the reaction media, 2 on ammonolysis with hydrazine
hydrate
afforded
[2-(1H-benzimidazolylsulfanyl)-acetyl]-
hydrazine (3). 1H-NMR confirms this compound with a signal
at d 8.02 ppm and d 4.13 ppm due to –CONH and –NH2,
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Arch. Pharm. Chem. Life Sci. 2011, 11, 311–319
Derivatives of Benzimidazole Moiety
313
NH2
N
N
(ii)
(i)
SH
SCH2COOC2H5
+ ClCH2COOC2H5
N
H
N
H
NH2
(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
R = a)
d)
e)
c)
b)
g)
Cl
OH
OH
CH3
NH2
OH
h)
f)
i)
j)
O
OMe
OMe
R1 = a)
b)
c)
e)
d)
i)
HO
OH
OH
Cl
OH
Scheme 1. Synthesis of 4-thiazolidinone and
1,3,4-oxadiazole derivatives containing 2-mer-
capto benzimidazole moiety.
Cl
f)
HO
g)
h)
j)
OH
N
OH
NH2
NO2
NO2
lowest concentrations of the compounds that prevented
visible growth. It was determined that the solvent had
no anti-microbial activity against any of the test
microorganisms.
number of –OH group increases, the activity also enhanced
which could be seen for compounds 6e by two-fold and 6f by
four-fold compared to others.
Anti-fungal activity assay
Anti-bacterial activity assay
MIC values for the in vitro anti-fungal studies of the com-
pounds 5a–j, 6a–j and the standard are represented in
Table 2. Among test compounds 5b, 5c, 5d, 5g, 5i, 6b, and
6i induced markedly anti-fungal activity compared to stan-
dard fluconazole against C. albicans and A. fumigatus compared
to control fluconazole with MIC values of 8–2 mg/mL. The
compounds 5e, 5f, 5h, 6a, 6g, 6j showed at least an activity of
62.5–125 mg/mL against both the fungi. The presence of an
–OH group as per the structural demand of fluconazole was
behind the enhancement in activities of these compounds.
Also the presence of halogen –Cl and the electron
withdrawing group -NO2 equally influenced the activities.
MIC values for the in vitro anti-bacterial studies of the
compounds 5a–j, 6a–j and the standard are represented in
Table 1. The anti-bacterial activity of all the compounds
against S. aureus and E. faecalis as Gram positive, K. pneumoniae
and E. coli as Gram negative bacteria showed good potencies
compared to control drug ciprofloxacin. Among the synthe-
sized compounds 5b, 5d, 5i, 6b, 6e, 6f, and 6i showed very
good to moderate activity with MIC values of 16–2 mg/mL
against all the bacterial strains. Electron withdrawing nature
of the substituents –NO2, –Cl, –OH on the aromatic ring
highly influenced the activity. It was observed that as the
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K. M. Hosamani et al.
Arch. Pharm. Chem. Life Sci. 2011, 11, 311–319
Table 1. In vitro anti-bacterial activity of synthesized compounds 5a–j and 6a–j in MIC (mg/mL).
Comp.
S. aureus (25923)a
E. faecalis (29212)
K. pneumonia (13883)
E. coli (25922)
5a
5b
16.125
4
31.250
8
62
8
31.250
8
5c
5d
5e
5f
5g
5h
5i
5j
6a
6b
6c
6d
6e
16.125
08
62.5
08
62.5
31.250
16
31.250
16.125
62.5
125
4
4
16.125
16.125
31.250
31.250
16.125
31.250
16.125
31.250
62.5
08
16.125
31.250
62.5
2
31.250
16.125
16.25
62.5
02
62.5
31.250
62.5
31.250
16.125
62.5
125
4
8
8
4
8
8
4
16.125
16.125
2
08
08
4
6f
6g
6h
6i
1
1
1
2
62.5
8
62.5
16.125
8
62.5
16.125
2
31.25
16.125
4
4
6j
Ciprofloxacin
31.250
0.78
62.5
0.70
125
0.19
62.5
0.19
a
ATCC number.
The active compounds are marked in bold letters.
Cytotoxic activity assay
evident that the compounds 5b, 5g, 5i, 6b, 6f, 6h and 6i
displayed potent cytotoxic activity against Artemia salina,
while the other compounds have shown moderate activity
in this assay. Compound 6f showed a maximum activity
(LD50 ¼ 6.330 ꢁ 10ꢀ4 M) in the present series of compounds.
Thus, the structure activity relationship studies of these
All synthesized compounds 5a–j, 6a–j were screened for their
cytotoxicity (brine shrimp bioassay) using the protocol of
Meyer et al. [29]. From the data recorded in Table 3, it is
Table 2. In vitro anti-fungal activity of synthesized compounds 5a–j
and 6a–j in MIC (mg/mL).
Comp.
C. albicans (10145)a
A. fumigatus (36607)
Table 3. Brine shrimp bioassay data for compounds 5a–j and 6a–j.
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
6a
6b
6c
6d
6e
62.5
16.125
16.125
8
62.5
125
16.125
31.250
16.125
16.125
31.250
4
62.5
8
4
Comp.
LD50 (mM)
5a
5b
5c
5d
5e
5f
5g
5h
5i
3.425
0.5825
4.28
3.725
3.21
2.458
0.5616
2.023
0.5994
3.720
4.789
0.6221
4.390
4.781
3.693
0.6330
5.23
8
125
62.5
16.125
31.25
16.125
31.250
62.5
8
8
8
2
2
62.5
8
4
62.5
2.0
5j
8
4
4
2
6a
6b
6c
6d
6e
6f
6g
6h
6i
6f
6g
6h
6i
62.5
4
4
31.250
2.0
6j
Fluconazole
0.5628
0.5956
5.616
6j
a
ATCC number.
The active compounds are marked in bold letters.
The active compounds are marked in bold letters.
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Arch. Pharm. Chem. Life Sci. 2011, 11, 311–319
Derivatives of Benzimidazole Moiety
315
CDCl3) d ppm: 1.40 (t, 3H, J ¼ 7 Hz, –COOCH2CH3), 3.85 (q, 2H,
J ¼ 6.5 Hz, –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, 55.89; H,
5.01; N, 11.86.
compounds revealed that R and R1 with functional groups
–Cl, –OH at 2, 3, or 4 positions, -NO2 at 4 position showed
good cytotoxicity.
Conclusion
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 from ethanol to obtain compound 3
(1.77 g, 75%). Pinkish white solid; m. p.: 1958C; IR (KBr)
The main aim of the present work is to synthesize thiazoli-
dinone and oxadiazole containing benzimidazole derivatives
and investigate for various bioassays with the hope of dis-
covering new structure leads serving as potential broad spec-
trum pharmacological agents. Among the synthesized
compounds 5b, 6b, 6e, and 6f were found to be remarkably
anti-microbial active showing excellent MIC values compared
to reference drugs such as ciprofloxacin and fluconazole. SAR
studies revealed the critical role of –OH function in the target
compounds that showed very promising in-vitro activities.
Compounds with –Cl, -NO2 and –OH functional groups exhib-
ited attractive cytotoxicity properties.
ꢀ1
;
1H-NMR
–
n: 3311, 3369 (–NHNH ), 1680 (>C O of amide) cm
–
2
(300 MHz, CDCl3) d ppm: 3.90 (s, 2H, –NH2), 4.35 (s, 2H, S–CH2),
6.95–7.90 (m, 4H, Ar-H), 7.55 (s, 1H, –CONH–), 10.25 (s, 1H,
–NH–benzimidazole). Anal. calcd. for C9H10N4OS: C, 48.64; H,
4.80; N, 25.22. Found: C, 48.59; H, 4.79; N, 25.18.
Synthesis of (1H-Benzimidazol-2-ylsulfanyl)-acetic acid
hydrazide 4
A mixture of compound 3 (2.22 g, 0.01 mol) and benzaldehyde
(1.06 mL, 0.01 mol) and 2–3 drops of glacial acetic acid in etha-
nol (20 mL) was refluxed on a water bath for about 6 h. The
solvent was removed and the residue was recrystallized from
chloroform/methanol mixture to yield the required compound.
The compounds 4b–j were prepared similarly by treating with
respective aldehydes.
Experimental
Materials and methods
All reagents and solvents were used as obtained from the sup-
plier or recrystallized/redistilled as necessary. Melting points of
the synthesized compounds 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 Bruker Avanace-300 (300 MHz)
model spectrophotometer in CDCl3 and DMSO as 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 shifts were measured in ppm downfield
from internal TMSi at d ¼ 0. The mass spectra were recorded on
Schimadzu GCMS-QP2010S at 70 eV. TLC was performed on
alumina silica gel 60 F254 (Merck). The mobile phase was ethyl
acetate and n-hexane (1:1) and detection was made using UV light
and iodine vapors. All the compounds gave C, H, and N analysis
within ꢂ0.5% of the theoretical values.
(1H-Benzimidazol-2-ylsulfanyl)-acetic acid benzylidene
hydrazide 4a
Pale yellow crystals; m. p.: 218–2208C; IR (KBr) n: 3320,1342
ꢀ1
–
–
–
–
(–NH–), 1682 (>C O), 1640 (–N CH–) cm
–
;
1H-NMR (300 MHz,
CDCl ) d ppm: 4.02 (s, 1H, –N CH–), 6.87–7.78 (m, 4H, Ar-H), 7.95
–
3
(s, 1H, –CONH–), 10.5 (s, 1H, –NH–benzimidazole). Anal. calcd. for
C16H14N4OS: C, 61.92; H, 4.55; N, 18.05. Found: C, 61.88; H, 4.57;
N, 18.12.
(1H-Benzoimidazol-2-ylsulfanyl)-acetic acid (4-chloro-
benzylidene)-hydrazide 4b
Colorless crystals; m. p.: 255–2578C; IR (KBr) n: 3315, 1330 (–NH–),
1660 (>C O), 1635 (–N CH–) cmꢀ1; 1H-NMR (300 MHz, CDCl3) d
–
–
–
–
–
ppm: 4.07 (s, 1H, –N CH–), 6.54–7.69 (m, 4H, Ar-H), 7.85 (s, 1H,
–
–CONH–), 10.0 (s, 1H, –NH–benzimidazole). Anal. calcd. for
C16H13ClN4OS: C, 55.73; H, 3.80; N, 16.25. Found: C, 55.69; H,
3.79; N, 16.17.
Chemistry
General procedure for the preparation of compounds
(1H-Benzimidazol-2-ylsulfanyl)-acetic acid (2-hydroxy-
benzylidene)-hydrazide 4c
Synthesis of 2-mercapto benzimidazole 1 Compound 1
was prepared according to the reported procedure [16].
Colorless crystals; m. p.: 202–2048C; IR (KBr) n: 3325, 1340 (–NH–),
ꢀ1
–
–
1671 (>C O), 1639 (–N CH–) cm
–
;
1H-NMR (300 MHz, CDCl3)
–
–
Synthesis of ethyl 2-(benzimidazolyl-thio) acetate 2
d ppm: 4.10 (s, 1H, –N CH–), 6.59–7.70 (m, 4H, Ar-H), 7.82 (s, 1H,
–
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
distillation and the residue was recrystallized from chloroform
to furnish compound 2 (1.055 g, 70%). White solid; m. p.: 60–
–
–CONH–), 10.01 (s, 1H, –NH–benzimidazole). Anal. calcd. for
C16H14N4O2S: C, 58.88; H, 4.32; N, 17.17. Found: C, 58.80; H,
4.29; N, 17.20.
(1H-Benzimidazol-2-ylsulfanyl)-acetic acid (4-hydroxy-
benzylidene)-hydrazide 4d
628C; IR (KBr) n: 3042 (aromatic ring), 638 (C-S), 1719 (>C O of
–
–
ester), 1684 (-C N-), 1320 and 1234 (C–O–C), 830 (C-S-C) and 2955,
1H-NMR (300 MHz,
Colorless crystals; m. p.: 238–2408C; IR (KBr) n: 3321, 1339 (–NH–),
–
ꢀ1
2889, 1443, 714, (–CH2 and –CH3) cmꢀ1
;
1669 (>C O), 1641 (–N CH–) cm
;
1H-NMR (300 MHz, CDCl3)
–
–
–
–
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316
K. M. Hosamani et al.
Arch. Pharm. Chem. Life Sci. 2011, 11, 311–319
–
d ppm: 4.08 (s, 1H, –N CH–), 6.65–7.75 (m, 4H, Ar-H), 7.79 (s, 1H,
–
Synthesis of (1H-benzimidazol-2-ylsulfanyl)-thiazolidin-4-
one 5
–CONH–), 9.75 (s, 1H, –NH–benzimidazole). Anal. calcd. for
C16H14N4O2S: C, 58.88; H, 4.32; N, 17.17. Found: C, 58.81; H,
4.28; N, 17.19.
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 into 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.
(1H-Benzimidazol-2-ylsulfanyl)-acetic acid (4-methyl-
benzylidene)-hydrazide 4e
Pale yellow crystals; m. p.: 206–2088C; IꢀR1 (KBr) n: 3330, 1325
1H-NMR (300 MHz,
–
–
–
(–NH–), 1672 (>C O), 1645 (–N CH–) cm
;
–
–
CDCl ) d ppm: 4.05 (s, 1H, –N CH–), 6.62–7.70 (m, 4H, Ar-H), 7.81
–
3
3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-phenyl-
thiazolidin-4-one 5a
(s, 1H, –CONH–), 9.91 (s, 1H, –NH–benzimidazole). Anal. calcd. for
C17H16N4OS: C, 62.94; H, 4.97; N, 17.27. Found: C, 62.90; H, 4.90;
N, 17.22.
Pale yellow crystals; m. p.: 230–2328C; IR (KBr) n: 3212.4, 13ꢀ718
–
–
–
(–NH–), 1522.9 (-C N), 1593.7 (–CONH), 1640.0 (ring >C O) cm
;
–
1H-NMR (300 MHz, CDCl3) d ppm: 3.60 (s, 2H, –CH2, ring), 3.65 (s,
2H, S–CH2), 3.70 (d, 1H, CH-Ar), 7.0–7.94 (m, 9H, Ar-H), 8.08 (s, 1H,
–CONH–), 11.9 (br, 1H, –NH–benzimidazole, D2O exchangeable);
13C-NMR (75 MHz, CDCl3) d ppm: 31.63 (ring S–CH2), 36.63
(S–CH2), 54.98 (–CH), 121.50, 122.4, 127.53, 129.21, 129.46,
(1H-Benzimidazol-2-ylsulfanyl)-acetic acid (4-methoxy-
benzylidene)-hydrazide 4f
Light brown crystals; m. p.: 212–2148C; IR (KBr) n: 3329, 1331
ꢀ1
;
1H-NMR (300 MHz,
–
–
–
–
(–NH–), 1675 (>C O), 1642 (–N CH–) cm
–
–
–
130.05, 135.52, 143.15 (heteroaromatics), 163.18 (amide >C O),
þ
CDCl ) d ppm: 4.09 (s, 1H, –N CH–), 6.59–7.81 (m, 4H, Ar-H), 7.79
–
3
–
172.35 (ring >C O); MS m/z: 384 [M ], 385 [M þ 1], 386 [M þ 2],
–
(s, 1H, –CONH–), 10.01 (s, 1H, –NH–benzimidazole). Anal. calcd.
for C17H16N4O2S: C, 59.98; H, 4.74; N, 16.46. Found: C, 59.92; H,
4.72; N, 16.40.
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, 56.30; H, 4.20; N, 14.50.
(1H-Benzimidazol-2-ylsulfanyl)-acetic acid (2-hydroxy-3-
methoxy-benzylidene)-hydrazide 4g
3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-(4-chloro-
phenyl)-thiazolidin-4-one 5b
Yellow crystals; m. p.: 235–2378C; IR (KBr) n: 3206.3, 1377.0
Light brown crystals; m. p.: 180–1828C; IR (KBr) n: 3333, 1345
ꢀ1
–
–
–
–
(–NH–), 1670 (>C O), 1650 (–N CH–) cm
–
;
1H-NMR (300 MHz,
–
–
–
(–NH–), 1531.3 (C N), 1595.8 (–CONH), 1639.1 (ring >C O),
;
–
CDCl ) d ppm: 4.05 (s, 1H, –N CH–), 6.55–7.80 (m, 4H, Ar-H), 7.81
–
3
Ar–Cl (825.6) cmꢀ1
1H-NMR (300 MHz, CDCl3) d ppm: 3.50
(s, 1H, –CONH–), 10.05 (s, 1H, –NH–benzimidazole). Anal. calcd.
for C17H16N4O3S: C, 57.29; H, 4.52; N, 15.72. Found: C, 57.15; H,
4.54; N, 15.78.
(s, 2H, S–CH2), 3.58 (s, 2H, –CH2, ring), 3.72 (d, 1H, CH-Ar),
6.98–7.90 (m, 9H, Ar-H), 8.12 (s, 1H, –CONH–), 11.78 (br, 1H,
–NH–benzimidazole, D2O exchangeable); 13C-NMR (75 MHz,
CDCl3) 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,
(1H-Benzimidazol-2-ylsulfanyl)-acetic acid furan-2-
ylmethylene-hydrazide 4h
–
135.3, 145.85 (heteroaromatics), 164.72 (amide >C O), 173.87
þ
–
Light brown crystals; m. p.: 222–2248C; IR (KBr) n: 3330, 1341
–
–
(ring >C O); MS m/z: 418 [M ], 419 [M þ 1], 420 [M þ 2], 231, 215,
ꢀ1
–
–
–
–
(–NH–), 1672 (>C O), 1655 (–N CH–) cm
–
;
1H-NMR (300 MHz,
202, 200, 191, 194, 187, 170, 149, 117, 28. Anal. calcd. for
C18H15N4O2S2Cl: C, 51.58; H, 3.61; N, 13.30. Found: C, 51.56;
H, 3.65; N, 13.28.
CDCl ) d ppm: 4.02 (s, 1H, –N CH–), 6.52–7.77 (m, 4H, Ar-H), 7.79
–
3
(s, 1H, –CONH–), 10.00 (s, 1H, –NH–benzimidazole). Anal. calcd.
for C17H16N4O3S: C, 57.29; H, 4.52; N, 15.72. Found: C, 57.20; H,
4.54; N, 15.78.
3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-(2-hydroxy-
phenyl)-thiazolidin-4-one 5c
(1H-Benzimidazol-2-ylsulfanyl)-acetic acid (2-hydroxy-
naphthalen-1-ylmethylene)-hydrazide 4i
Brown crystals; m. p.: 135–1378C; IR (KBr) n: 3235, 1355 (–NH–),
1586.4 (C N), 1620.5 (–CONH), 1657.5 (ring >C O) cmꢀ1; 1H-NMR
–
–
–
–
Pale yellow crystals; m. p.: 218–2208C; IꢀR1 (KBr) n: 3329, 1335
(300 MHz, CDCl3) d ppm: 3.58 (s, 2H, –CH2, ring), 3.62 (s, 2H,
S–CH2), 3.75 (d, 1H, CH-Ar), 7.0–7.85 (m, 9H, Ar-H), 8.25 (s, 1H,
–CONH–), 11.54 (br, 1H, –NH–benzimidazole, D2O exchangeable);
13C-NMR (75 MHz, CDCl3) 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,
–
1H-NMR (300 MHz,
–
–
–
–
(–NH–), 1667 (>C O), 1649 (–N CH–) cm
;
–
CDCl ) d ppm: 4.07 (s, 1H, –N CH–), 6.64–7.72 (m, 4H, Ar-H), 7.82
–
3
(s, 1H, –CONH–), 10.04 (s, 1H, –NH–benzimidazole). Anal. calcd.
for C20H16N4O2S: C, 63.81; H, 4.28; N, 14.88. Found: C, 63.75; H,
4.24; N, 14.87.
136.9, 146.85, 156.5 (heteroaromatics), 164.53 (amide >C O),
–
þ
–
172.98 (ring >C O); MS m/z: 400 [M ], 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, 13.91.
(1H-Benzimidazol-2-ylsulfanyl)-acetic acid (4-amino-
benzylidene)-hydrazide 4j
Pale yellow crystals; m. p.: 198–2008C; IꢀR1 (KBr) n: 3342, 1328
–
–
–
–
(–NH–), 1659 (>C O), 1642 (–N CH–) cm
;
1H-NMR (300 MHz,
3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-(4-hydroxy-
phenyl)-thiazolidin-4-one 5d
–
CDCl ) d ppm: 4.10 (s, 1H, –N CH–), 4.65 (s, 2H, –NH ), 6.26–
–
3
2
7.29 (m, 4H, Ar-H), 7.65 (s, 1H, –CONH–), 10.21 (s, 1H,
–NH–benzimidazole). Anal. calcd. for C16H15N5OS: C, 59.06; H,
4.65; N, 21.52. Found: C, 59.02; H, 4.66; N, 21.49.
Yellow powder; m. p.: 140–1428C; IR (KBr) n: 3207.6, 1380.9
–
–
(–NH–), 1515.0 (C N), 1604.3 (–CONH), 1641.7 (ring >C O),
–
–
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2011, 11, 311–319
Derivatives of Benzimidazole Moiety
317
3448.8 (–OH) cmꢀ1; 1H-NMR (CDCl3) d ppm: 3.62 (s, 2H, ring –CH2),
3.69 (s, 2H, S–CH2), 3.72 (d, 1H, CH-Ar), 7.0–7.99 (m, 9H, Ar-H), 8.06
(s, 1H, –CONH–), 12.06 (br, 1H, –NH–benzimidazole, D2O
exchangeable); 13C-NMR (75 MHz, CDCl3) 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),þ164.53
1256.2 (C–O–C) cmꢀ1 1H-NMR (CDCl3) d (ppm): 3.62 (s, 2H,
;
–CH2, ring), 3.65 (s, 2H, S–CH2), 3.70 (d, 1H, CH-Ar), 7.0–7.94
(m, 9H, Ar-H), 8.21 (s, 1H, –CONH–), 11.54 (br, 1H,
–NH–benzimidazole, D2O exchangeable); 13C-NMR (75 MHz,
CDCl3) 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 (heteroaromaticþs),
–
–
–
165.81 (amide >C O), 174.2 (ring >C O); MS m/z: 374 [M ],
–
–
(amide >C O), 172.58 (ring >C O); MS m/z: 400 [M ], 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, 53.92; H, 4.00; N, 13.94.
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, 3.71; N, 14.95.
3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-p-tolyl-
thiazolidin-4-one 5e
3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-(3-hydroxy-
naphthalen-2-yl)-thiazolidin-4-one 5i
Pale white crystals; m. p.: 238–2408C; IR (KBr) n: 3224, 1346.3
Pale yellow crystals; m. p.: 240–2428C; IR (KBr) n: 3202.6, 1383.0
ꢀ1
–
–
–
–
(–NH–), 1590.6 (C N), 1639.9 (–CONH), 1680.5 (ring >C O) cm
;
(–NH–), 1585.0 (C N), 1624.6 (–CONH), 1678.8 (ring >C O),
–
–
–
;
–
1H-NMR (300 MHz, CDCl3) d ppm: 3.60 (s, 2H, S–CH2), 3.62 (s, 2H,
–CH2, ring), 3.81 (d, 1H, CH-Ar), 7.08–8.01 (m, 9H, Ar-H), 8.28 (s,
1H, –CONH–), 11.55 (br, 1H, –NH–benzimidazole, D2O exchange-
able); 13C-NMR (75 MHz, CDCl3) d ppm: 21.89 (–CH3), 32.54 (ring
S–CH2), 37.83 (S–CH2), 55.42 (–CH), 121.5, 128.5, 129.58, 129.82,
3450.5 (–OH) cmꢀ1
1H-NMR (300 MHz, CDCl3) d ppm: 3.55 (s,
2H, S–CH2), 3.62 (s, 2H, –CH2, ring), 3.72 (d, 1H, >CH-Ar), 7.52–
7.99 (m, 9H, Ar-H), 8.20 (s, 1H, –CONH–), 11.62 (br, 1H,
–NH–benzimidazole, D2O exchangeable); 13C-NMR (75 MHz,
CDCl3) d ppm: 32.5 (ring S–CH2), 37.82 (S–CH2), 56.28 (–CH),
121.18, 122.4, 125.29, 127.92, 129.19, 129.87, 129.95, 130.11,
–
129.88, 138.25, 145.28 (heteroaromatics), 168.8 (amide >C O),
þ
–
–
–
–
173.52 (ring >C O); MS m/z: 398 [M ], 399 [M þ 1], 400 [M þ 2],
135.98, 143.45 (heteroaromatics), 164.05 (amide >C O), 172.90
þ
–
–
–
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,
4.45; N, 14.10.
(ring >C O); MS m/z: 450 [M ], 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, 12.40.
3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-(4-methoxy-
phenyl)-thiazolidin-4-one 5f
White crystals; m. p.: 219–2208C; IR (KBr) n: 3208.0, 1378.9
3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-(4-amine-
phenyl)-thiazolidin-4-one 5j
–
–
(–NH–), 1513.8 (C N), 1606.0 (–CONH), 1637.6 (ring >C O),
;
Yellow crystals, (ethanol). Yield: 70.25%; m. p.: 218–2208C; IR
–
–
2831.8 (Ar-OCH3) cmꢀ1
1H-NMR (300 MHz, CDCl3) d ppm: 3.65
(KBr, cmꢀ1) n: 3346.6, 1376.6 (–NH–), 1575.0 (C N), 1620.6
–
–
(–CONH), 1675.2 (ring >C O), 3450.5 (–OH); 1H-NMR (300 MHz,
–
–
(s, 2H, S–CH2), 3.66 (s, 2H, –CH2, ring), 3.94 (d, 1H, >CH-Ar), 7.54–
7.91 (m, 9H, Ar-H), 8.28 (s, 1H, –CONH–), 11.52 (br, 1H,
–NH–benzimidazole, D2O exchangeable); 13C-NMR (75 MHz,
CDCl3) d ppm: 31.12 (ring S–CH2), 36.55 (S–CH2), 55.98 (–CH),
112.12, 121.77, 129.0, 129.51, 129.82, 130.55, 135.81, 142.42
CDCl3) d ppm: 3.52 (s, 2H, S–CH2), 3.64 (s, 2H, –CH2, ring), 3.75 (d,
1H, >CH-Ar), 7.50–7.85 (m, 9H, Ar-H), 8.20 (s, 1H, –CONH–), 11.60
(br, 1H, –NH– benzimidazole, D2O exchangeable); 13C-NMR
(75 MHz, CDCl3) 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)þ, 171.05 (amide
–
–
(heteroaromatics), 163.14 (amide >C O), 174.31 (ring >C O);
–
–
MS 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, 13.50. Found: C, 55.10; H, 4.30; N, 13.45.
–
–
–
>C O), 167.90 (ring >C O); MS m/z: 399 [M ], 400 [M þ 1],
–
401 [M þ 2], 262, 259, 245, 230, 216, 164, 115, 105, 58, 28.
Anal. calcd. for C22H18N4O3S2 (450.54): C, 54.12; H, 4.29; N,
17.53. Found: C, 54.10; H, 4.26; N, 17.57.
3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-(2-hydroxy-3-
methoxy-phenyl)-thiazolidin-4-one 5g
Yellow crystals; m. p.: 220–2228C; IR (KBr) n: 3280.9, 1382.7
Synthesis of 2-(5-phenyl-[1,3,4]-oxadiazole-2-
ylmethylsulfanyl)-1H-benzimidazole 6a–j
–
–
(–NH–), 1585.0 (C N), 1637.1 (–CONH), 1670.1 (ring >C O),
;
–
–
3410.9 (–OH), 2812 (Ar-OCH3) cmꢀ1
1H-NMR (300 MHz, CDCl3)
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 into crushed ice with stirring and the precipitated prod-
uct was neutralized with ammonia, filtered, washed with water
and recrystallized from chloroform to get the respective
oxadiazole.
d ppm: 3.60 (s, 2H, S–CH2), 3.65 (s, 2H, –CH2, ring), 3.82 (d, 1H,
CH-Ar), 7.55–8.01 (m, 9H, Ar-H), 8.08 (s, 1H, –CONH–), 11.9 (br, 1H,
–NH–benzimidazole, D2O exchangeable); 13C-NMR (75 MHz,
CDCl3) 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 (amide >C O), 174.29 (ring >C O);
–
–
MS 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, 53.08; H, 4.15; N, 12.99.
2-(5-Phenyl-[1,3,4]-oxadiazole-2-ylmethylsulfanyl)-1H-
benzimidazole 6a
Dark brown powder; m. p.: 198–2008C; IRꢀ(K1Br) n: 3237.6, 1338.7
1H-NMR (300 MHz,
3-(1H-Benzimidazol-2-ylsulfanylmethyl)-2-furan-2-yl-
thiazolidin-4-one 5h
–
–
(–NH–), 1267.1 (C–O–C), 1654.7 (C N) cm
;
CDCl3) d ppm: 3.39 (s, 2H, S–CH2), 7.17–8.53 (m, 9H, Ar-H), 11.45
(br, 1H, –NH–benzimidazole, D2O exchangeable); 13C-NMR
(75 MHz, CDCl3) d ppm: 37.23 (S–CH2), 117.2, 120.9, 129.5,
Brown crystals; m. p.: 155–1578C; IR (KBr) n: 3225.2, 1384.3
–
–
–
(–NH–), 1590.5 (C N), 1685.0 (–CONH), 1697.3 (ring >C O),
–
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

318
K. M. Hosamani et al.
Arch. Pharm. Chem. Life Sci. 2011, 11, 311–319
135.0, 136.8, 140.0 (heteroaromatics), 155.8 (C2, oxa), 172.6 (C5,
oxa); MS 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, 62.30; H, 3.88; N, 18.10.
exchangeable), 12.05 (s, 1H, –OH, D2O exchangeable); 13C-NMR
(75 MHz, CDCl3) d ppm: 35.44 (S–CH2), 122.90, 133.83, 137.25,
140.56, 145.2, 145.8 (heteroaromatics), 155.0 (C2, oxa), 172.11 (C5,
oxa); MS 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, 3.45; N, 15.69.
2-(5-Chloro-phenyl-[1,3,4]-oxadiazole-2-ylmethylsulfanyl)-
1H-benzimidazole 6b
4-[5-(1H-Benzimidazol-2-ylsulfanylmethyl)-[1,3,4]-
oxadiazole-2-yl]-phenylamine 6g
Dark brown powder; m. p.: 202–2048C; IR (KBr) n: 3322.4, ꢀ11340.1
–
–
(–NH–), 1275.8 (C–O–C), 1618.4 (C N), 3412.3 (–OH) cm
;
1H-
NMR (300 MHz, CDCl3) d ppm: 3.86 (s, 2H, S–CH2), 7.57–8.13 (m,
8H, Ar-H), 11.02 (br, 1H, –NH–benzimidazole, D2O exchangeable);
13C-NMR (75 MHz, CDCl3) d ppm: 36.65 (S–CH2), 122.7, 129.6,
136.25, 145.25, (heteroaromatics), 155.54 (C2, oxa), 172.81 (C5,
oxa); MS 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, 56.09; H, 3.28; N, 16.31.
Light brown crystals; m. p.: 228–2308C; IRꢀ(K1Br) n: 3346.6, 1376.6
1H-NMR (300 MHz,
–
–
(–NH–), 1269.5 (C–O–C), 1603.8 (C N) cm
;
CDCl3) d ppm: 3.29 (s, 2H, S–CH2), 7.17–8.55 (m, 8H, Ar-H), 10.92
(br, 1H, –NH–benzimidazole, D2O exchangeable); 13C-NMR
(75 MHz, CDCl3) 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);
MS 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,
59.48; H, 4.10; N, 21.69.
3-[5-(1H-Benzimidazol-2-ylsulfanylmethyl)-[1,3,4]-
oxadiazole-2-yl]-naphthalen-2-ol 6c
2-[5-(4-Nitro-phenyl)-[1,3,4]-oxadiazole-2-
ylmethylsulfanyl]-1H-benzimidazole 6h
Pale yellow crystals; m. p.: 205–2078C; IR ꢀ(K1Br) n: 3386.5, 1388.5
–
–
(–NH–), 1241.1 (C–O–C), 1636.4 (C N) cm
;
1H-NMR (300 MHz,
CDCl3) d ppm: 3.42 (s, 2H, S–CH2), 7.18–8.11 (m, 10H, Ar-H), 11.09
(br, 1H, –NH– benzimidazole, D2O exchangeable), 12.41 (s, 1H,
–OH, D2O exchangeable); 13C-NMR (75 MHz, CDCl3) d ppm: 37.26
(S–CH2), 122.85, 129.89, 136.85, 145.28 (heteroaromatics), 155.2
(C2, oxa), 172.65 (C5, oxa); MS 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, 64.12; H, 3.72; N, 14.95.
Brown crystals; m. p.: 164–1668C; IR (KBr) n: 3348.1, 1380.1
ꢀ1
;
1H-NMR (300 MHz,
–
(–NH–), 1269.2 (C–O–C), 1618.7 (C N) cm
–
CDCl3) d ppm: 3.11 (s, 2H, S–CH2), 7.28–8.21 (m, 8H, Ar-H),
10.85 (br, 1H, –NH–benzimidazole, D2O exchangeable); 13C-
NMR (75 MHz, CDCl3) d ppm: 36.14 (S–CH2), 122.82, 124.34,
133.82, 149.79 (heteroaromatics), 156.73 (C2, oxa), 172.6 (C5,
oxa); MS 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 54.32; H, 3.10; N, 19.85.
4-[5-(1H-Benzimidazol-2-ylsulfanylmethyl)-[1,3,4]-
oxadiazole-2-yl]-phenol 6d
2-[5-(2-Chloro-4-nitro-phenyl)-[1,3,4]-oxadiazole-2-
ylmethylsulfanyl]-1H-benzimidazole 6i
Yellow powder; m. p.: 215–2178C; IR (KBr) n: 3320.9, 1342.5 (–NH),
1
1280.4 (C–O–C), 1621.4 (C N) cmꢀ1; H-NMR (300 MHz, CDCl3) d
–
–
ppm: 3.38 (s, 2H, S–CH2), 7.07–7.95 (m, 8H, Ar-H), 11.15 (br, 1H,
–NH–benzimidazole, D2O exchangeable), 12.38 (s, 1H, –OH, D2O
exchangeable); 13C-NMR (75 MHz, CDCl3) d ppm: 35.82 (S–CH2),
122.10, 129.43, 135.87, 145.69 (heteroaromatics), 155.62 (C2, oxa),
172.87 (C5, oxa); MS 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, 3.73; N, 17.29.
Light brown crystals; m. p.: 208–2108C; IR (KBr) n: 3409.8, 1390.6
(–NH–), 1251.1 (C–O–C), 1657.4 (C N), 890.8 (C–Cl) cmꢀ1; 1H-NMR
–
–
(300 MHz, CDCl3) d ppm: 3.12 (s, 2H, S–CH2), 7.65–8.11 (m, 7H,
Ar-H), 11.25 (br, 1H, –NH–benzimidazole, D2O exchangeable);
13C-NMR (75 MHz, CDCl3) d 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); MS 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, 2.55; N, 18.02.
6-[5-(1H-Benzimidazol-2-ylsulfanylmethyl)-[1,3,4]-
oxadiazole-2-yl]-naphthalene-1,7-diol 6e
2-(5-Pyridin-3-yl-[1,3,4]-oxadiazole-2-ylmethylsulfanyl]-
1H-benzimidazole 6j
Brown crystals; m. p.: 187–1898C; IR (KBr) n: 3322.4, 1340.1 (–NH–),
1275.8 (C–O–C), 1618.4 (C N), 3412.3 (–OH) cmꢀ1; 1H-NMR (300 MHz,
–
–
CDCl3) d ppm: 3.60 (s, 2H, S–CH2), 6.92–8.52 (m, 9H, Ar-H), 11.42 (br,
1H, –NH–benzimidazole, D2O exchangeable), 12.20 (s, 1H, –OH, D2O
exchangeable); 13C-NMR (75 MHz, CDCl3) d ppm: 35.93 (S–CH2),
123.45, 128.65, 136.85, 146.73, 148.0 (heteroaromatics), 154.73 (C2,
oxa), 171.96 (C5, oxa); MSm/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, 61.56; H, 3.65; N, 14.32.
Light brown crystals; m. p.: 201–2028C; IR (KBr) n: 3348.5, 1354.0
(–NH–), 1275.1 (C–O–C), 1610 (C N) cmꢀ1; 1H-NMR (300 MHz,CDCl3)
–
–
d ppm: 3.15 (s, 2H, S–CH2), 7.46–8.28 (m, 8H, Ar-H), 11.45 (br, 1H,
–NH–benzimidazole, D2O exchangeable); 13C-NMR (75 MHz, CDCl3)
d ppm: 36.42 (S–CH2), 122.0, 134.2, 138.2, 142.9, 148.15, 149.82,
(heteroaromatics), 156.2 (C2, oxa), 172.64 (C5, oxa); MS 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, 58.20; H, 3.55;
N, 22.59.
5-[5-(1H-Benzimidazol-2-ylsulfanylmethyl)-[1,3,4]-
oxadiazole-2-yl]-benzene-1,2,3-triol 6f
Biological evaluation
Anti-bacterial activity assay
The in vitro anti-microbial activity of the compounds was tested
by the tube dilution technique [30]. The cultures were obtained
Brown crystals; m. p.: 196–1988C; IR (KBr) n: 3166.1, 1387.8
ꢀ1
–
(–NH–), 1269.5 (C–O–C), 1642.7 (C N), 3499.0 (–OH) cm
;
–
1H-NMR (300 MHz, CDCl3) d ppm: 3.29 (s, 2H, S–CH2), 7.18–
8.53 (m, 6H, Ar-H), 10.42 (br, 1H, –NH–benzimidazole, D2O
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Arch. Pharm. Chem. Life Sci. 2011, 11, 311–319
Derivatives of Benzimidazole Moiety
319
in Mueller-Hinton Broth (Difco) for all the bacteria after 18–24 h
of incubation at 37 ꢂ 18C. Testing was carried out in Mueller-
Hinton Broth at pH ¼ 7.4 and twofold dilution technique was
applied. A set of tubes containing only inoculated broth was kept
as controls. After incubation for 18–24 h at 37 ꢂ 18C, the last
tube with no growth of microorganism was recorded to
represent MIC expressed in mg/mL. Ciprofloxacin was used as
standard drug.
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ferred to nine vials (three for each dilutions were used for each
test sample and LD50 is the mean of three values) and one vial was
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This research work is financially supported by the University Grants
Commission (UGC), New Delhi 110 002. (Ref. No F.33-296/2007 (SR)
dated 28-02-2008.
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The authors have declared no conflict of interest.
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ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com