Synthesis and evaluation of some new benzimidazole derivatives as potential antimicrobial agents

Article abstract of DOI:10.1016/j.ejmech.2008.01.022

The efficient synthesis of novel azetidin-2-ones 6 has been established. Thus, condensation of 5-[(2-methyl-1H-benzimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine 4 with various aromatic aldehydes afforded 5-[(2-methyl-1H-benzimidazol-1-yl)methyl]-N-[(subs

Full text of DOI:10.1016/j.ejmech.2008.01.022

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European Journal of Medicinal Chemistry 44 (2009) 2294e2299
http://www.elsevier.com/locate/ejmech
Laboratory note
Synthesis and evaluation of some new benzimidazole
derivatives as potential antimicrobial agents
*
K.F. Ansari, C. Lal
Department of Chemistry, Harcourt Butler Technological Institute, Nawabganj, Kanpur 208004, Uttar Pradesh, India
Received 11 November 2007; received in revised form 11 January 2008; accepted 17 January 2008
Available online 31 January 2008
Abstract
The efficient synthesis of novel azetidin-2-ones 6 has been established. Thus, condensation of 5-[(2-methyl-1H-benzimidazol-1-yl)methyl]-1,3,
4-thiadiazol-2-amine 4 with various aromatic aldehydes afforded 5-[(2-methyl-1H-benzimidazol-1-yl)methyl]-N-[(substituted) phenylmethylidene]-
1,3,4-thiadiazol-2-amine 5 which on cycloaddition with chloroacetyl chloride in the presence of triethylamine catalyst yielded 3-chloro-1-{5-[(2-
methyl-1H-benzimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-yl}-4-(substituted) phenylazetidin-2-one 6. Structures of the synthesized compounds
have been elucidated on the basis of their elemental analyses and spectral data. All the synthesized compounds were screened for their antimicrobial
activity.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords: 2-Benzimidazoles; Azetidin-2-ones; Thiadiazole; Antibacterial activity; Antifungal activity
1. Introduction
2. Results and discussion
Despite a numerous attempts to develop new structural
prototype in the search for more effective antimicrobials, the
benzimidazoles still remain as one of the most versatile class
of compounds against microbes [1e8] and, therefore, are use-
ful substructures for further molecular exploration. Recently,
the chemistry and biological profiles of various pharmaco-
phores of 1N- substituted and 2-substituted benzimidazoles
derivatives have been worked out in detail [9e20]. On the
other side, literature survey revealed that 1,3,4-thiadiazole
and 2-azetidinones are also associated with pharmacological
activities like antimicrobial, antiviral, anesthetic, anticonvul-
sant [21e23], etc. These findings prompted us to synthesize
1,3,4-thiadiazole and 2-azetidinones derivatives of 2-methyl-
1H-benzimidazoles. Each of the benzimidazoles analogues
prepared has been tested for their antimicrobial activities
and the results are reported in this paper.
The reaction sequence for different title compounds is out-
lined in Scheme 1. 2-Methyl-1H-benzimidazole 1 required as
the starting material was prepared according to the literature pro-
cedure [24]. 2-Methyl-1H-benzimidazole 1 on N-ethoxylation
with ethylchloroacetate in the presence of anhyd. potassium car-
bonate in dry acetone gave ethyl (2-methyl-1H-benzimidazol-1-
yl)acetate 2 which on treatment with thiasemicarbazide resulted
in the formation of 2-[(2-methyl-1H-benzimidazol-1-yl)acetyl]-
hydrazinecarbothioamide 3. Dehydrated annulation of com-
pound 3 with conc. H2SO4 followed by NH3 treatment yielded
5-[(2-methyl-1H-benzimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-
amine 4 which on condensation with various selected aromatic
aldehydes furnished Schiff’s bases, 5-[(2-methyl-1H-benzimida-
zol-1-yl)methyl]-N-[(substituted)
phenylmethylidene]-1,3,4-
thiadiazol-2-amine 5ael. The four membered b-lactam ring in
compound 5 was introduced by the cycloaddition of (compounds
5ael) chloroacetyl chloride in the presence of triethylamine
catalyst to give 3-chloro-1-{5-[(2-methyl-1H-benzimidazol-1-
yl)methyl]-1,3,4-thiadiazol-2-yl}-4-(substituted) phenylazeti-
din-2-one 6ael. The purity of the compounds was monitored
* Corresponding author. Tel.: þ91 945 0333851; fax: þ91 512 2533812.
E-mail address: c_lal12@rediffmail.com (C. Lal).
0223-5234/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.01.022

K.F. Ansari, C. Lal / European Journal of Medicinal Chemistry 44 (2009) 2294e2299
2295
Scheme 1.
by TLC and the structures of all the derivatives (5ael and 6ael)
1
were supported by spectral data. The IR, H NMR and mass
3. Biological activities
spectra are in agreement with the proposed structures. Physical
and analytical data of the synthesized compounds are reported
in Table 1.
The compounds 5ael and 6ael were screened for their an-
tibacterial activity against Bacillus subtilis MTCC 121 (Gram-
positive) and Escherichia coli ATCC 25922 (Gram-negative)
Table 1
Physical and analytical data of the compounds 2, 3, 4, 5ael and 6ael
Compounds
Ar
Yield
(%)
M.P. (ꢀC)
Mol. formula
Analysis % found (calculated)
C
H
N
2
e
88
83
79
82
67
79
80
84
85
89
80
75
73
84
81
81
89
85
82
78
86
77
85
84
88
82
87
186e188
195e197
182e184
198e200
188e190
176e178
181e183
166e168
165e167
182e184
161e162
154e156
150e151
157e159
166e167
212e214
200e202
203e205
187e189
181e183
178e180
166e168
175e177
170e172
161e163
173e175
189e190
C12H14N2O2
66.04 (66.02)
50.17 (50.15)
53.86 (53.83)
64.81 (64.84)
52.41 (52.43)
58.75 (58.77)
58.76 (58.77)
62.77 (62.79)
62.76 (62.79)
65.65 (65.68)
65.67 (65.68)
61.85 (61.87)
61.84 (61.87)
61.85 (61.87)
62.02 (62.05)
58.58 (58.60)
54.04 (54.06)
58.04 (54.06)
57.30 (57.33)
57.31 (57.33)
59.47 (59.50)
59.48 (59.50)
59.48 (59.50)
56.38 (56.40)
56.37 (56.40)
56.38 (56.40)
56.30 (56.53)
6.47 (6.45)
4.98 (4.96)
4.52 (4.50)
4.52 (4.53)
3.40 (3.42)
3.81 (3.84)
3.83 (3.84)
4.69 (4.71)
4.68 (4.71)
4.93 (4.93)
4.91 (4.93)
4.30 (4.33)
4.32 (4.33)
4.30 (4.33)
4.62 (4.63)
3.91 (3.93)
3.38 (3.40)
3.39 (3.40)
4.10 (4.12)
4.10 (4.12)
4.27 (4.28)
4.25 (4.28)
4.25 (4.28)
3.75 (3.79)
3.76 (3.79)
3.77 (3.79)
4.00 (4.03)
12.84 (12.81)
26.60 (26.57)
28.55 (28.52)
21.00 (21.01)
16.97 (16.99)
9.62 (9.64)
3
e
C11H13N5OS
C11H11N5S
C18H15N5S
4
e
eC6H5
5a
5b
5c
5d
5e
5f
5g
5h
5i
4-BrC6H4
2-ClC6H4
4-ClC6H4
2-OCH3C6H4
4-OCH3C6H4
2-CH3C6H4
3-CH3C6H4
2-OHC6H4
3-OHC6H4
4-OHC6H4
4-NH2C6H4
eC6H5
C18H14N5SBr
C18H14N5SCl
C18H14N5SCl
C19H17N5OS
C19H17N5OS
C19H17N5S
9.62 (9.64)
19.26 (19.27)
19.24 (19.27)
20.12 (20.16)
20.13 (20.16)
20.00 (20.04)
20.01 (20.04)
20.00 (20.04)
24.11 (24.12)
17.05 (17.09)
15.72 (15.76)
17.75 (15.76)
15.89 (15.92)
15.90 (15.92)
16.50 (16.52)
16.48 (16.52)
16.50 (16.52)
16.41 (16.44)
16.43 (16.44)
16.42 (16.44)
19.77 (19.78)
C19H17N5S
C18H15N5OS
C18H15N5OS
C18H15N5OS
C18H16N6S
5j
5k
5l
6a
6b
6c
6d
6e
6f
6g
6h
6i
C20H16N5OSCl
C20H15N5OSCl2
C20H15N5OSCl2
C21H18N5O2SCl
C21H18N5O2SCl
C21H18N5OSCl
C21H18N5OSCl
C21H18N5OSCl
C20H16N5O2SCl
C20H16N5O2SCl
C20H16N5O2SCl
C20H17N6OSCl
2-ClC6H4
4-ClC6H4
2-OCH3C6H4
4-OCH3C6H4
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
2-OHC6H4
3-OHC6H4
4-OHC6H4
4-NH2C6H4
6j
6k
6l

2296
K.F. Ansari, C. Lal / European Journal of Medicinal Chemistry 44 (2009) 2294e2299
Table 3
Antibacterial activity of compounds 5ael and 6ael against Escherichia coli
bacterial strains. Ampicillin was used as a reference standard.
The results of the antibacterial activity screening of the tested
compounds are summarized in Tables 2 and 3. The compounds
not shown in tables have no antibacterial activity. Some of the
compounds tested were found to have good antibacterial activ-
ity against B. subtilis, however, they were found to have less or
poor activity against E. coli. The compounds having o-chloro,
o-methyl, p-methoxy, o-hydroxy and p-amino group in phenyl
ring showed good antibacterial activity.
The antifungal activity of the compounds 5ael and 6ael
was assayed by using the cup-plate agar diffusion method
[25] against Candida albicans MTCC 1637, Aspergillus flavus
AIIMS and Aspergillus niger AIIMS fungal strains using am-
photericin B as standard. Antifungal results indicated that
some of the derivatives possessed a broad spectrum of activity
against tested fungi, however, none of the derivatives showed
a better spectrum of activity than the reference drug (Table 4).
The compounds which have no antifungal activity are not in-
cluded in the table.
Compounds
Concentrations
1 mg/ml
10 mg/ml
100
mg/ml
200
mg/ml
500
mg/ml
App.
MIC
mg/ml
5a
5b
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þ
þ
P
e
P
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
200
500
100
200
100
200
200
200
500
100
200
100
500
200
500
500
200
10
þþ
þ
þ
e
þ
e
P
5c
e
e
e
e
e
e
P
5f
5g
þþ
þ
5i
5k
þþ
þ
P
5l
6a
þ
P
þþ
þ
þ
e
P
6b
6e
e
e
e
þ
e
P
þ
6f
6h
þ
e
þ
P
þ
6i
þ
6j
6k
þ
þ
þ
P
þþ
þ
P
6l
Ampicillin
e
e
e
e
4. Experimental protocol
Symbols: total inhibition (no growth of organism) ¼ (e); poor growth com-
pared to control ¼ (P); medium growth compared to control ¼ (þ); confluent
growth (no inhibition) ¼ (þþ).
4.1. Chemistry
Melting points were determined in open capillary tubes
and are uncorrected. FTIR spectra were recorded on Per-
kineElmer RX1 spectrophotometer and H NMR spectra in
4.2. Synthetic methods
1
CDCl3 on a Brucker 400 MHz spectrometer using TMS as
an internal reference (chemical shift in d ppm). Mass spectra
were taken on a Jeol SX-102 instrument. Elemental analyses
were carried out with Elementar-Vario EL III elemental ana-
lyzer. The purity of the compounds was checked on a silica
gel-G plates and visualization was done using iodine/UV
lamp.
4.2.1. Synthesis of ethyl (2-methyl-1H-benzimidazol-1-
yl)acetate 2
Ethylchloroacetate (0.028 mol, 3 ml) was added to a solu-
tion of 2-methyl-1H-benzimidazoles (0.028 mol, 3.7 g) in
dry acetone (40 ml). To this mixture, anhyd. K2CO3 (3 g)
Table 4
Antifungal activity of compounds 5ael and 6ael
Table 2
Antibacterial activity of compounds 5ael and 6ael against Bacillus subtilis
Compounds
Zone of inhibition (30 mg/ml)
Compounds
Concentrations
Candida
albicans
Aspergillus
niger
Aspergillus
flavus
1 mg/ml
10 mg/ml
100
mg/ml
200
mg/ml
500
mg/ml
App.
MIC
5a
5d
þþ
þ
þþþ
e
þþ
þþ
e
þþþ
þ
mg/ml
5a
5b
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þ
þ
e
þ
e
e
P
e
P
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
100
500
100
100
200
100
200
100
200
200
200
100
500
100
200
200
100
10
5e
þ
þþ
þþ
þ
þþ
þ
5f
5g
þ
5c
e
e
e
e
e
e
e
e
e
e
P
þ
5f
5g
þ
5j
5k
þþþ
þþ
þþ
þþ
e
þ
þ
þþ
þ
þþ
þ
þþ
þþþ
þ
5i
5k
e
P
5l
6a
P
þþ
e
5l
6a
P
e
þ
P
6d
6e
e
e
þþ
þþ
þ
þ
e
6b
6e
6f
6h
þ
e
þþ
þ
P
e
þþ
þ
6f
6h
þ
e
þ
e
P
6i
6k
þ
þþ
þþ
þ
þþ
P
þþ
þþ
þþþ
þþ
þ
6i
e
e
e
e
e
6l
Amphotericin B
6j
6k
þþ
þ
þ
þþþ
þþþ
þ
P
Symbols: zone diameter of growth inhibition: (e) ¼ Inactive (<10 mm);
(þ) ¼ weakly active (10e15 mm); (þþ) moderately active (16e21 mm);
(þþþ) ¼ highly active (22e28 mm); (þþþ) ¼ amphotericin B.
6l
Ampicillin
þ
P
e
e
þ
e

K.F. Ansari, C. Lal / European Journal of Medicinal Chemistry 44 (2009) 2294e2299
2297
was added and the reaction mixture refluxed for 10 h. Acetone
was removed in vacuo and the residue crystallized from
ethanol to give 2, yield 88%, mp 186e188 ꢀC, IR (KBr):
1613 (eC]N), 1720 (eC]O ester), 1460 (eNeCH2)
8.15 (s, 1H, eN]CH), 2.28 (s, 3H, eCH3), 7.29e7.70
(m, 8H, AreH); EI-MS: 413 (Mþ þ 1).
4.2.4.3.
N-[(2-Chlorophenyl)methylidene]-5-[(2-methyl-1H-
cmꢁ1 1H NMR (CDCl3): 3.67 (s, 2H, eNeCH2), 4.21 (q,
;
benzimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine (5c). The
following spectral data were recorded for compound 5c: IR
(KBr): 1598 (eC]N), 1475 (eNeCH2), 1580 (eN]CH),
2H, eCOOCH2CH3), 1.32 (t, 3H, eCOOCH2CH3), 2.92 (s,
3H, eCH3), 6.69e7.71 (m, 4H, AreH); EI-MS: 219 (Mþ þ 1).
1
701 (CeSeC) cmꢁ1; H NMR (CDCl3): 3.85 (s, 2H, eNe
CH2), 8.12 (s, 1H, eN]CH), 2.25 (s, 3H, eCH3), 7.28e
7.73 (m, 8H, AreH); EI-MS: 368 (Mþ þ 1).
4.2.2. Synthesis of 2-[(2-methyl-1H-benzimidazol-1-yl)
acetyl]hydrazinecarbothioamide 3
A mixture of compound 2 (0.03 mol, 6.5 g) and thiosemicar-
bazide (0.03 mol) in 1,4-dioxan (40 ml) was refluxed on a water
bath for about 7 h. The excess solvent was removed under re-
duced pressure and the product crystallized from acetone to
give compound 3, yield 83%, mp 195e197 ꢀC, IR (KBr):
1605 (eC]N), 1652 (eCONH), 3189 (eNH, eNH2), 1138
4.2.4.4.
N-[(4-Chlorophenyl)methylidene]-5-[(2-methyl-1H-
benzimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine (5d). The
following spectral data were recorded for compound 5d: IR
(KBr): 1618 (eC]N), 1469 (eNeCH2), 1585 (eN]CH),
705 (CeSeC) cmꢁ1; H NMR (CDCl3): 3.80 (s, 2H, eNe
CH2), 8.11 (s, 1H, eN]CH), 2.32 (s, 3H, eCH3), 7.15e
7.72 (m, 8H, AreH); EI-MS: 368 (Mþ þ 1).
1
1
(eC]S) cmꢁ1; H NMR (CDCl3): 3.15 (s, 2H, eNeCH2),
8.33 (m, 4H, eNHNHCSNH2), 2.85 (s, 3H, eCH3), 6.62e
7.80 (m, 4H, AreH); EI-MS: 264 (Mþ þ 1).
4.2.4.5. N-[(2-Methoxyphenyl)methylidene]-5-[(2-methyl-1H-
benzimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine (5e). The
following spectral data were recorded for compound 5e: IR
(KBr): 1620 (eC]N), 1460 (eNeCH2), 1582 (eN]CH),
4.2.3. Synthesis of 5-[(2-methyl-1H-benzimidazol-1-yl)
methyl]-1,3,4-thiadiazol-2-amine 4
712 (CeSeC) cmꢁ1; H NMR (CDCl3): 3.92 (s, 2H, eNe
1
The compound 3 (0.02 mol, 5.3 g) with conc. H2SO4
(15 ml) was kept overnight at room temperature, then poured
into ice cold water, neutralized with ammonia and extracted
with ether. The ethereal extract was distilled off and the prod-
uct obtained was crystallized from methanol to afford 4, yield
79%, mp 182e184 ꢀC, IR (KBr): 1610 (eC]N), 1469 (eNe
CH2), 3341 (eNH2), 714 (CeSeC) cmꢁ1; 1H NMR (CDCl3):
3.29 (s, 2H, eNeCH2), 4.14 (s, 2H, eCeNH2), 2.83 (s, 3H,
eCH3), 6.90e7.89 (m, 4H, AreH); EI-MS: 246 (Mþ þ 1).
CH2), 8.13 (s, 1H, eN]CH), 3.15 (s, 3H, eOCH3), 2.10 (s,
3H, eCH3), 7.82e7.96 (m, 8H, AreH); EI-MS: 364 (Mþ þ 1).
4.2.4.6. N-[(4-Methoxyphenyl)methylidene]-5-[(2-methyl-1H-
benzimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine (5f). The
following spectral data were recorded for compound 5f: IR
(KBr): 1609 (eC]N), 1466 (eNeCH2), 1570 (eN]CH),
720 (CeSeC) cmꢁ1; H NMR (CDCl3): 3.99 (s, 2H, eNe
1
CH2), 8.05 (s, 1H, eN]CH), 3.52 (s, 3H, eOCH3), 2.22 (s,
3H, eCH3), 7.80e7.95 (m, 8H, AreH); EI-MS: 364 (Mþ þ 1).
4.2.4. General procedure for the synthesis of compounds
5ael
4.2.4.7.
5-[(2-Methyl-1H-benzimidazol-1-yl)methyl]-N-[(2-
To a stirred solution of compound 4 (0.02 mol, 5 g) in metha-
nol (50 ml) containing a glacial acetic acid (2 ml) was added ap-
propriate aromatic aldehyde (0.02 mol) and the mixture refluxed
for 6e8 h on a water bath. The separated solvent was distilled off
at reduced pressure and the resulting solid was collected, dried
and crystallized from chloroformebenzene mixture to give the ti-
tle compounds.
methylphenyl)methylidene]-1,3,4-thiadiazol-2-amine (5g). The
following spectral data were recorded for compound 5g: IR
(KBr): 1621 (eC]N), 1458 (eNeCH2), 1581 (eN]CH),
1
695 (CeSeC) cmꢁ1; H NMR (CDCl3): 3.70 (s, 2H, eNe
CH2), 8.51 (s, 1H, eN]CH), 2.10 (s, 3H, eCH3), 6.60e
6.82 (m, 8H, AreH); EI-MS: 348 (Mþ þ 1).
4.2.4.8.
5-[(2-Methyl-1H-benzimidazol-1-yl)methyl]-N-[(3-
4.2.4.1. 5-[(2-Methyl-1H-benzimidazol-1-yl)methyl]-N-(phenyl
methylidene)-1,3,4-thiadiazol-2-amine (5a). The following
spectral data were recorded for compound 5a: IR (KBr):
1615 (eC]N), 1475 (eNeCH2), 1580 (eN]CH), 703
methylphenyl)methylidene]-1,3,4-thiadiazol-2-amine (5h). The
following spectral data were recorded for compound 5h: IR
(KBr): 1616 (eC]N), 1470 (eNeCH2), 1578 (eN]CH),
702 (CeSeC) cmꢁ1; H NMR (CDCl3): 3.72 (s, 2H, eNe
1
1
(CeSeC) cmꢁ1; H NMR (CDCl3): 3.82 (s, 2H, eNeCH2),
CH2), 8.58 (s, 1H, eN]CH), 2.55 (s, 3H, eCH3), 6.62e
6.80 (m, 8H, AreH); EI-MS: 348 (Mþ þ 1).
8.20 (s, 1H, eN]CH), 2.25 (s, 3H, eCH3), 7.12e7.79 (m,
9H, AreH); EI-MS: 334 (Mþ þ 1).
4.2.4.2.
N-[(4-Bromophenyl)methylidene]-5-[(2-methyl-1H-
4.2.4.9.
2-[({5-[(2-Methyl-1H-benzimidazol-1-yl)methyl]-
benzimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine (5b). The
following spectral data were recorded for compound 5b: IR
(KBr): 1608 (eC]N), 1462 (eNeCH2), 1583 (eN]CH), 682
1,3,4-thiadiazol-2-yl}imino)methyl]phenol (5i). The following
spectral data were recorded for compound 5i: IR (KBr):
1618 (eC]N), 1468 (eNeCH2), 1574 (eN]CH), 680
(CeSeC) cmꢁ1; H NMR (CDCl3): 3.70 (s, 2H, eNeCH2),
1
1
(CeSeC) cmꢁ1; H NMR (CDCl3): 3.80 (s, 2H, eNeCH2),

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K.F. Ansari, C. Lal / European Journal of Medicinal Chemistry 44 (2009) 2294e2299
8.72 (s, 1H, eN]CH), 5.60 (s, 1H, AreOH), 2.65 (s, 3H, e
CH3), 7.25e7.80 (m, 8H, AreH); EI-MS: 350 (Mþ þ 1).
6c: IR (KBr): 1602 (eC]N), 1683 (eC]O), 714 (CeSeC),
1
775 (eCeCl) 1721 (>C]O monocyclic b-lactam) cmꢁ1; H
NMR (CDCl3): 3.81 (s, 2H, eNeCH2), 4.11 (s, 1H, eNeCH),
5.25 (s, 1H, eCHeCl), 2.55 (s, 3H, eCH3), 7.30e7.84 (m,
8H, AreH); EI-MS: 445 (Mþ þ 1).
4.2.4.10.
3-[({5-[(2-Methyl-1H-benzimidazol-1-yl)methyl]-
1,3,4-thiadiazol-2-yl}imino)methyl]phenol (5j). The following
spectral data were recorded for compound 5j: IR (KBr):
1604 (eC]N), 1470 (eNeCH2), 1580 (eN]CH), 708
4.2.5.4.
3-Chloro-4-(2-methoxyphenyl)-1-{5-[(2-methyl-1H-
1
(CeSeC) cmꢁ1; H NMR (CDCl3): 3.75 (s, 2H, eNeCH2),
benzimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-yl}azetidin-2-one
(6d). The following spectral data were recorded for compound
6d: IR (KBr): 1611 (eC]N), 1689 (eC]O), 670 (CeSeC),
8.71 (s, 1H, eN]CH), 5.55 (s, 1H, AreOH), 2.60 (s, 3H,
eCH3), 7.28e7.93 (m, 8H, AreH); EI-MS: 350 (Mþ þ 1).
1
778 (eCeCl) 1728 (>C]O monocyclic b-lactam) cmꢁ1; H
4.2.4.11.
4-[({5-[(2-Methyl-1H-benzimidazol-1-yl)methyl]-
NMR (CDCl3): 3.75 (s, 2H, eNeCH2), 4.15 (s, 1H, eNeCH),
5.37 (s, 1H, eCHeCl), 4.08 (s, 3H, eOCH3), 3.72 (s, 3H,
eCH3), 7.37e7.92 (m, 8H, AreH); EI-MS: 440 (Mþ þ 1).
1,3,4-thiadiazol-2-yl}imino)methyl]phenol (5k). The follow-
ing spectral data were recorded for compound 5k: IR (KBr):
1625 (eC]N), 1480 (eNeCH2), 1585 (eN]CH), 710
(CeSeC) cmꢁ1; H NMR (CDCl3): 3.84 (s, 2H, eNeCH2),
1
4.2.5.5.
3-Chloro-4-(4-methoxyphenyl)-1-{5-[(2-methyl-1H-
8.67 (s, 1H, eN]CH), 5.46 (s, 1H, AreOH), 2.67 (s, 3H,
eCH3), 7.25e7.90 (m, 8H, AreH); EI-MS: 350 (Mþ þ 1).
benzimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-yl}azetidin-2-one
(6e). The following spectral data were recorded for compound
6e: IR (KBr): 1619 (eC]N), 1690 (eC]O), 705 (CeSeC),
1
4.2.4.12. N-[(4-Aminophenyl)methylidene]-5-[(2-methyl-1H-
benzimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine (5l). The
following spectral data were recorded for compound 5l: IR
(KBr): 1618 (eC]N), 1473 (eNeCH2), 1580 (eN]CH),
765 (eCeCl) 1722 (>C]O monocyclic b-lactam) cmꢁ1; H
NMR (CDCl3): 3.66 (s, 2H, eNeCH2), 4.10 (s, 1H, eNeCH),
5.33 (s, 1H, eCHeCl), 4.12 (s, 3H, eOCH3), 3.83 (s, 3H,
eCH3), 7.62e7.98 (m, 8H, AreH); EI-MS: 440 (Mþ þ 1).
1
712 (CeSeC) cmꢁ1; H NMR (CDCl3): 3.82 (s, 2H, eNe
CH2), 8.65 (s, 1H, eN]CH), 4.08 (s, 2H, eCeNH2), 2.62 (s,
3H, eCH3), 7.72e7.95 (m, 8H, AreH); EI-MS: 349 (Mþ þ 1).
4.2.5.6.
3-Chloro-1-{5-[(2-methyl-1H-benzimidazol-1-yl)-
methyl]-1,3,4-thiadiazol-2-yl}-4-(2-methylphenyl)azetidin-2-one
(6f). The following spectral data were recorded for compound
6f: IR (KBr): 1615 (eC]N), 1685 (eC]O), 669 (CeSeC),
760 (eCeCl) 1727 (>C]O monocyclic b-lactam) cmꢁ1; H
4.2.5. General procedure for the synthesis of compounds
6ael
1
To a stirred solution of the particular 5-[(2-methyl-1H-ben-
zimidazol-1-yl)methyl]-N-[(substituted) phenylmethylidene]-
1,3,4-thiadiazol-2-amine 5ael (0.02 mol) and triethylamine
(0.01 mol) in dioxan (50 ml), chloroacetyl chloride (0.01 mol)
was added dropwise at 0e5 ꢀC. The reaction mixture stirred
for 3 h and the separated solid was crystallized from methanol
to give the title compounds.
NMR (CDCl3): 3.82 (s, 2H, eNeCH2), 4.20 (s, 1H, eNeCH),
5.29 (s, 1H, eCHeCl), 3.45 (s, 3H, eCH3), 7.20e7.90 (m,
8H, AreH); EI-MS: 424 (Mþ þ 1).
4.2.5.7.
3-Chloro-1-{5-[(2-methyl-1H-benzimidazol-1-yl)-
methyl]-1,3,4-thiadiazol-2-yl}-4-(3-methylphenyl)azetidin-2-one
(6g). The following spectral data were recorded for compound
6g: IR (KBr): 1620 (eC]N), 1688 (eC]O), 690 (CeSeC),
1
4.2.5.1. Synthesis of 3-chloro-1-{5-[(2-methyl-1H-benzimida-
zol-1-yl)methyl]-1,3,4-thiadiazol-2-yl}-4-phenylazetidin-2-one
(6a). The following spectral data were recorded for compound
6a: IR (KBr): 1600 (eC]N), 1748 (eC]O), 702 (CeSeC),
762 (eCeCl) 1718 (>C]O monocyclic b-lactam) cmꢁ1; H
NMR (CDCl3): 3.75 (s, 2H, eNeCH2), 4.26 (s, 1H, eNeCH),
5.17 (s, 1H, eCHeCl), 3.32 (s, 3H, eCH3), 7.33e7.98 (m,
8H, AreH); EI-MS: 424 (Mþ þ 1).
1
766 (eCeCl) cmꢁ1; H NMR (CDCl3): 3.90 (s, 2H, eNe
CH2), 4.11 (s, 1H, eNeCH), 5.15 (s, 1H, eCHCl), 2.23 (s,
3H, eCH3), 7.00e7.82 (m, 9H, AreH); EI-MS: 410 (Mþ þ 1).
4.2.5.8.
3-Chloro-1-{5-[(2-methyl-1H-benzimidazol-1-yl)-
methyl]-1,3,4-thiadiazol-2-yl}-4-(4-methylphenyl)azetidin-2-one
(6h). The following spectral data were recorded for com-
pound 6h: IR (KBr): 1600 (eC]N), 1748 (eC]O), 713
(CeSeC), 767 (eCeCl) 1728 (>C]O monocyclic b-lactam)
cmꢁ1; 1H NMR (CDCl3): 3.70 (s, 2H, eNeCH2), 4.18 (s, 1H,
eNeCH), 5.25 (s, 1H, eCHeCl), 3.30 (s, 3H, eCH3), 7.40e
7.92 (m, 8H, AreH); EI-MS: 424 (Mþ þ 1).
4.2.5.2. 3-Chloro-4-(2-chlorophenyl)-1-{5-[(2-methyl-1H-ben-
zimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-yl}azetidin-2-one
(6b). The following spectral data were recorded for compound
6b: IR (KBr): 1616 (eC]N), 1673 (eC]O), 718 (CeSeC),
1
780 (eCeCl) 1718 (>C]O monocyclic b-lactam) cmꢁ1; H
NMR (CDCl3): 3.99 (s, 2H, eNeCH2), 4.13 (s, 1H, eNeCH),
5.30 (s, 1H, eCHeCl), 2.55 (s, 3H, eCH3), 7.32e7.78 (m,
8H, AreH); EI-MS: 445 (Mþ þ 1).
4.2.5.9.
3-Chloro-4-(2-hydroxyphenyl)-1-{5-[(2-methyl-1H-
benzimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-yl}azetidin-2-one
(6i). The following spectral data were recorded for com-
pound 6i: IR (KBr): 1605 (eC]N), 1750 (eC]O), 705
(CeSeC), 762 (eCeCl) 1720 (>C]O monocyclic b-
4.2.5.3.
3-Chloro-4-(4-chlorophenyl)-1-{5-[(2-methyl-1H-
benzimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-yl}azetidin-2-one
(6c). The following spectral data were recorded for compound
lactam) cmꢁ1; H NMR (CDCl3): 3.78 (s, 2H, e NeCH2),
1

K.F. Ansari, C. Lal / European Journal of Medicinal Chemistry 44 (2009) 2294e2299
2299
4.10 (s, 1H, eNeCH), 5.10 (s, 1H, eCHeCl), 5.79 (s, 1H, eCe
OH), 2.45 (s, 3H, eCH3), 7.69e8.08 (m, 8H, AreH); EI-MS:
426 (Mþ þ 1).
Acknowledgement
Authors are thankful to Head, RSIC, Central Drug Re-
search Institute, Lucknow for providing spectral and analytical
data of the compounds.
4.2.5.10. 3-Chloro-4-(3-hydroxyphenyl)-1-{5-[(2-methyl-1H-
benzimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-yl}azetidin-2-one
(6j). The following spectral data were recorded for compound
6j: IR (KBr): 1601 (eC]N), 1738 (eC]O), 675 (CeSeC),
References
1
780 (eCeCl) 1722 (>C]O monocyclic b-lactam) cmꢁ1; H
NMR (CDCl3): 3.75 (s, 2H, eNeCH2), 4.17 (s, 1H, eNeCH),
5.22 (s, 1H, eCHeCl), 5.78 (s, 1H, eCeOH), 2.44 (s, 3H,
eCH3), 7.60e7.92 (m, 8H, AreH); EI-MS: 426 (Mþ þ 1).
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766 (eCeCl) 1720 (>C]O monocyclic b-lactam) cmꢁ1; H
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6l: IR (KBr): 1609 (eC]N), 1744 (eC]O), 702 (CeSeC),
1
763 (eCeCl) 1725 (>C]O monocyclic b-lactam) cmꢁ1; H
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4.3. Microbiology
4.3.1. Antibacterial activity test
For the antibacterial activity of compounds 5ael and 6ael,
the test organisms were grown overnight at 37 ꢀC in buffered
glucose broth. A loopful (5mm diameter) of the test organisms
was added to the buffered glucose broth containing test com-
pounds and incubated at 37 ꢀC for 24 h. The control experi-
ments were run in a similar manner and contained equal
amounts of buffered and test compound. The last dilution
inhibition growth was taken as minimum inhibitory concentra-
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The synthesized compounds 5ael and 6ael were tested for
their antifungal activity in vitro, in comparison with amphoter-
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agar media by measuring the inhibition zone in millimeters.
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