Design and one-pot and microwave-assisted synthesis of 2-amino/5-aryl-1,3, 4-oxadiazoles bearing a benzimidazole moiety as antioxidants

Article abstract of DOI:10.1002/ardp.201100440

In this study, two new series of 2-amino-1,3,4-oxadiazoles and 5-aryl-1,3,4-oxadiazoles carrying a benzimidazole moiety were synthesized. The antioxidant properties of these compounds were investigated in vitro by the determination of the microsomal NADPH-dependent inhibition of lipid peroxidation levels (LP), the microsomal ethoxyresorufin O-deethylase activity (EROD), and DPPH radical scavenger effects. Among the tested compounds, 2-[(2-(4- chlorophenyl)-1H-benzo[d]imidazole-1-yl)methyl]-5-(4-fluorophenyl)-1,3, 4-oxadiazole (9) was found to be the most active compound in all three in vitro systems. Two new series of 2-amino-1,3,4-oxadiazoles and 5-aryl-1,3,4- oxadiazoles carrying a benzimidazole moiety were synthesized and their antioxidant properties were investigated in vitro. 2-[(2-(4-Chlorophenyl)-1H- benzo[d]imidazole-1-yl)methyl]-5-(4-fluorophenyl)-1,3,4-oxadiazole (9) was found to be the most active compound in all three in vitro systems. Copyright

Full text of DOI:10.1002/ardp.201100440

Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
1
Full Paper
Design and One-Pot and Microwave-Assisted Synthesis of
2-Amino/5-Aryl-1,3,4-oxadiazoles Bearing a Benzimidazole
Moiety as Antioxidants
1
Ilgar Kerimov , Gu¨lgu¨n Ayhan-Kılcıgil , Elc¸in Deniz Ozdamar , Benay Can-Eke , Tu¨lay C¸ oban ,
1
2
2
2
˙
¨
3
Su¨heyla Ozbey , and Canan Kazak
4
¨
1 Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara University, Ankara, Turkey
2 Faculty of Pharmacy, Department of Toxicology, Ankara University, Ankara, Turkey
3 Faculty of Engineering, Department of Engineering Physics, Hacettepe University, Beytepe, Ankara, Turkey
4 Faculty of Arts and Sciences, Department of Physics, Ondokuz Mayıs University, Kurupelit, Samsun,
Turkey
In this study, two new series of 2-amino-1,3,4-oxadiazoles and 5-aryl-1,3,4-oxadiazoles carrying
a benzimidazole moiety were synthesized. The antioxidant properties of these compounds were
investigated in vitro by the determination of the microsomal NADPH-dependent inhibition of lipid
peroxidation levels (LP), the microsomal ethoxyresorufin O-deethylase activity (EROD), and DPPH
radical scavenger effects. Among the tested compounds, 2-[(2-(4-chlorophenyl)-1H-benzo[d]imidazole-1-
yl)methyl]-5-(4-fluorophenyl)-1,3,4-oxadiazole (9) was found to be the most active compound in all
three in vitro systems.
Keywords: Antioxidant activity / Benzimidazoles / Oxadiazoles / X-ray
Received: December 8, 2011; Revised: January 19, 2012; Accepted: February 16, 2012
DOI 10.1002/ardp.201100440
Introduction
important heterocyclic compound because of its different
biological activities such as anticancer [5], antibacterial [6,
7], antifungal [7], anticonvulsant [8], antimycobacterial [9],
analgesic-antiinflammatory [10–12], antiviral [13], and glyco-
gen synthase kinase-3b inhibitory effects [14]. Several syn-
thetic methods have been reported for the preparation of
1,3,4-oxadiazoles [10, 15–22]. 2-Amino-1,3,4-oxadiazoles were
synthesized by the reaction of hydrazides with cyanogen
bromide [10, 21]. One of the popular methods involves the
microwave assisted one-step synthesis of some 5-aryl-1,3,4-
oxadiazoles by reaction of hydrazides and aryl carboxylic
acids in the presence of thionyl chloride or phosphorus oxy-
chloride [22, 23]. As a part of our ongoing investigation on
developing potent antioxidant compounds [24–30], we report
here the synthesis of a new class of 2-amino- or 5-aryl-1,3,4-
oxadiazole bearing benzimidazole derivatives and the bio-
logical evaluation of their antioxidant properties.
Free radicals and other oxygen-derived species are generated
in aerobic organisms as part of the normal physiological and
metabolic processes or from exogenous factors and agents.
Overproduction of the free radicals can be responsible for
damage to biological molecules, especially to DNA, lipids,
and proteins that cause many health problems which include
cancer, Alzheimer’s and other neurodegenerative diseases,
and atherosclerosis [1–3]. Free radicals are involved in normal
physiological functions and antioxidant defence systems
scavenge and minimize the formation of oxygen-derived
species. But excess formation of free radicals or decrease in
antioxidant level leads to oxidative stress. Hence, antioxi-
dants are considered as potential drugs that may be particu-
larly important in diminishing cumulative oxidative damage
and helping to stay healthier [2–4]. 1,3,4-Oxadiazole is an
Results and discussion
Correspondence: Gu¨lgu¨n Ayhan-Kılcıgil, Faculty of Pharmacy,
Department of Pharmaceutical Chemistry, University of Ankara, 06100
Tandogan, Ankara, Turkey.
E-mail: kilcigil@pharmacy.ankara.edu.tr
Fax: 00903122131081
The target 2-amino (1–4) and 5-aryl (5–24) oxadiazoles were
derived from 2-phenyl/substituted phenyl-1H-benzimidazole acetic
acid hydrazides (1a–4a). Compounds 1a–4a were synthesized
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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I. Kerimov et al.
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
N
N
starting from o-phenylenediamine and benzaldehyde or
p-substituted benzaldehydes via oxidative condensation.
Treatment of 1H-benzimidazole derivatives with ethylchloro-
acetate in KOH/DMSO yielded ester compounds and then
reaction with hydrazine hydrate of these compounds
resulted in the desired hydrazide compounds (1a–4a)
(Scheme 1). The hydrazides (1a–4a) were converted to 2-
amino-5-[(2-phenyl/p-substituted phenyl)-1H-benzimidazole-1-yl-
methyl]oxadiazoles (1–4) using cyanogen bromide (Scheme 2)
[10, 21]. Reaction of 2-p-chlorophenyl 1H-benzimidazol-1-yl)-
acetic acid hydrazide (2a) with different aromatic acids in the
presence of phosphorus oxychloride (Scheme 3) gave 5-aryl-
1,3,4-oxadiaxoles (5–24). The mass spectra of all of the
synthesized compounds showed a MþH ion peak which is
conforming with the molecular formula of the compounds
and Mþ2 and Mþ4 isotope peaks belonging chloro and
bromo atoms.
NH2
O
CH2CONHNH2
N
N
N
CNBr
R1
R1
N
_
1 4
R1: H, Cl, OCH3, OCH2C6H5
_
1a 4a
Scheme 2. Synthesis of 2-amino-1,3,4-oxadiazole (1–4)
derivatives.
at 10ꢀ3 M concentration. Compounds 6 and 10 also decreased
the LP levels by about 31 and 26%, respectively. Rest of the
compounds showed pro-oxidant properties at the same
concentration.
It was observed that the effects of the compounds on the
DPPH radical, LP, and EROD activity levels were variable. The
observation of distinct effects of the synthesized compounds
on the DPPH radical, LP levels, and EROD is not surprising
since the mechanisms of production of oxidative stress using
these methods are different.
The synthesized compounds were tested for their anti-
oxidant properties by using various in vitro systems.
Compounds 1, 6, 9, and 15 were found to be slightly scav-
engers of the DPPH radical (32, 47, 40, and 40%, respectively),
when compared with BHT (88%). The DPPH radical scavenger
capacities of compounds 2 (19%), 4 (26%), 11 (10%), 12 (15%),
16 (10%), and 19 (17%) were rather limited.
The ORTEP drawing [31] of the structure 20 shown in Fig. 1
clearly establishes the structural formula and also shows the
conformation of the molecule. The benzimidazole ring sys-
tem is almost planar; the displacements of all nine atoms
The in vitro effects of compounds and caffeine on ethoxy-
resorufin O-deethylase activity (EROD) are shown in Table 1.
As can be seen from Table 1, the strong inhibitory activities
were observed by compounds 9 (70%), 10 (68%), 11 (71%), and
16 (71%) which were close to the specific inhibitor caffeine
(85%) at 10ꢀ3 M concentration. Significant inhibitory activi-
ties were also observed by other compound in the range of
47–66%. Compounds containing fluoro, bromo, or methoxy
substituent at the 4th position of the phenyl ring have better
activity than the other compounds except compound 16. In
addition, 2-amino-1,3,4-oxadiazoles or disubstituted aryl-
1,3,4-oxadiazoles exhibited weaker EROD activity than the
monosubstituted aryl compounds.
˚
contained in the ring are less than 0.031 (5) A (for C4) from
the least-squares plane. The orientation of the oxadiazoyl-
methyl substituent at N1 is defined by the torsion angles of
C1–N1–C14–C15 105.5(3)8 and N1–C14–C15–N4 ꢀ107.1(4)8.
The oxadiazole ring is also planar [maximum deviation
˚
0.005(3) A for C16] and forms a dihedral angle of 63.75(8)8
with the best plane of the benzimidazole ring system. The 3,5-
dinitrophenyl ring attached to the oxadiazole ring is nearly
coplanar with this ring and makes a dihedral angle of 3.59(8)8
with the oxadiazole ring plane. The planar p-chlorophenyl
moiety at C2 makes a dihedral angle of 42.58(8)8 with the
benzimidazole ring; the orientation of the phenyl moiety is
also defined by the torsion angle N1–C1–C8–C9 135.0(3)8. The
packing diagram (Fig. 2) shows that the molecules are
arranged into infinite one-dimensional chains along the
c-axis. C–H Cl interactions between molecules related
by the screw symmetry running down the c-axis, [H4
The NADPH-dependent lipid peroxidation (LP) inhibition
produced by the new compounds in rat liver microsomes was
examined by measuring the formation of 2-thiobarbituric
acid reactive substance (TBARS) for their antioxidant
capacity. It appears that compound 9 was found to be a good
inhibitor (54%) of liver LP levels when compared to BHT (65%)
CH2CONHNH2
N
CH2COOEt
N
R1
H
NH2
N
NH2NH2
ClCH2COOEt
R1
R1
+
R1
N
N
N
NH2
_
1a 4a
CHO
R1= H, Cl, OCH3, OCH2C6H5
Scheme 1. Synthesis of compounds 1a–4a.
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
2-Amino/5-Aryl-oxadiazoles Synthesized as Antioxidants
3
N
N
R2
O
R2
Cl
N
N
COOH
O
NH2
N
H
_
5 23
N
N
POCl3
MW
Cl
Br
N
O
N
2a
O
N
Cl
COOH
N
Scheme 3. Synthesis of 5-aryl-1,3,4-oxadi-
azoles (5–24).
Br
O
24
Table 1. The in vitro effects of some compounds on liver LP levels, on EROD, and DPPH free radical scavenging activitiesa)
Br
N
N
O
N
N
N
N
O
NH2
O
O
R2
N
N
N
N
N
N
Cl
Cl
R1
_
_
24
1 4
5 23
Compd.
R1
R2
EROD
(pmol/mg/min)
% of
contr.
LP
(nmol/mg/min)
% of
contr.
DPPH (% of control)
(1 mM)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
H
Cl
22.18 ꢁ 2.33
14.38 ꢁ 0.01
16.72 ꢁ 0.31
19.60 ꢁ 0.01
21.25 ꢁ 0.13
15.05 ꢁ 0.71
15.32 ꢁ 0.22
14.55 ꢁ 1,65
12.68 ꢁ 0.08
13.75 ꢁ 1.41
12.49 ꢁ 0.30
20.17 ꢁ 0.52
nt
22.34 ꢁ 3.20
19.04 ꢁ 0.07
12.39 ꢁ 0.05
16.03 ꢁ 0.70
22.43 ꢁ 0.33
16.59 ꢁ 0.21
nt
53
35
40
47
50
35
36
34
30
32
29
47
23.87 ꢁ 0.30
35.54 ꢁ 3.54
22.09 ꢁ 0.41
32.43 ꢁ 4.35
23.28 ꢁ 2.53
11.27 ꢁ 1.02
24.82 ꢁ 3.81
23.66 ꢁ 2.74
7.45 ꢁ 1.55
12.02 ꢁ 2.02
27.00 ꢁ 2.42
31.31 ꢁ 3.32
nt
21.30 ꢁ 1.26
24.58 ꢁ 1.12
18.84 ꢁ 0.48
32.29 ꢁ 2.98
18.30 ꢁ 0.52
16.70 ꢁ 1.30
nt
147
218
136
199
143
69
152
146
46
68 ꢁ 3.0
81 ꢁ 2.5
ne
OCH3
OCH2C6H5
74 ꢁ 3.0
4-C2H5
4-CH3
3-CH3
2-CH3
4-F
4-OCH3
4-Br
4-CF3
3-CN
4-Cl
3-Cl
2-Cl
2,4-diCl
4-NO2
3-NO2
ne
53 ꢁ 3.2
ne
ne
60 ꢁ 3
74
166
193
ne
90 ꢁ 1.4
85 ꢁ 2.4
nt
53
45
29
38
53
39
131
151
115
198
113
103
ne
60 ꢁ 2.0
90 ꢁ 2.0
ne
ne
83 ꢁ 2.0
3,5-diNO2
3-NO2 4-OCH3
3-NO2 4-Cl
2-F 5-NO2
nt
ne
20.65 ꢁ 0.38
17.34 ꢁ 0.36
18.05 ꢁ 0.89
15.54 ꢁ 0.49
–
49
41
43
37
–
21.07 ꢁ 3.37
33.39 ꢁ 0.35
30.66 ꢁ 3.47
40.08 ꢁ 4.39
5.68 ꢁ 0.22
–
130
205
188
246
35
ne
ne
ne
12 ꢁ 3.0
BHT
Caffeine
Controlb)
6.41 ꢁ 036
15
100
–
100
–
100
41.53 ꢁ 0.99
16.25 ꢁ 1.45
a)
Each value represents the mean ꢁ SD of 2–4 independent experiments.
b)
Dimethylsulfoxide only, control for compounds, BHT and caffeine ne.
no effect; nt: not tested.
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
Varian Mercury 400 MHz instrument using TMS as an internal
standard; CDCl3 and DMSO-d6, coupling constants (J) are reported
in Hertz. Chemical shifts were reported in ppm units with use of
d scale. ES-MS were obtained with a Waters ZQ Micromass LC-MS
spectrometer with positive electrospray ionization method. The
reactions were carried out in an unmodified domestic micro-
wave oven (White Westinghouse SG Typ KM97UL, 1400 Watt,
US). All instrumental analyses were performed at the Central
Laboratory, Faculty of Pharmacy, Ankara University. The chemi-
cal reagents used in synthesis were purchased from E. Merck and
Aldrich. Butylated hydroxy toluene (BHT) and caffeine were
obtained from Sigma. Analytical thin-layer chromatography
was performed with Merck precoated TLC plates and spots were
visualized with ultraviolet light.
Figure 1. ORTEP drawing of compound 20 with the displacement
2-Phenyl/(p-chlorophenyl)/(p-methoxyphenyl)/
(p-benzyloxyphenyl)-1H-benzimidazol-1-yl)-acetic acid
hydrazides (1a–4a)
ellipsoids drawn at the 35% probability level.
2-Phenyl/(p-chlorophenyl)/(p-methoxyphenyl)/(p-benzyloxy-
phenyl)-1H-benzimidazole-1-yl)-acetic acid hydrazides were syn-
thesized starting from o-phenylenediamine and corresponding
benzaldehydes according to the literature methods (Scheme 1)
[27, 29].
i
˚
˚
Cl1 ¼ 2.818(1) A; C18 Cl1 ¼ 3.727(3) A, C18- H4 Cl1 ¼
165.78(0.17); symmetry code (i) ¼ ꢀ x,ꢀy þ 1,ꢀz þ 2]; this
is a presumably weak.
Experimental
General synthesis of 2-amino-1,3,4-oxadiazole (1–4)
Compounds 1a–4a (0.33 mmol) and cyanogen bromide
(0.33 mmol) were dissolved in absolute ethanol (2 mL) and warmed
at 60–708C for 6 h. The resulting solution was cooled and neutral-
ized with sodium bicarbonate solution. Solid product was collected
by filtration, washed with water, and crystallized from ethanol.
Chemistry
Melting points were measured in open capillary tubes on a
Thermo Scientific Electrothermal melting point apparatus and
are uncorrected. 1H NMR and 13C spectra were measured with a
5-[(2-Phenyl)-1H-benzo[d]imidazo-1-yl)methyl]-1,3,4-
oxadiazole-2-amine (1)
Yield 60%, m.p.: 2658C, 1H NMR d ppm (DMSO-d6, 400 MHz): 5.60
(s, 2H, –CH2), 7.11 (s, 2H, NH2), 7.27–7.33 (m, 2H, Ar–H), 7.58–7.64
(m, 4H, Ar–H), 7.71 (dd, 1H, Jo ¼ 7.03 Hz, Jm ¼ 1.57 Hz, Ar–H),
7.83–7.85 (m, 2H, Ar–H), 13C NMR d ppm (DMSO-d6, 100 MHz):
110.8, 119.2, 122.5, 123.0, 128.3, 128.8, 130.9, 134.8, 135.6, 142.2,
151.7, 154.5, 164.0, LC-MS m/z (ESIþ): 292.0 (MþH).
5-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazo-1-yl)methyl]-
1,3,4-oxadiazole-2-amine (2)
Yield 37%, m.p.: 2568C, 1H NMR d ppm (DMSO-d6, 400 MHz): 5.62
(s, 2H, –CH2), 7.11 (s,2H, NH2), 7.27–7.34 (m, 2H, Ar–H), 7.63–7.73
(m, 4H, Ar–H), 7.86 (d, 1H, Jo ¼ 8.60 Hz, Ar–H), LC-MS m/z (ESIþ):
326.1 (MþH) (76%), 328.1 (Mþ2) (24%).
5-[(2-(4-Methoxyphenyl)-1H-benzo[d]imidazo-1-yl)-
methyl]-1,3,4-oxadiazole-2-amine (3)
Yield 33%, m.p.: 2658C, 1H NMR d ppm (DMSO-d6, 400 MHz): 3.85
(s, 3H, OCH3), 5.58 (s, 2H, –CH2), 7.11–7.30 (m, 6H, NH2, Ar–H),
7.59–7.69 (m, 2H, Ar–H), 7.79 (d, 1H, Jo ¼ 8.60 Hz, Ar–H), LC-MS
m/z (ESIþ): 322.1 (MþH).
5-[(2-(4-Benzyloxyphenyl)-1H-benzo[d]imidazo-1-yl)-
methyl]-1,3,4-oxadiazole-2-amine (4)
Yield 38%, m.p.: 2558C, 1H NMR d ppm (DMSO-d6, 400 MHz): 5.21
(s, 2H, OCH2), 5.58 (s, 2H, –CH2), 7.11 (s, 2H, NH2), 7.21 (d, 2H,
Figure 2. The crystal packing in 20, showing the stacks of mole-
cules running down the b-axis.
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
2-Amino/5-Aryl-oxadiazoles Synthesized as Antioxidants
5
Jo ¼ 8.60 Hz, Ar–H), 7.26–7.44 (m, 5H, Ar–H), 7.50 (d, 2H,
Jo ¼ 7.03 Hz, Ar–H), 7.59–7.69 (m, 2H, Ar–H), 7.79 (d, 2H,
Jo ¼ 8.60 Hz, Ar–H), 13C NMR d ppm (DMSO-d6, 100 MHz):
69.3, 110.6, 114.9, 118.9, 121.8, 122.2, 122.5, 127.7, 127.8,
128.4, 130.7, 135.6, 136.6, 142.4, 152.8, 154.6, 159.5, 164.0,
LC-MS m/z (ESIþ)ꢂꢂ: 398.2 (MþH).
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
methyl]-5-(4-fluorophenyl)-1,3,4-oxadiazole (9)
Yield 31%, m.p.: 1998C, 1H NMR d ppm (CDCl3, 400 MHz): 5.62 (s, 2H,
CH2), 7.16–7.20 (td, 2H, Ar–H), 7.35–7.38 (m, 2H, Ar–H), 7.56–7.61
(m, 3H, Ar–H), 7.83–7.86 (m, 3H, Ar–H), 7.93–7.97 (m, 2H, Ar–H).
13C NMR
d ppm (CDCl3, 100 MHz): 39.9, 110.2, 116.8
(d, J ¼ 22.2 Hz), 119.5 (d, J ¼ 3.8 Hz), 120.6, 124.0 (d, J ¼ 32.4 Hz),
127.9, 129.5, 129.6, 129.7, 131.1, 135.7, 137.0, 143.1, 152.8, 161.4,
165.3, 165.4 (d, J ¼ 254.57 Hz), LC-MS m/z (ESIþ): 405.8 (MþH) (74%),
407.8 (Mþ2) (26%).
General synthesis of 5-aryl-1,3,4-oxadiazoles (5–24)
2-(p-Chlorophenyl)-1H-benzimidazol-1-yl-acetic acid hydrazide
(0.166 mmol) (2a) and appropriate aromatic acid (0.166 mmol)
in 1 mL phosphorus oxychloride were ground with a mortar in a
beaker and then heated in a domestic microwave irradiation for
30 min. After the cooling to room temperature crushed ice-water
was added with continuous stirring, solid mass was filtered, and
neutralized with sodium bicarbonate solution (10% w/v). The
resulting solid was filtered, washed with water, and was purified
with column chromatograpy using hexane–ethyl acetate (2:1) as
eluent.
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
methyl]-5-(4-methoxyphenyl)-1,3,4-oxadiazole (10)
1
Yield 19%, m.p.: 167.58C, H NMR d ppm (CDCl3, 400 MHz): 3.86
(s, 3H,–OCH3), 5.60 (s, 2H, –CH2), 6.98 (d, 2H, Jo ¼ 8.8 Hz, Ar–H),
7.34–7.39 (m, 2H, Ar–H), 7.56–7.63 (m, 3H, Ar–H), 7.82–7.89
(m, 5H, Ar–H), LC-MS m/z (ESIþ): 417.8 (MþH) (74%), 419.8
(Mþ2) (26%).
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
methyl]-5-(4-ethylphenyl)-1,3,4-oxadiazole (5)
methyl]-5-(4-bromophenyl)-1,3,4-oxadiazole (11)
Yield 21%, m.p.: 2018C, 1H NMR d ppm (CDCl3, 400 MHz): 5.62
(S, 2H, –CH2), 7.36–7.38 (m, 2H, Ar–H), 7.56–7.65 (m, 10H, Ar–H),
13C NMR d ppm (CDCl3,100 MHz): 39.9, 110.2, 120.6, 122.1, 123.8,
124.2, 127.4, 127.9, 128.6, 129.7, 131.1, 132.8, 135.7, 137.1, 143.1,
152.7, 161.5, 165.4, LC-MS m/z (ESIþ): 465.7 (MþH) (36%), 467.7
(Mþ2) (51%), 469.7 (Mþ4) (13%).
Yield 22%, m.p.: 1788C, 1H NMR d ppm (DMSO-d6, 400 MHz): 1.16
(t, 3H, CH2-CH3), 2.64 (q, 2H, CH2-CH3), 5.88 (s, 2H, –CH2), 7.22–
7.24 (m, 2H, Ar–H), 7.39 (d, 2H, Jo ¼ 8.21 Hz, Ar–H), 7.64 (d, 2H,
Jo ¼ 8.59 Hz, Jm ¼ 1.96 Hz, Ar–H), 7.71 (dd, 2H, Jo ¼ 7.43 Hz,
Jm ¼ 1.17 Hz, Ar–H), 7.77 (d, 2H, Jo ¼ 8.20 Hz, Ar–H), 7.86
(dd, 2H, Jo ¼ 8.60 Hz, Ar–H), LC-MS m/z (ESIþ): 415.8 (MþH)
(74%), 417 (Mþ2) (26%).
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
methyl]-5-(4-trifluoromethylphenyl)-1,3,4-oxadiazole (12)
Yield 15%, m.p.: 1788C, 1H NMR d ppm (CDCl3, 400 MHz): 5.65
(s, 2H, CH2), 7.35–7.38 (m, 2H, Ar–H), 7.56–7.60 (m, 3H, Ar–H),
7.76 (d, 2H, Jo ¼ 8.00 Hz, Ar–H), 7.83–7.86 (m, 3H, Ar–H), 8.07
(d, 2H, Jo ¼ 8.40 Hz, Ar–H), 13C NMR d ppm (CDCl3, 100 MHz):
39.9, 110.1,120.6, 122.2, 123.8, 124.9, 126.4 (q), 127.6, 127.8,
131.1, 134.0, 134.3, 135.6, 137.1, 143.1, 152.7, 162.0, 164.9,
LC-MS m/z (ESIþ): 455.8 (MþH) (73%), 457.8 (Mþ2) (27%).
methyl]-5-p-tolyl-1,3,4-oxadiazole (6)
Yield 38%, m.p.: 1328C, 1H NMR d ppm (CDCl3, 400 MHz): 2.62
(s, 3H,CH3), 5.65 (s, 2H, CH2), 7.28–7.44 (m, 5H, Ar–H), 7.57 (d, 2H,
Jo ¼ 8.20 Hz, Ar–H), 7.62–7.65 (m, 1H, Ar–H), 7.80 (d, 1H,
Jo ¼ 7.82 Hz, Ar–H), 7.84–7.86 (m, 1H, Ar–H), 7.89 (d, 2H,
Jo ¼ 8.21 Hz, Ar–H), 13C NMR d ppm (CDCl3, 100 MHz): 22.3,
39.9, 110.3, 120.5, 123.7, 124.1, 126.5, 129.2, 129.6, 131.2,
132.0, 132.1, 135.7, 137.0, 138.8, 143.1, 152.8, 160.9, 166.5,
LC-MS m/z (ESIþ): 401.1 (MþH) (74%), 403.4 (Mþ2) (26%).
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
methyl]-5-(3-cyanophenyl)-1,3,4-oxadiazole (13)
Yield 9%, m.p.: 147.58C, 1H NMR d ppm (CDCl3, 400 MHz): 5.66
(s, 2H, –CH2), 7.36–7.41 (m, 2H, Ar–H), 7.58 (dd, 2H, Jo ¼ 8.00 Hz,
Jm ¼ 2.00 Hz, Ar–H) 7.65 (td, 2H, Jo ¼ 8.00 Hz, 7.60 Hz, Ar–H),
7.85 (qd, 2H, Jo ¼ 7.2 0Hz, 6.80 Hz, Ar–H), 8.18 (d, 1H,
Jo ¼ 7.60 Hz, Ar–H), 8.22 (s, 1H, Ar–H), LC-MS m/z (ESIþ): 412.8
(MþH) (70%), 414.8 (Mþ2) (30%).
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
methyl]-5-m-tolyl-1,3,4-oxadiazole (7)
Yield 21%, m.p.: 1478C, 1H NMR d ppm (CDCl3, 400 MHz): 2.39
(s, 3H, CH3), 5.60 (s, 2H, CH2), 7.32–7.38 (m, 4H, Ar–H), 7.55–7.60
(m, 3H, Ar–H), 7.70–7.87 (m, 5H, Ar–H), 13C NMR d ppm (CDCl3,
100 MHz): 21.5, 39.9, 110.3, 120.5, 123.1, 123.7, 124.2, 124.3,
127.7, 127.9, 129.3, 129.7, 131.1, 133.4, 135.7, 137.0, 139.3,
143.0, 152.7, 161.2, 166.3, LC-MS m/z (ESIþ): 401.3 (MþH) (76%),
403.3 (Mþ2) (24%).
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
methyl]-5-(4-chlorophenyl)-1,3,4-oxadiazole (14)
Yield 10%, m.p.: 1998C, 1H NMR d ppm (CDCl3, 400 MHz): 5.62
(s, 2H, CH2), 7.34–7.39 (m, 2H, Ar–H), 7.47 (d, 2H, Jo ¼ 8.40 Hz,
Ar–H), 7.56–7.60 (m, 3H, Ar–H), 7.83–7.89 (m, 5H, Ar–H), LC-MS m/z
(ESIþ): 421.7 (MþH) (47%), 423.7 (Mþ2) (44%), 425.7 (Mþ4) (9%).
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
methyl]-5-o-tolyl-1,3,4-oxadiazole (8)
Yield 23%, m.p.: 1468C, 1H NMR d ppm (CDCl3, 400 MHz): 2.59
(s, 3H, CH3), 5.62 (s, 2H, CH2), 7.25–7.41 (m, 5H, Ar–H), 7.53–7.56
(m, 3H, Ar–H), 7.76–7.87 (m, 4H, Ar–H), 13C NMR d ppm (CDCl3,
100 MHz): 22.3, 40.0, 110.4, 120.3, 122.2, 124.1, 124.5, 126.5,
129.2, 129.7, 131.3, 131.4, 132.1, 132.2, 135.4, 137.4, 138.9,
151.2, 152.5, 160.7, 166.4, LC-MS m/z (ESIþ): 401.8 (MþH) (73%),
403.8 (Mþ2) (27%).
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
methyl]-5-(3-chlorophenyl)-1,3,4-oxadiazole (15)
Yield 11%, m.p.: 1908C, 1H NMR d ppm (CDCl3, 400 MHz): 5.62
(s, 2H, –CH2), 7.35–7.59 (m, 7H, Ar–H), 7.81–7.85 (m, 4H, Ar–H),
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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I. Kerimov et al.
6
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
7.92–7.93 (m, 1H, Ar–H), LC-MS m/z (ESIþ): 421.7 (MþH) (46%),
423.7 (Mþ2) (44%), 425.7 (Mþ4) (10%), 13C NMR d ppm (CDCl3,
100 MHz): 39.9, 110.2, 120.6, 123.8, 124.2, 124.8, 125.3, 127.2,
127.9, 129.7, 130.8, 131.1, 132.6, 135.6, 135.7, 137.1, 143.1, 152.7,
161.7, 164.9.
Ar–H), 8.39 (d, 1H, Jm ¼ 1.95 Hz, Ar–H), 13C NMR d ppm
(CDCl3, 100 MHz): 39.8, 57.2, 110.1, 114.5, 115.6, 120.6, 123.8,
124.2, 124.8, 127.8, 129.7, 131.1, 132.7, 135.6, 137.1, 139.9, 143.0,
152.7, 155.7, 161.5, 164.1, LC-MS m/z (ESIþ): 462.8 (MþH) (72%),
464.8 (Mþ2) (28%).
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
methyl]-5-(2-chlorophenyl)-1,3,4-oxadiazole (16)
Yield 13%, m.p.: 1938C, 1H NMR d ppm (CDCl3, 400 MHz): 5.65
(s, 2H, –CH2), 7.35–7.41 (m, 3H, Ar–H), 7.46–7.58 (m, 4H, Ar–H),
7.64–7.67 (m, 1H, Ar–H), 7.82–7.85 (m, 1H, Ar–H), 7.91 (dd, 2H,
Jo ¼ 8.60 Hz, Jm ¼ 1.96 Hz, Ar–H), 7.96 (dd, 1H, Jo ¼ 7.81 Hz,
Jm ¼ 1.56 Hz, Ar–H), LC-MS m/z (ESIþ): 421.7 (MþH) (55%), 423.7
(Mþ2) (38%), 425.8 (Mþ4) (7%).
methyl]-5-(3-nitro-4-chlorophenyl)-1,3,4-oxadiazole (22)
Yield 28%, m.p.: 2178C, 1H NMR d ppm (DMSO-d6, 400 MHz): 5.93
(s, 2H, –CH2), 7.31–7.38 (m, 2H, Ar–H), 7.66 (d, 2H, Jo ¼ 8.59 Hz,
Ar–H), 7.75 (d, 2H, Jo ¼ 7.42 Hz, Ar–H), 7.89 (d, 2H, Jo ¼ 8.59 Hz,
Ar–H), 7.99 (d, 1H, Jo ¼ 8.59 Hz, Ar–H), 8.18 (dd, 1H,
Jo ¼ 8.60 Hz, Jm ¼ 1.95 Hz, Ar–H), 8.52 (d, 1H, Jm ¼ 1.95 Hz,
Ar–H), 13C NMR d ppm (DMSO-d6, 100 MHz): 111.0, 119.1, 122.8,
123.1, 123.2, 123.5, 127.9, 128.4, 128.9, 131.1, 131.2, 133.0, 135.0,
135.5, 141.8, 147.9, 151.9, 162.5, 162.8, LC-MS m/z (ESIþ): 466.9
(MþH) (56%), 468.8 (Mþ2) (35%), 470.7 (Mþ4) (9%).
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
methyl]-5-(2,4-dichlorophenyl)-1,3,4-oxadiazole (17)
Yield 29%, m.p.: 1998C, 1H NMR d ppm (CDCl3, 400 MHz): 5.65
(s, 2H, –CH2), 7.34–7.42 (m, 3H, Ar–H), 7.54–7.64 (m, 4H, Ar–H),
7.82–7.92 (m, 4H, Ar–H), 13C NMR d ppm (CDCl3, 100 MHz): 39.7,
110.2, 120.1, 120.8, 123.8, 124.1, 127.7, 127.8, 129.5, 130.7, 131.0,
131.3, 132.0, 133.8, 135.3, 137.0, 138.9, 152.4, 161.6, 163.7, LC-MS
m/z (ESIþ): 455.9 (MþH) (45%), 457.9 (Mþ2) (39%), 459.8 (Mþ4)
(16%).
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
methyl]-5-(2-fluoro-5-nitrophenyl)-1,3,4-oxadiazole (23)
Yield 20%, m.p.: 1508C, 1H NMR d ppm (CDCl3, 400 MHz): 5.65
(s, 2H, CH2), 7.39–7.43 (m, 3H, Ar–H), 7.55–7.61 (m, 3H, Ar–H),
7.78–7.86 (m, 3H, Ar–H), 8.37–8.41 (m, 1H, Ar–H), 8.90–8.92
(m, 1H, Ar–H), 13C NMR
d ppm (CDCl3, 100 MHz): 39.7,
110.3, 113.1 (d, J ¼ 13.78 Hz), 118.7 (d, J ¼ 23.64 Hz), 120.6,
124.1 (d, J ¼ 38.33 Hz), 126.07 (d, J ¼ 3.02), 127.7, 129.3
(d, J ¼ 9.96 Hz), 129.7, 131.2, 135.5, 137.2, 142.9, 146.6, 152.8,
161.1, 161.2, 162.4, 163.0 (d, J ¼ 269.07 Hz), LC-MS m/z (ESIþ):
450.8 (MþH) (72%), 452.8 (Mþ2) (28%).
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
methyl]-5-(4-nitrophenyl)-1,3,4-oxadiazole (18)
Yield 17%, m.p.: 2378C, 1H NMR d ppm (CDCl3, 400 MHz): 5.67
(s, 2H, –CH2), 7.36–7.38 (m, 2H, Ar–H), 7.57 (d, 2H, Jo ¼ 8.21 Hz,
Ar–H) 7.82 (d, 2H, Jo ¼ 8.20 Hz, Ar–H), 8.13 (d, 2H, Jo ¼ 8.59 Hz,
Ar–H), 8.35 (d, 2H, Jo ¼ 8.99 Hz, Ar–Ar–H), 13C NMR ii ppm
(CDCl3, 100 MHz): 39.9, 110.0, 120.7, 123.9, 124.3, 124.7, 124.8,
128.2, 128.6, 129.7, 131.1, 135.6, 137.2, 143.1, 150.1, 152.7, 162.4,
164.3, LC-MS m/z (ESIþ): 432.8 (MþH) (73%), 434.9 (Mþ2) (27%).
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
methyl]-5-(5-bromo-2-furyl)-1,3,4-oxadiazole (24)
Yield 50%, m.p.: 1388C, 1H NMR d ppm (DMSO-d6, 400 MHz): 5.90
(s, 2H, –CH2), 6.94 (d, 1H, Jo ¼ 3.52 Hz, Furil-H), 7.31–7.35 (m, 2H,
Ar–H), 7.38 (d, 1H, Jo ¼ 3.52 Hz, Furil-H), 7.65–7.76 (m, 4H, Ar–H),
7.84 (dd, 2H, Jo ¼ 8.59 Hz, Jm ¼ 1.95 Hz, Ar–H), LC-MS m/z
(ESIþ): 455.1 (MþH) (34%), 457.6 (Mþ2) (55%), 459.7 (Mþ4) (11%).
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
methyl]-5-(3-nitrophenyl)-1,3,4-oxadiazole (19)
Yield 18%, m.p.: 2198C, 1H NMR d ppm (CDCl3, 400 MHz): 5.67
(s, 2H, –CH2), 7.38–7.85 (m, 9H, Ar–H), 8.29–8.41 (m, 2H, Ar–H),
8.77 (s, 1H, Ar–H), 13C NMR d ppm (CDCl3, 100 MHz): 39.8, 110.2,
120.7, 122.2, 123.9, 124.3, 124.8, 126.9, 127.9, 129.7, 130.8, 131.1,
132.6, 135.6, 137.2, 143.1, 148.8, 152.8, 162.1, 164.2, LC-MS m/z
(ESIþ): 432.8 (MþH) (73%), 434.8 (Mþ2) (27%).
Antioxidant activity
Lipid peroxidation level
Male albino Wistar rats (200–225 g) used in the experiments
were fed with standard laboratory rat chow and tap water
ad libitum. The animals were starved for 24 h prior to sacrifice
and then killed by decapitation under anesthesia. The livers were
removed immediately and washed in ice-cold distilled water and
the microsomes were prepared as described previously [32].
NADPH-dependent LP was determined using the optimum con-
ditions determined and described previously [32] and measured
spectrophotometrically by estimation of TBARS. Amounts of
TBARS were expressed in terms of nmol malondialdehyde
(MDA)/mg protein. The assay was essentially derived from the
methods of Wills [33, 34] as modified by Bishayee and
Balasubramanian [35]. LP was determined spectrophotometri-
cally at 532 nm as the thiobarbituric acid reactive material.
Compounds inhibit the production of MDA and therefore the
produced color after addition of thiobarbituric acid is less inten-
sive. A typical optimized assay mixture contained 10ꢀ3 M test
compound, 0.2 nM Feþþ, 90 mM KCl, 62.5 mM potassium phos-
phate buffer, pH 7.4, NADPH-generating system consisting of
0.25 mM NADPþ, 2.5 mM MgCl2, 2.5 mM glucose-6-phosphate,
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
methyl]-5-(3,5-dinitrophenyl)-1,3,4-oxadiazole (20)
Yield 13%, m.p.: 2318C, 1H NMR d ppm (DMSO-d6, 400 MHz): 5.98
(s, 2H, CH2), 7.30–7.39 (m, 2H, Ar–H), 7.67 (dd, 2H, Jo ¼ 8.59 Hz,
Jm ¼ 1.95 Hz, Ar–H), 7.74–7.78 (m, 2H, Ar–H), 7.90 (dd, 2H,
Jo ¼ 8.60 Hz, Jm ¼ 1.96 Hz, Ar–H), 8.87 (d, 2H, Jm ¼ 2.35 Hz,
Ar–H), 8.99 (td, 1H, Jm ¼ 2.34 Hz, 1.96 Hz, Ar–H), LC-MS m/z
(ESIþ): 477.8 (MþH) (72%), 479.7 (Mþ2) (28%).
2-[(2-(4-Chlorophenyl)-1H-benzo[d]imidazole-1-yl)-
methyl]-5-(4-methoxy-3-nitrophenyl)-1,3,4-oxadiazole (21)
Yield 16%, m.p.: 1958C, 1H NMR d ppm (CDCl3, 400 MHz): 4.03
(s, 3H, –OCH3), 5.63 (s, 2H, –CH2), 7.21 (d, 1H, Jo ¼ 8.99 Hz, Ar–H),
7.35–7.38 (m, 2H, Ar–H), 7.56–7.59 (m, 2H, Ar–H), 7.82–7.85
(m, 3H, Ar–H), 8.13 (dd, 1H, Jo ¼ 8.99 Hz, Jm ¼ 2.35 Hz,
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
2-Amino/5-Aryl-oxadiazoles Synthesized as Antioxidants
7
1.0 U glucose-6-phosphate dehydrogenase, and 14.2 mM potas- Table 3. Selected bond distances (A), bond angles (8), and torsion
sium phosphate buffer pH 7.8 and 0.2 mg microsomal protein in
a final volume of 1.0 mL.
angles (8) of compound (20)
C11–C11
O1–N6
O2–N6
O3–N5
O4–N5
O5–C15
O5–C16
N1–C1
1.743(3)
1.214(4)
1.231(4)
1.207(4)
1.222(4)
1.359(4)
1.353(3)
1.384(4)
1.387(4)
1.456(4)
1.3048(4)
124.4(3)
118.1(3)
128.4(3)
111.8(3)
123.1(3)
105.5(3)
ꢀ107.1(4)
178.0(3)
N3–C16
N4–C15
N6–C21
N2–C7
N3–N4
N2–C7
C14–C15
C16–C17
C21–C22
1.285(4)
1.295(5)
1.470(4)
1.371(4)
1.410(4)
1.371(4)
1.485(5)
1.461(4)
1.373(4)
1.477(4)
1.471(4)
124.5(3)
117.9(3)
130.0(3)
111.0(2)
117.4(2)
135.0(3)
ꢀ173.9(3)
172.9(3)
EROD enzyme activity
EROD activity was measured by the spectrofluorometric method
of Burke et al. [36]. A typical optimized assay mixture contained
1.0 mM ethoxyresorufin, 10ꢀ3 M test compound, 100 mM Tris–
HCl buffer pH 7.8, NADPH generating system consisting of
0.25 mM NADPþ, 2.5 mM MgCl2, 2.5 mM glucose-6-phosphate,
1.0 U glucose-6-phosphate dehydrogenase, and 14.2 mM potas-
sium phosphate buffer pH 7.8 and 0.2 mg liver microsomal
protein in a final volume of 1.0 mL.
N1–C2
N1–C14
N2–C1
N5–C19
C1–C8
O1–N6–O2
O1–N6–C21
C1–N1–C14
N2–C1–N1
N2–C1–C8
C1–N1–C14–C15
N4–C15–C14–N1
C22–C17–C16–N3
O3–N5–O4
O3–N5–C19
N4–C15–C14
N1–C14–C15
O5–C16–C17
N1–C1–C8–C9
O1–N6–C21–C20
C18–C19–N5–O4
DPPH free radical scavenging activity
The radical scavenging assay was determined by the modified
method described by Blois [37]. BHT and stock solutions of
the compounds were prepared at 10ꢀ2 M in DMSO. A series of
solutions in DMSO were diluted to varying concentrations in 96-
well microplates. Then, methanolic DPPH solution (100 mM) was
added to each well. The plate was shaken and placed in
the dark. After 30 min, the optical density (OD) of the solution
was read at 517 nm. The methanolic solution of DPPH
served as a control. Percentage inhibition was calculated using
the following formula: % Inhibition ¼ (ODcontrol ꢀ ODsample)/
ODcontrol ꢃ 100, where ODcontrol is the absorbance of the control
with DMSO and ODsample is the absorbance of the sample in the
presence of the compounds. A dose–response curve was plotted
to determine the IC50 values. IC50 is defined as the concentration
sufficient to obtain 50% of a maximum scavenging capacity. All
tests and analyses were run in triplicate and averaged. The
standard used in this assay was BHT.
X-ray analysis of compound 20
The intensity reflections were measured by using a STOE IPDS 2
diffractometer using graphite monochromatized MoKa radi-
˚
ation [l ¼ 0.71073 A] and v/2u scan mode to 2u ¼ 528. 4068
reflections were used for refinement on F2. An integration
absorption correction was applied to the data. The structure
was solved by direct methods [38] and subjected to full-matrix
refinement [39]. The refinement was made with anisotropic dis-
placement factors for all non-hydrogen atoms. All hydrogen
atoms were calculated to their idealized positions and refined
as riding atoms. Crystal data and a summary of intensity data
collection and structure refinement are presented in Table 2;
the selected bond lengths, bond angles, and torsion angles are
given in Table 3.
Table 2. Crystal data and details of the structure determination of
(20)
Formula
C22H13ClN6O5
476.83
Monoclinic
P21/c
Formula weight
Crystal system
Space group
Cell constants
˚
a (A)
20.0095(6)
7.8099(3)
13.6096(9)
90
103.565(4)
90
2067.49(15)
4; 1.532
0.236
˚
b (A)
˚
c (A)
a (8)
b (8)
The authors have declared no conflict of interest.
g (8)
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V (A )
˚
Z; Dcalc,(g/cm3)
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