Some novel oxadiazolyl/azetidinyl benzimidazole derivatives: Synthesis and in vitro biological evaluation

Article abstract of DOI:10.1080/00397911.2011.580881

In a wide search program for new and efficient antimicrobial agents, a series of oxadiazole/azetidinone-incorporated benzimidazoles have been synthesized and evaluated against different Gram-positive and Gram-negative bacteria. Derivatives having long alkyl chain on the oxadiazole/azetidinone moiety with three or more carbon atoms have shown less antibacterial activity.

Full text of DOI:10.1080/00397911.2011.580881

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Some Novel Oxadiazolyl/Azetidinyl
Benzimidazole Derivatives: Synthesis
and in Vitro Biological Evaluation
K. F. Ansari a , C. Lal a & D. L. Parmar b
a Department of Chemistry, Harcourt Butler Technological Institute,
Kanpur, India
b Department of Civil Engineering, Harcourt Butler Technological
Institute, Kanpur, India
Accepted author version posted online: 29 May 2012.Published
online: 20 Aug 2012.
To cite this article: K. F. Ansari , C. Lal & D. L. Parmar (2012): Some Novel Oxadiazolyl/Azetidinyl
Benzimidazole Derivatives: Synthesis and in Vitro Biological Evaluation, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:24, 3553-3568
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Synthetic Communications1, 42: 3553–3568, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.580881
SOME NOVEL OXADIAZOLYL/AZETIDINYL
BENZIMIDAZOLE DERIVATIVES: SYNTHESIS
AND IN VITRO BIOLOGICAL EVALUATION
K. F. Ansari,1 C. Lal,1 and D. L. Parmar2
1Department of Chemistry, Harcourt Butler Technological Institute,
Kanpur, India
2Department of Civil Engineering, Harcourt Butler Technological Institute,
Kanpur, India
GRAPHICAL ABSTRACT
Abstract In a wide search program for new and efficient antimicrobial agents, a series of
oxadiazole/azetidinone-incorporated benzimidazoles have been synthesized and evaluated
against different Gram-positive and Gram-negative bacteria. Derivatives having long alkyl
chain on the oxadiazole/azetidinone moiety with three or more carbon atoms have shown
less antibacterial activity.
Keywords Antibacterial activity; azetidin-2-one; Bacillus subtilis; benzimidazole;
Escherichia coli; oxadiazole; Staphylococcus aureus
INTRODUCTION
The emergence and spread of antimicrobial resistance has become one of the
most serious public health concerns across the world. Antimicrobial resistance refers
Received February 21, 2011.
Address correspondence to C. Lal, Department of Chemistry, Harcourt Butler Technological
Institute, Nawabganj, Kanpur 208002, India. E-mail: c_lal12@rediffmail.com
3553

3554
K. F. ANSARI, C. LAL, AND D. L. PARMAR
to microorganisms that have developed the ability to inactivate, exclude, or block the
inhibitory or lethal mechanism of the antimicrobial agents.[1] The incidence of anti-
microbial resistance has been increasing over the past few decades. Data from the
World Health Organization indicated that 50–90% of microbially caused conditions
in India and Sri Lanka are resistant to commonly used antimicrobial drugs.[2] In the
United States, about 70% of hospital-acquired infections were found to be resist-
ant.[3] Although the judicious use of antibacterial agents is an important in approach
to control the emergence of bacterial resistance, the discovery and development of
newer agents are desirable for the successful treatment of infections caused by resist-
ant pathogenic bacteria. The study of benzimidazole derivatives has become of much
interest in recent years on account of their antibacterial, antifungal, antiviral, anti-
oxidant, and anti-inflammatory activities.[4–12] 2-Azetidinones containing benzimida-
zole derivatives dramatically increase the diversity of certain biological properties
such as antibacterial, antifungal, anti-inflammatory, and anthelmintic[13–16] and
recently benzimidazole derivatives containing the 2-azetidinone moiety have been
reported as antimicrobial agents.[17] In this article the oxadiazolyl and azetidinyl
derivatives of benzimidazole have been synthesized by multistep reactions starting
with o-phenylenediamine. The activities of these compounds were screened in vitro
against the panel of standard Gram-positive and Gram-negative bacteria.
RESULTS AND DISCUSSION
Chemistry
In view of obtaining some potential antibacterial compounds, we have described
the syntheses of some benzimidazole derivatives. The relevant step in the synthetic
sequence was the initial condensation of o-phenylenediamine 1 with chloroacetic
acid[18] to provide 2-(chloromethyl)-1H-benzimidazole 2 in sufficient yields. The sub-
sequent condensation of 2 with alkylamine yielded 1-(1H-benzimidazol-2-yl)-N-
methylmethanamine 3 in good yield. This was followed by the chloroacetylation
to give ethyl f2-[(methylamino)methyl]-1H-benzimidazol-1-ylgacetate 4. The key inter-
mediate 2-f2-[(methylamino)methyl]-1H-benzimidazol-1-ylgacetohydrazide 5 was
obtained by the hydrazinolysis of compound 4. The intermediate 5 was subsequently
reacting with appropriate long-chain carboxylic acid in phophoryl chloride to give
the respective compounds 6a–l in excellent yields. The target azetidinones 8a–l were
obtained by the condensation of 5a–l with various selected aliphatic or aromatic alde-
hydes furnished Schiff’s bases N’-[(1E)-alkylidene=arylidene]-2-f2-[(methylamino)
methyl]-1H-benzimidazol-1-ylgacetohydrazide 7a–l followed by the cycloaddition of
7a–l with chloroacetyl chloride in the presence of triethylamine catalyst.
The structures of the compounds synthesized were confirmed by the examin-
1
ation of their H NMR, 13C NMR, mass spectral (MS), and infrared (IR) spectra.
1
The H NMR spectra of the investigated compounds revealed that the character-
istic chemical shifts agreed with their proposed structures. The signals due to aze-
tidinone ring protons appeared at about d 3.70–3.79 ppm as multiplet, d 5.05–5.10
as doublets (8a–g) and d 5.00–5.46 as doublets (8h–l). Appearance of broad singlets
within the range d 2.0–2.6 ppm corresponds to the one proton of –NH– and con-
firms the formation of methanamine. The methylene group at position 2 of

OXADIAZOLYL/AZETIDINYL BENZIMIDAZOLE DERIVATIVES
3555
2-(chloromethyl)-1H-benzimidazole ring appeared at about d 4.26–4.32 as a singlet.
1
With the help of H NMR spectral data the stereochemistry of the b-lactam ring
was observed as cis-form. The coupling constants of H-3 and H-4 are 3.1–6.7 Hz
for b-lactam (8a–l) indicating their cis-stereochemistry.[19,20] All the aromatic pro-
tons were well separated and observed at the expected regions. The structures of
synthesized compounds were further verified by EI-MS spectra (70 eV). The m=z
values of molecular ion peaks were in complete agreement with calculated molecu-
lar weights for individual compounds. For all compounds investigated the IR spec-
=
tra were recorded. The C N groups of oxadiazole rings were observed within the
ꢀ1
range n 1733–1716 cmꢀ1, C O groups showed the vibration at n 1662–1678ꢀcm1
=
=
whereas the aromatic moieties (C C) appeared between n 1599 and 1460 cm
.
Antibacterial Evaluation
The in vitro antibacterial activity was performed using the tube dilution
method with different strains of bacteria. Ampicillin and nalidixic acid were used
as positive control against bacteria.
Some of compounds 7a–k and 8a–k were tested in vitro against Staphylococcus
aureus (ATCC 29213), Bacillus subtilis (MTCC 121), and Escherichia coli (ATCC
25922). Compounds 6a and 6b showed considerable bactericidal activities against
Gram-positive bacteria. Compound 6b showed significant activity against S. aureus
but was less active against B. subtilis. Other compounds showed intermediate activi-
ties against S. aureus and B. subtilis but most of them were inactive against E. coli.
CONCLUSIONS
In conclusion, several benzimidazole derivatives were synthesized starting with
o-phenylenediamine. The antibacterial study was undertaken to evaluate the effect of
the synthesized compounds on different bacterial strains. As regards the structure–
activity relationship of the derivatives, it can be inferred that oxadiazoles are more
active than azetidinones. It is also noted that the alkyl side chain on 5-position of
oxadiazole ring produced better resistance to bacterial strains than the substituted
aryl group on the same position.
More extensive study is needed to confirm these preliminary results and studies
involving the mechanism of action are necessary for a complete understanding of
their antimicrobial activity and structural modifications on the final investigated
compounds to improve their biological activity.
EXPERIMENTAL
All the chemicals and solvents were purchased from Merck (Germany) and
were used without further purification. Melting points (mp) were determined in open
capillaries and are uncorrected. The purity of the compounds was confirmed by
thin-layer chromatography (TLC) performed on Merck silica-gel 60 F254 aluminium
sheets, using developing system chloroform=acetone (9:1). Spots were detected by
their absorption under ultraviolet (UV) light and by visualization with 10% HCl.
Elemental analysis for C, H, and N were carried out by a micro method using the

3556
K. F. ANSARI, C. LAL, AND D. L. PARMAR
Table 1. Physical and analytical data of the compounds 2–8
Analysis (%) calculated (found)
Yield
(%)
Mol.
formula
Compound
R=R1
Mp (ꢁC)
160–162
C
H
N
2
—
82
85
88
79
84
81
76
87
78
80
77
84
88
72
71
75
84
74
85
73
71
84
81
86
70
C8H7N2Cl
(166.60)
57.67
(57.65
67.06
(67.05
63.14
(63.13
56.64
(56.62
60.69
(60.67
61.89
(61.87
63.14
(63.12
64.19
(64.17
65.15
(65.14
66.03
(66.01
66.83
(66.81
67.70
(67.68
68.45
(68.43
69.14
(69.12
69.78
(69.76
70.38
(70.37
60.21
(60.20
61.52
(61.50
62.70
(62.69
63.76
(63.73
64.73
(64.72
65.62
(65.60
66.44
(66.41
67.27
(67.25
68.04
(68.02
4.23
4.21
6.88
6.86
6.93
6.90
6.48
6.46
5.88
5.87
6.32
6.30
6.71
6.70
7.07
7.05
7.40
7.38
7.70
7.68
7.97
7.96
5.37
5.35
5.74
5.72
6.09
6.07
6.41
6.39
6.71
6.70
6.61
6.59
7.01
7.00
7.37
7.35
7.69
7.68
7.99
7.97
8.26
8.23
8.51
8.50
5.96
5.94
6.31
6.29
16.81
16.80)
26.072
6.05)
3
—
—
192–194
184–186
195–197
201–203
208–210
215–217
220–222
241–243
254–256
280–282
198–100
183–185
178–180
184–186
188–190
232–234
249–251
260–262
273–275
279–281
297–299
302–304
203–205
201–203
C9H11N3
(161.20)
4
C13H17N3O2
(247.29)
16.99
16.97)
30.02
30.00)
27.22
27.20)
25.81
25.78)
24.54
24.52)
23.39
23.37)
22.35
22.33)
21.39
21.37)
20.51
20.48)
21.93
21.91)
21.01
21.00)
20.16
20.14)
19.381
9.36)
5
—
C11H15N5O
(233.26)
6a
6b
6c
6d
6e
6f
6g
6h
6i
CH3-
C13H15N5O
(257.29)
CH3CH2-
CH3(CH2)2-
CH3(CH2)3-
CH3(CH2)4-
CH3(CH2)5-
CH3(CH2)6-
C6H5-
C14H17H5O
(271.31)
C15H19N5O
(285.34)
C16H21N5O
(299.37)
C17H23N5O
(313.39)
C18H25N5O
(327.42)
C19H27N5O
(341.45)
C18H17N5O
(319.36)
C6H5CH3-
C6H5CH3CH2-
C6H5CH3(CH2)2-
C6H5CH3(CH2)3-
CH3-
C19H19N5O
(333.38)
6j
C20H21N5O
(347.41)
6k
6l
C21H23N5O
(361.44)
C22H25N5O
(375.46)
18.65
18.63)
27.01
26.98)
25.62
25.60)
24.37
24.35)
23.24
23.21)
22.20
(22.18)
21.26
(21.23)
20.39
(20.36)
21.79
(21.77)
20.88
20.86)
7a
7b
7c
7d
7e
7f
7g
7h
7i
C13H17N5O
(259.30)
CH3CH2-
CH3(CH2)2-
CH3(CH2)3-
CH3(CH2)4-
CH3(CH2)5-
CH3(CH2)6-
C6H5-
C14H19N5O
(273.33)
C15H21N5O
(287.36)
C16H23N5O
(301.38)
C17H25N5O
(315.41)
C18H27N5O
(329.43)
C19H29N5O
(343.46)
C18H19N5O
(321.37)
C6H5CH3-
C19H21N5O
(335.40)
(Continued )

OXADIAZOLYL/AZETIDINYL BENZIMIDAZOLE DERIVATIVES
3557
Table 1. Continued
Analysis (%) calculated (found)
Yield
(%)
Mol.
formula
Compound
R=R1
Mp (ꢁC)
215–217
230–232
246–248
C
H
N
7j
C6H5CH3CH2-
C6H5CH3(CH2)2-
C6H5CH3(CH2)3-
CH3-
79
80
85
84
69
77
81
80
83
80
79
82
84
68
75
C20H23N5O
(349.42)
68.74
(68.72
69.40
(69.38
70.00
(69.97
53.65
(53.62
54.94
(54.92
56.12
(56.10
57.21
(57.19
58.23
(58.21
59.18
(59.16
60.06
(60.04
60.38
(60.36
61.24
(61.21
62.04
(62.02
62.79
(62.77
63.50
(63.48
6.63
6.60
6.93
6.91
7.21
7.19
5.40
5.38
5.76
5.74
6.09
6.07
6.40
6.37
6.69
6.68
6.95
6.92
7.20
7.18
5.07
5.05
5.38
5.36
5.68
5.66
5.96
5.95
6.22
6.20
20.04
20.01)
19.27
19.25)
18.55
18.52)
20.86
20.84)
20.02
20.00)
19.25
19.22)
18.53
18.51)
17.87
17.85)
17.25
17.23)
16.68
16.66)
17.60
17.59)
17.00
16.98)
16.44
16.43)
15.92
15.90)
15.43
15.41)
7k
7 l
8a
8b
8c
8d
8e
8f
C21H25N5O
(363.45)
C22H27N5O
(377.48)
187–189 C15H18N5O2Cl
(335.78)
CH3CH2-
196–198 C16H20N5O2Cl
(349.81)
CH3(CH2)2-
CH3(CH2)3-
CH3(CH2)4-
CH3(CH2)5-
CH3(CH2)6-
C6H5-
208–210 C17H22N5O2Cl
(363.84)
220–222 C18H24N5O2Cl
(377.86)
234–236 C19H26N5O2Cl
(391.89)
240–242 C20H28N5O2Cl
(405.92)
8 g
8 h
8i
261–263 C21H30N5O2Cl
(419.94)
165–167 C20H20N5O2Cl
(397.85)
C6H5CH3-
174–176 C21H22N5O2Cl
(411.88)
8j
C6H5CH3CH2-
C6H5CH3(CH2)2-
C6H5CH3(CH2)3-
187–189 C22H24N5O2Cl
(425.91)
8k
8 l
196–198 C23H26N5O2Cl
(439.93)
200–202 C24H28N5O2Cl
(453.96)
Elementar Vario EL III elemental analyzer. The results of elemental analyses were
within ꢂ0.4% of the theoretical values (Table 1).
IR spectra were recorded in KBr on a Perkin-Elmer RX1 spectrophotometer.
1H NMR and 13C NMR spectra were obtained in a Brucker DRX 300-MHz spec-
trometer, in CDCl3. Chemical shifts are reported in d values (ppm) relative to tetra-
methylsilane (TMS) d ¼ 0 (1H), as internal standard. Signal multiplicities are
represented by the following abbreviations: s (singlet), d (doublet), dd (double doub-
let), and m (multiplet). For chosen compounds 6, 7, and 8 the MS were recorded on a
Jeol SX-102 mass spectrometer operating at 70 eV.
Synthesis of 2-(Chloromethyl)-1h-benzimidazole (2)
We heated together the mixture of 5.43 g (0.03 mol) of o-phenylenediamine
dihydrochloride, 20 ml of water, and 6.20 ml (0.09 mol) of chloroacetic acid under
reflux for 1.5 h, made the cooled reaction mixture distinctly basic by gradual addition

3558
K. F. ANSARI, C. LAL, AND D. L. PARMAR
of concentrated ammonia solution, collected the precipitate product, and recrystal-
lized it from 10% aqueous ethanol. Yield 82%, mp 160–162 ꢁC; IR (KBr): 1145
1
(-C-N), 1455 (-N-CH2), 1624 (-C N), 1730 (-C O ester), 2850 (-C-CH3) cmꢀ1; H
NMR (CDCl3): d 4.26 (s, 2H, -CH2), 7.22–7.59 (m, 4H, J ¼ 10.2, 3.4 Hz, Ar-H),
12.18 (s, 1H, NH); MS (m=z): 167 [Mþ þ 1].
=
=
Synthesis of 1-(1H-Benzimidazol-2-yl)-N-methylmethanamine (3)
Alkyl=aryl amine (0.202 mol) was added dropwise with stirring to a solution of
2-(chloromethyl)-1H-benzimidazole 2 (0.02 mol) in ethanol and the reaction mixture
was refluxed for 4 h. Ethanol was removed, and the solid obtained was washed with
chloroform and recrystallized with a chloroform–ethanol mixture. Yield 85%, mp
ꢁ
=
=
192–94 C; IR (KBr): 1624 (-C N), 1145 (-C-N), 1730 (-C O ester), 1455 (-N-
1
CH2), 2850 (-C-CH3) cmꢀ1; H NMR (CDCl3): d 4.26 (s, 2H, -CH2), 7.22–7.59
(m, 4H, J ¼ 10.2, 3.4 Hz, Ar-H), 12.18 (s, 1H, NH); MS (m=z): 162 [Mþ þ 1].
Synthesis of Ethylf2-[(methylamino)methyl]-1H-benzimidazol-
1-ylgacetate (4)
Ethyl chloroacetate (0.028 mol, 3 ml) was added to
a solution of
1-(1H-benzimidazol-2-yl)-N-methylmethanamine 3 (0.028 mol, 4.51 g) in dry acetone
(40 ml). Anhydrous K2CO3(3 g) was added to this solution, and the reaction mixture
was refluxed for 10 h. Acetone was removed, and the residue was crystallized from
ethanol. Yield 88%, mp 184–186 ꢁC; IR (KBr): 1150 (-C-N), 1460 (-N-CH2), 1690
1
(-C N), 1735 (-C O ester), 2882 (-C-CH3) cmꢀ1; H NMR (CDCl3): d 1.29 (t,
3H, J ¼ 7.5 Hz, -CH3), 2.0 (s, 1H, -NH), 3.26 (s, 3H, -CH3), 3.81 (s, 2H, -CH2),
4.13 (q, 2H, J ¼ 8.2, 5.6, 1.1 Hz, -CH2), 4.69 (s, 2H, -CH2), 7.22–7.59 (m, 4H,
J ¼ 7.7, 4.2 Hz, Ar-H); MS: [Mþ þ 1] at m=z: 248.
=
=
Synthesis of 2-f2-[(Methylamino)methyl]-1H-
benzimidazol-1-ylgacetohydrazide (5)
To a solution of compound ethyl f2-[(methylamino)methyl]-1H-benzimidazol-
1-ylgacetate (4) (0.01 mol) dissolved in dry methanol (50 ml), 99% hydrazine hydrate
(1 ml) was added, and the mixture was refluxed for 4–5 h. The reaction mixture was
cooled, and the solid obtained was filtered and washed with small quantity of cold
methanol. Yield 79%, mp 195–197 ꢁC; IR: 1152 (-C-N), 1464 (-N-CH2), 1695
1
(-C N), 1737 (-C O ester), 2886 (-C-CH3) cmꢀ1; H NMR (CDCl3): d 2.0 (s, 1H,
-NH), 3.26 (s, 3H, -CH3), 3.81 (s, 2H, -CH2), 4.62 (s, 2H, -CH2), 7.22–7.59 (m,
4H, J ¼ 8.9, 4.1 Hz, ArH), 8.0 (s, 2H, NH2); MS: [Mþ þ 1] at m=z: 234.
=
=
Synthesis of N-Methyl-1-f1-[(5-alkyl/aryl-1,3,4-oxadiazol-2-
yl)methyl]-1H-benzimidazol-2-ylgmethanamine (6a–l)
An equimolar mixture of compound 2-f2-[(methylamino)methyl]-1H-
benzimidazol-1-ylgacetohydrazide (5) (0.001 mol) and substituted carboxylic acid
in phosphoryl chloride was refluxed for 12–15 h. The reaction mixture was cooled,

3559

3560

3561

3562

3563

3564

OXADIAZOLYL/AZETIDINYL BENZIMIDAZOLE DERIVATIVES
3565
poured into ice-cold water, and neutralized with 20% NaHCO3 solution. The result-
ant solid was filtered, washed with water, and recrystallized from ethanol.
Spectroscopic data of the derivatives 6a–l are given in Table 2.
Synthesis of N’-[(1E)-Alkylidene/
arylidene]-2-f2-[(methylamino)methyl]-1H-
benzimidazol-1-ylgacetohydrazide (7a–l)
Aldehyde (30 mmol) was added to
a stirred solution of compound
2-f2-[(methylamino)methyl]-1H-benzimidazol-1-ylgacetohydrazide (5) (30 mmol)
containing four or five drops of glacial acetic acid in methanol (30 ml) and the mix-
ture was refluxed for 5–7 h on a steam bath. Methanol was removed under vacuum,
and the resultant semisolid was treated with distilled water (3 ꢃ 10 ml). The separated
solid was filtered, dried, and recrystallized from ethanol to give the title compounds.
Spectroscopic data of the derivatives 7a–l are given in Table 2.
Synthesis of N-(3-Chloro-2-oxo-4-(alkyl/aryl) azetidin-1-yl)-2-
(2-((methylamino)methyl)-1H-benzimidazol-1-yl)acetamide (8a–l)
Chloroacetyl chloride (10 mmol) was added dropwise to a stirred solution
compound
benzimidazol-1-ylgacetohydrazide (7) (20 mmol) and triethylamine (10 mmol) in
of
N’-[(1E)-alkylidene=arylidene]-2-f2-[(methylamino)methyl]-1H-
Table 3. Antibacterial activity of compounds 6a–6l and 8a–8l against Staphylococcus aureus
Concentrations
Compounds
1.0 mg=ml
10 mg=ml
100 mg=ml
200 mg=ml
500 mg=ml
App. MIC mg=ml
6a
6b
þ
þ
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
þ
þ
–
–
P
–
–
–
–
–
–
–
–-
–
–
–
–
–
–
–
–
–
–
–
–
–
10
10
6c
6d
þþ
þþ
þþþ
þþþ
þþ
þþ
þþ
þþþ
þ
þ
–
100
100
200
200
200
100
100
200
100
100
200
200
500
500
200
200
500
10
þ
–
6e
þ
P
þ
P
–
6f
6 g
þþ
þ
6 h
6i
þ
þ
–
6j
8a
þþ
P
P
–
8b
8c
þ
P
–
þþ
þþ
þþþ
þþþ
þþ
þþ
þþþ
þ
þ
P
þ
þ
þ
þ
þ
P
–
8d
8e
þ
þþ
þþ
þ
8f
8 h
8i
8 l
þ
þþ
–
Ampicillin
Notes: Total inhibition (no growth of organism), –; poor growth compared to control, P; medium
growth compared to control, þ; and confluent growth (no inhibition), þ þ.

3566
K. F. ANSARI, C. LAL, AND D. L. PARMAR
Table 4. Antibacterial activity of compounds 6a–6 l and 8a–8 l against Bacillus subtilis
Concentrations
Compounds
1.0 mg=ml
10 mg=ml
100 mg=ml
200 mg=ml
500 mg=ml
App. MIC mg=ml
6a
6b
þ
þþ
þþ
þ
–
þ
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
P
P
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
10
100
100
100
200
200
200
200
100
100
200
100
200
500
500
100
200
10
6c
6d
þþ
þ
–
–
6e
þþ
þþ
þþ
þþ
þ
þ
P
þ
P
P
–
6f
6g
þþ
þþ
þ
6h
6i
8a
P
þþ
þþ
þþ
þþþ
þþþ
þþ
þþ
þþþ
þ
þ
–
8b
8c
þ
P
–
þ
8d
8e
þþ
þþ
þ
P
P
þ
–
8f
8h
P
8i
Ampicillin
þþ
–
þ
–
Notes: Total inhibition (no growth of organism), –; poor growth compared to control, P; medium
growth compared to control, þ; and confluent growth (no inhibition), þ þ.
Table 5. Antibacterial activity of compounds 6a–6 l and 8a–8 l against Escherichia coli
Concentrations
Compounds
1.0
10
100
200
500 (mg=ml)
App. MIC (mg=ml)
6a
6b
þþ
þþ
þ
þ
–
–
–
–
–
–
–
–
–
–
P
–
–
–
P
P
–
–
P
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
100
100
100
200
200
200
200
200
500
100
100
200
500
500
200
200
500
10
6c
6d
þþþ
þþþ
þþþ
þþ
P
–
þþ
þ
þ
P
P
P
P
þ
–
6e
6g
þ
6h
6i
þþ
P
þþþ
þþþ
þþ
þþ
þþ
þ
6l
8a
8b
8c
þþ
P
–
þþþ
þþ
þ
P
þ
P
þ
þ
þ
–
8f
8g
þþ
þ
þþ
8h
þþ
þ
8i
8k
þþ
þ
þþ
þþ
–
Nalidixic acid
þ
Notes: Total inhibition (no growth of organism), –; poor growth compared to control, P; medium
growth compared to control, þ; and confluent growth (no inhibition), þþ.

OXADIAZOLYL/AZETIDINYL BENZIMIDAZOLE DERIVATIVES
3567
dry dioxane (50 ml) at room temperature. The reaction mixture was stirred for 1 h
and then refluxed for 5–10 h. The solid obtained after removal of dioxane was
crystallized from aqneous ethanol to give the title compounds.
Spectroscopic data of the derivatives 8a–l are given in Table 2.
Antibacterial Activity Test
The compounds were added to the medium as dimethylsulfoxide (DMSO)
solutions. No inhibition zone was observed in controls (i.e., for DMSO). The con-
centrations used were as follows: 500, 200, 100, 10 and 1.0 mg=ml. Minimum inhibi-
tory concentration (MIC) values used were determined after incubation at 37 ꢁC for
48 h and determined using tube dilution method according to the standard pro-
cedure.[21] Ampicillin and nalidixic acid were used as the antibacterial standard,
and DMSO was used both as a solvent and as a control. Antibacterial activity results
are presented in Tables 3–5.
ACKNOWLEDGMENT
Authors are thankful to the University Grants Commission, New Delhi, India,
for providing financial grant vide F. No. 37-494=2009 (SR).
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