Synthesis and antioxidant activity of bis and tris heterocycles

Article abstract of DOI:10.1002/ardp.201300290

A variety of bis heterocycles, oxazolyl/thiazolyl/imidazolyl oxadiazoles having a styryl sulfonylmethyl group at the 5-position of oxadiazole and tris heterocycles having a pyrrolyl/pyrazolyl sulfonylmethyl group at the 5-position of oxadiazole were prepared adopting simple and versatile synthetic methodologies. All the compounds were screened for their antioxidant activities. Compound 5b displayed radical scavenging activity in all the three methods greater than the standard ascorbic acid, whereas compounds 8b and 14b showed activities equal to the standard ascorbic acid. A variety of bis heterocycles and tris heterocycles were prepared and screened for their antioxidant activities. Compound 5b displayed radical scavenging activity greater than the standard ascorbic acid whereas compounds 8b and 14b showed activities equal to ascorbic acid.

Full text of DOI:10.1002/ardp.201300290

54
Arch. Pharm. Chem. Life Sci. 2014, 347, 54–67
Full Paper
Synthesis and Antioxidant Activity of Bis and Tris Heterocycles
Nabhubygari Mahaboob Basha1, Dandu Seenaiah1, Adivireddy Padmaja1,
Venkatapuram Padmavathi1, Desaraju Suresh Bhargav2, and Tartte Vijaya2
1
Department of Chemistry, Sri Venkateswara University, Tirupati, Andhra Pradesh, India
Department of Botany, Sri Venkateswara University, Tirupati, Andhra Pradesh, India
2
A variety of bis heterocycles, oxazolyl/thiazolyl/imidazolyl oxadiazoles having a styryl sulfonylmethyl
group at the 5-position of oxadiazole and tris heterocycles having a pyrrolyl/pyrazolyl sulfonylmethyl
group at the 5-position of oxadiazole were prepared adopting simple and versatile synthetic
methodologies. All the compounds were screened for their antioxidant activities. Compound 5b
displayed radical scavenging activity in all the three methods greater than the standard ascorbic acid,
whereas compounds 8b and 14b showed activities equal to the standard ascorbic acid.
Keywords: Antioxidant activity / 1,3,4-Oxadiazoles / Pyrazole / Pyrrole
Received: August 6, 2013; Revised: August 31, 2013; Accepted: September 5, 2013
DOI 10.1002/ardp.201300290
Introduction
15–18]. Among fused heterocycles, imidazole based com-
pounds exhibit antibacterial [19, 20], anti-tubercular [21],
antiparasitic [22], and anticancer [23, 24] activities. On the
other hand, five membered heterocycles having three
heteroatoms, viz., 1,3,4-oxadiazole, possess anticancer [25],
antibacterial [26, 27], antifungal [27], anti-inflammatory [28–
30], and antiviral [31] activities. In our earlier studies, we have
identified the compounds having 1,3,4-oxadiazole unit as
excellent antioxidant agents when compared with those
having 1,3,4-thiadiazole and 1,2,4-triazole moieties [32, 33].
Very recently we have synthesized acetamidomethylsulfonyl
linked bis heterocycles-oxazolyl/thiazolyl/imidazolyl 1,3,4-
oxadiazoles having aryl moiety at 5-position of the oxadi-
azoles and studied their antioxidant activity. The oxadiazol-
ylmethylsulfonyloxazolyl-acetamide displayed noticeable
antioxidant activity [34]. The compounds with good antioxi-
dant activity are expected to possess anti-inflammatory
activity [35]. Encouraged by the results and our continued
interest in the development of molecules having potential
pharmacophoric units the present work is taken up.
The widespread applications of heteroarenes in medicinal
chemistry and in materials science have driven the develop-
ment of a new class of heterocyclic cores. Pyrrole and its
derivatives play a major role in drug discovery exhibiting
various biological activities such as antibacterial [1],
antifungal [2], anti-tubercular [1], antidiabetic [3], anti-
inflammatory [4], antiviral [5], and anticancer [6]. Pyrazoles
are significant in the agrochemical and pharmaceutical
industry. They are known for their antitumor [7],
antimicrobial [8], anti-inflammatory [9], antiviral [10], anti-
convulsant, and antidepressant activities [11]. Celecoxib, a
pyrazole derivative, is used successfully as an analgesic in
arthritis [12]. Oxazoles are considered as an important class of
heterocyclic compounds since they are structural subunits of
various biologically active natural products and are valuable
synthetic precursors and pharmaceuticals [13]. Oxazoles are
associated with antibacterial, antifungal, anti-inflammatory,
and antitumor activities and can be used as peptide mimetics
or enzyme inhibitors [14]. Thiazole derivatives are well known
common motifs in medicinal chemistry due to their broad
application in drug development as antiviral, anticancer,
antibacterial, antifungal, and anti-inflammatory agents [10,
Results and discussion
Chemistry
The reaction sequence to achieve the molecules in the present
study is depicted in Scheme 1. The synthetic intermediates 2-
((4-aryloxazol-2-ylcarbamoyl)methylsulfonyl)acetohydrazide
(1), 2-((4-arylthiazol-2-ylcarbamoyl)methylsulfonyl)aceto-
hydrazide (2), and 2-((4-aryl-1H-imidazol-2-ylcarbamoyl)-
Correspondence: Venkatapuram Padmavathi, Department of Chemistry,
Sri Venkateswara University, Tirupati 517 502, Andhra Pradesh, India.
E-mail: vkpuram2001@yahoo.com
Fax: þ91 877 2249532
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2014, 347, 54–67
Synthesis and Antioxidant Activity of Bis and Tris Heterocycles
55
Ar
O
O
O
O
O
Ph
N
S
O
O
OH
S
NH2
+
N
H
N
H
X
HA
HB
1 / 2 / 3
4
i
Ar
O
N N
N
3'
4'
O
O
O
O
4
5
3
2
Ph
2'
5'
S
S
1'
1
N
O
X
H
HA
HB
5 / 6 / 7
iii
ii
Ar
Ar
O
O
N N
N N
O
HA
Ph
HM
HX
N
N
O
O
O
O
O
O
O
O
Ph
S
S
S
S
N
N
H
O
3"
4"
3" 4"
2" 5"
X
X
H
2"
5"
1"
N
1"
N
N
H
H
11 / 12 / 13
8 / 9 / 10
iv
Ar
O
N N
N
O
O
O
O
Ph
S
S
N
O
X
H
N
N
H
(i) POCl3
14 / 15 / 16
(ii) TosMIC / NaH / DMSO / Et2O
(iii) CH2N2 / Et3N / Et2O
(iv) Chloranil / Xylene
X = O / S / NH
Ar = a) Ph
b) 4-Me.Ph
c) 4-Cl.Ph
Scheme 1. Synthesis of bis and tris heterocycles.
methylsulfonyl)acetohydrazide (3) were prepared as per
the literature procedure [34]. The reaction of with
NMR spectra of 5a, 6a, and 7a produced three singlet signals
at d 4.37, 4.32, 4.44; 4.69, 4.62, 4.64; and 4.95, 4.92, 4.94 ppm
due to methylene protons attached to C-20, C-50, and those
present between carbonyl and sulfonyl groups. The olefin
proton, HB, displayed a doublet at d 6.71 in 5a, at 6.59 in 6a,
and at 6.75 ppm in 7a, while the other proton, HA, exhibited
signals in a more downfield region and merged with aromatic
protons. The coupling constant value J ꢀ 9.7 Hz indicated
that they are in cis geometry.
1
styrylsulfonylacetic acid (4) gave 2-((50-((styrylsulfonyl)-
methyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-(4-aryloxazol-
2-yl)acetamide (5). Similarly the cyclocondensation of 2 and
3 with 4 furnished 2-((50-((styrylsulfonyl)methyl)-10,30,40-oxa-
diazol-20-yl)methylsulfonyl)-N-(4-arylthiazol-2-yl)acetamide (6),
and 2-((50-((styrylsulfonyl)methyl)-10,30,40-oxadiazol-20-yl)meth-
ylsulfonyl)-N-(4-aryl-1H-imidazol-2-yl)acetamide (7). The 1H
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

56
N. Mahaboob Basha et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 54–67
The 1,3 dipolar cycloaddition of tosylmethyl isocyanide in
phenyl-100H-pyrazol-300-ylsulfonyl)methyl)-10,30,40-oxadiazol-
20-yl)methylsulfonyl)-N-(4-aryloxazol-2-yl)acetamide (14), 2-((50-
((400-phenyl-100H-pyrazol-300-ylsulfonyl)methyl)-10,30,40-oxadiazol-
20-yl)methylsulfonyl)-N-(4-arylthiazol-2-yl)-acetamide (15), and
2-((50-((400-phenyl-100H-pyrazol-300-ylsulfonyl)methyl)-10,30,40-oxa-
diazol-20-yl)methylsulfonyl)-N-(4-aryl-1H-imidazol-2-yl)acetamide
(16). The absence of an AMX splitting pattern due to pyrazoline
ring protons in 14, 15, and 16 indicated that aromatization took
place. The multiplets observed in the regions d 7.31–8.18 in 14a,
and 7.28–8.04 ppm in 16a were accounted for C5-H, C500-H, and
aromatic protons. However, in 15a, the multiplet present in the
region d 7.33–8.10 was attributed to C500-H and Ar–H and the
singlet at 6.58ppm was assigned to C5-H. The structures of all
the compounds were further established by IR and 13C NMR
spectral data.
the presence of NaH and in a solvent mixture of Et2O and
DMSO to compound 5 gave 2-((50-((40-phenyl-100H-pyrrol-300-
ylsulfonyl)methyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-(4-
aryloxazol-2-yl)acetamide (8). Adopting similar methodology,
2-((50-((400-phenyl-100H-pyrrol-300-ylsulfonyl)methyl)-10,30,40-oxa-
diazol-20-yl)methylsulfonyl)-N-(4-arylthiazol-2-yl)acetamide (9)
and 2-((50-((400-phenyl-100H-pyrrol-300-ylsulfonyl)methyl)-10,30,40-
oxadiazol-20-yl)methylsulfonyl)-N-(4-aryl-1H-imidazol-2-yl)acet-
amide (10) were prepared from 6 and 7, respectively. In the 1H
NMR spectra of 8a, 9a, and 10a, the presence of a singlet at d
6.51, 6.48, and 6.49 corresponding to C500-H of pyrrole ring
00
confirmed their formation. The other proton C2 -H displayed
signal in slightly downfield region and merged with aromatic
protons. On the other hand, the cycloaddition of diazo-
methane to 5, 6, and 7 at ꢁ15 to ꢁ20°C for 42–46 h yielded 2-
((50-((400,500-dihydro-400-phenyl-100H-pyrazol-300-ylsulfonyl)meth-
yl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-(4-aryloxazol-2-yl)-
acetamide (11), 2-((50-((400,500-dihydro-400-phenyl-100H-pyrazol-300-
ylsulfonyl)methyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-
(4-arylthiazol-2-yl)acetamide (12), and 2-((50-((400,500-dihydro-400-
phenyl-100H-pyrazol-300-ylsulfonyl)methyl)-10,30,40-oxadiazol-
20-yl)methylsulfonyl)-N-(4-aryl-1H-imidazol-2-yl)acetamide (13).
The pyrazoline ring protons in 11a, 12a, and 13a displayed an
AMX splitting pattern. The double doublets observed at d 4.54,
4.10, 3.63 in 11a, at 4.61, 4.25, 3.55 in 12a, and at 4.56, 4.19,
3.60 ppm in 13a were assigned to HA, HM, and HX, respectively.
The coupling constant values JAM ꢀ 12.2, JMX ꢀ 10.5, and
JAX ꢀ 6.4 Hz indicated that HA, HM, are cis, HA, HX are trans and
HM, HX are geminal. Aromatization of the compounds 11, 12,
and 13 with chloranil gave the aromatized products 2-((50-((400-
Biological results
Antioxidant activity
The compounds 5–16 were tested for antioxidant activity by
2,2,-diphenyl-1-picrylhydrazyl (DPPH) [36, 37], nitric oxide
(NO) [38, 39], and 2,20-azino-bis(3-ethylbenzthiazoline-6-sul-
fonic acid) (ABTS) [40] methods. The results are presented in
Tables 1–3 and Figs. 1–3. The bis heterocyclic systems having
styryl sulfonyl moiety 5, 6, and 7 exhibited more activity than
the respective tris heterocyclic compounds 8–16. This may be
due to the presence of more electron withdrawing styrylsul-
fonyl group at 5-position of 1,3,4-oxadiazole. In fact, 2-((50-
((styrylsulfonyl)methyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-
N-(4-p-tolyloxazol-2-yl)-acetamide (5b) showed excellent antiox-
idant activity greater than the standard ascorbic acid. Among
tris heterocyclic systems, 2-((50-((400-phenyl-100H-pyrrol-300-
95
5a
5b
90
5c
6a
6b
7a
6c
7b
85
80
75
70
65
60
55
50
45
40
7c
8b
9a
9c
10b
11a
11c
12b
13a
13c
14b
15a
15c
16b
8a
8c
9b
10a
10c
11b
12a
12c
13b
14a
14c
15b
16a
16c
50μg/mL
75μg/mL
100μg/mL
Ascorbic acid
Concentration (μg/mL)
Figure 1. The in vitro antioxidant activity of
5–16 in DPPH method.
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2014, 347, 54–67
Synthesis and Antioxidant Activity of Bis and Tris Heterocycles
57
95
90
85
80
75
70
65
60
55
50
45
40
5a
5c
6b
7a
7c
8b
9a
9c
10b
11a
11c
12b
13a
13c
14b
15a
5b
6a
6c
7b
8a
8c
9b
10a
10c
11b
12a
12c
13b
14a
14c
15b
16a
16c
15c
16b
Ascorbic acid
50μg/mL
75μg/mL
100μg/mL
Concentration (μg/mL)
Figure 2. The in vitro antioxidant activity of
5–16 in NO method.
40
35
30
25
20
15
10
5
5a
5c
6b
7a
7c
8b
9a
9c
10b
11a
11c
12b
13a
13c
14b
15a
5b
6a
6c
7b
8a
8c
9b
10a
10c
11b
12a
12c
13b
14a
14c
15b
16a
16c
15c
16b
50μg/mL
75μg/mL
100μg/mL
Ascorbic acid
Concentration (μg/mL)
Figure 3. The in vitro antioxidant activity of
5–16 in ABTS method.
ylsulfonyl)methyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-(4-
p-tolyloxazol-2-yl)acetamide (8b) and 2-((50-((400-phenyl-100H-pyr-
azol-300-ylsulfonyl)methyl)-10,30,40-oxadiazol-20-yl)methylsul-
fonyl)-N-(4-p-tolyloxazol-2-yl)acetamide (14b) displayed radical
scavenging activity almost equal to the standard ascorbic
acid. The compounds 2-((50-((400-phenyl-100H-pyrrol-300-ylsulfonyl)
methyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-(4-p-tolylthia-
zol-2-yl)acetamide (9b) and 2-((50-((400-phenyl-100H-pyrazol-300-
ylsulfonyl)methyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-(4-
p-tolyloxazol-2-yl)acetamide (15b) exhibited good activity.
On the other hand, the compounds 7, 10, 11, and 16
displayed least activity whereas the compounds 12 and 13
showed no activity. Thus the results exemplified that
aromatized heterocycles showed greater activity than non-
aromatized compounds. It was also observed that there was
no marked difference in activity between the compounds
having pyrrole and pyrazole moieties. The presence of methyl
substituent on the aromatic ring enhanced the activity, which
may be due to þI effect of methyl group. Furthermore the
compounds having more oxygen atoms displayed more
activity. This was evidenced by the fact that oxazolyl
oxadiazoles 5, 8, and 14 showed activity greater than the
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

58
N. Mahaboob Basha et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 54–67
Table 1. The in vitro antioxidant activity of 5–16 in DPPH method.
Concentration
Compound
50 mg/mL
75 mg/mL
100 mg/mL
IC50 mmol/mL
5a
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
8c
9a
9b
9c
72.25 ꢂ 0.54
79.36 ꢂ 1.02
60.35 ꢂ 1.34
65.54 ꢂ 0.98
73.64 ꢂ 1.32
59.71 ꢂ 0.84
52.37 ꢂ 0.67
58.34 ꢂ 1.11
45.33 ꢂ 1.46
69.35 ꢂ 0.85
76.12 ꢂ 1.57
56.45 ꢂ 1.72
59.76 ꢂ 0.33
70.31 ꢂ 0.42
47.33 ꢂ 0.65
–
73.79 ꢂ 1.12
82.44 ꢂ 0.33
62.47 ꢂ 1.09
66.79 ꢂ 1.23
75.58 ꢂ 0.88
60.96 ꢂ 0.62
53.84 ꢂ 1.13
59.79 ꢂ 1.56
46.91 ꢂ 1.05
70.58 ꢂ 0.55
78.98 ꢂ 0.43
58.04 ꢂ 0.18
61.35 ꢂ 1.67
71.47 ꢂ 1.71
49.54 ꢂ 1.44
–
75.64 ꢂ 0.62
86.57 ꢂ 0.45
63.98 ꢂ 0.14
68.32 ꢂ 0.52
76.95 ꢂ 1.17
62.07 ꢂ 1.44
55.52 ꢂ 0.94
61.36 ꢂ 0.36
48.04 ꢂ 0.84
72.37 ꢂ 1.62
82.34 ꢂ 1.06
59.94 ꢂ 1.14
63.74 ꢂ 1.32
72.89 ꢂ 0.98
50.98 ꢂ 0.72
–
0.065 ꢂ 0.36
0.058 ꢂ 0.18
0.073 ꢂ 0.72
0.070 ꢂ 0.64
0.060 ꢂ 1.02
0.072 ꢂ 0.28
0.090 ꢂ 0.44
0.079 ꢂ 1.16
0.098 ꢂ 0.82
0.063 ꢂ 0.52
0.056 ꢂ 0.48
0.073 ꢂ 1.37
0.071 ꢂ 1.24
0.059 ꢂ 0.98
0.085 ꢂ 0.25
–
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
14a
14b
14c
15a
15b
15c
16a
16b
16c
Ascorbic acid
Blank
45.32 ꢂ 1.28
–
47.04 ꢂ 0.90
–
48.79 ꢂ 1.41
–
0.094 ꢂ 1.12
–
–
–
–
–
37.45 ꢂ 1.02
–
38.59 ꢂ 0.65
–
40.05 ꢂ 1.52
–
0.114 ꢂ 0.86
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
71.35 ꢂ 0.66
77.09 ꢂ 1.15
58.37 ꢂ 1.55
60.49 ꢂ 0.97
72.62 ꢂ 0.51
52.45 ꢂ 0.14
–
72.58 ꢂ 1.03
80.34 ꢂ 0.92
60.15 ꢂ 0.29
62.73 ꢂ 0.18
73.95 ꢂ 0.94
53.79 ꢂ 1.16
–
73.96 ꢂ 0.66
83.05 ꢂ 1.11
61.94 ꢂ 0.48
64.85 ꢂ 1.34
75.04 ꢂ 1.66
55.24 ꢂ 0.87
–
0.061 ꢂ 0.56
0.055 ꢂ 0.37
0.071 ꢂ 0.48
0.070 ꢂ 1.33
0.057 ꢂ 1.45
0.076 ꢂ 0.49
–
45.97 ꢂ 0.67
–
47.85 ꢂ 1.32
–
49.34 ꢂ 0.39
–
0.093 ꢂ 0.72
–
77.15 ꢂ 0.32
–
80.98 ꢂ 1.44
–
83.82 ꢂ 0.92
–
0.183 ꢂ 0.56
–
(–) Showed no scavenging activity.
Values were the means of three replicates ꢂ SD.
respective thiazolyl oxadiazoles 6, 9, and 15 and imidazolyl
oxadiazoles 7, 10, and 16. In our communication, we have
reported that oxazolyloxadiazole having 2-chlorophenyl
results indicated that the antioxidant activity is independent
of time.
group at 5-position of oxadiazole displayed good antioxidant Conclusion
activity [34]. The replacement of 2-chlorophenyl moiety with
styrylsulfonylmethyl, pyrrolylsulfonylmethyl and pyrazolyl-
sulfonylmethyl units increases the antioxidant activity. The
free radical scavenging activity of the compounds 5a, 5b, 6b,
8b, 9b, 14a, 14b, and 15b was measured at different
concentrations and monitored the change in absorbance at
10, 20, and 30 min in DPPH method as shown in Table 4. At
these 10 min intervals, the values are very close and the
A variety of bis heterocycles, oxazolyl/thiazolyl/imidazolyl
oxadiazoles having styryl sulfonylmethyl group at 5-position
of oxadiazole and tris heterocycles having pyrrolyl/pyrazolyl
sulfonylmethyl group at 5-position of oxadiazole were
prepared adopting simple and versatile synthetic methodolo-
gies. All the compounds were screened for their antioxidant
activity. The compound 5b displayed radical scavenging
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2014, 347, 54–67
Synthesis and Antioxidant Activity of Bis and Tris Heterocycles
59
Table 2. The in vitro antioxidant activity of 5–16 in NO method.
Concentration
Compound
50 mg/mL
75 mg/mL
100 mg/mL
5a
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
8c
9a
9b
9c
78.56 ꢂ 0.76
84.12 ꢂ 0.28
65.42 ꢂ 0.16
68.57 ꢂ 1.32
76.32 ꢂ 0.84
62.61 ꢂ 0.18
58.43 ꢂ 1.62
60.72 ꢂ 1.12
51.92 ꢂ 0.76
72.16 ꢂ 0.58
79.43 ꢂ 0.23
60.48 ꢂ 1.18
62.93 ꢂ 0.66
74.19 ꢂ 1.34
53.68 ꢂ 0.98
–
79.43 ꢂ 1.52
86.28 ꢂ 1.08
66.74 ꢂ 1.24
70.03 ꢂ 1.16
77.68 ꢂ 0.28
64.94 ꢂ 1.33
60.26 ꢂ 1.02
61.58 ꢂ 1.64
53.72 ꢂ 1.45
73.52 ꢂ 0.81
82.76 ꢂ 0.38
62.27 ꢂ 0.73
64.02 ꢂ 1.11
75.56 ꢂ 1.06
54.82 ꢂ 0.66
–
81.34 ꢂ 0.17
88.64 ꢂ 0.42
70.08 ꢂ 0.95
74.15 ꢂ 0.39
79.04 ꢂ 0.67
66.28 ꢂ 1.12
62.09 ꢂ 0.33
62.64 ꢂ 0.69
54.22 ꢂ 0.28
75.04 ꢂ 1.66
84.69 ꢂ 1.54
63.12 ꢂ 1.18
65.71 ꢂ 1.68
77.01 ꢂ 0.24
56.33 ꢂ 1.45
–
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
14a
14b
14c
15a
15b
15c
16a
16b
16c
Ascorbic acid
Blank
49.53 ꢂ 1.22
–
51.75 ꢂ 0.24
–
53.84 ꢂ 1.03
–
–
–
–
42.11 ꢂ 0.78
–
43.82 ꢂ 0.38
–
45.48 ꢂ 0.86
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
74.37 ꢂ 1.04
79.18 ꢂ 1.38
63.27 ꢂ 1.78
67.42 ꢂ 0.86
73.94 ꢂ 1.02
58.19 ꢂ 0.72
–
75.92 ꢂ 0.92
82.64 ꢂ 0.74
65.02 ꢂ 1.16
68.71 ꢂ 1.04
75.62 ꢂ 0.63
60.29 ꢂ 0.32
–
77.06 ꢂ 0.19
84.25 ꢂ 0.44
66.53 ꢂ 0.56
69.44 ꢂ 0.22
77.68 ꢂ 1.06
61.82 ꢂ 1.62
–
50.34 ꢂ 0.55
–
52.13 ꢂ 1.34
–
55.07 ꢂ 0.94
–
79.02 ꢂ 0.48
–
82.46 ꢂ 0.88
–
84.53 ꢂ 0.52
–
(–) Showed no scavenging activity.
Values were the means of three replicates ꢂ SD.
activity in all the three methods greater than the standard
ascorbic acid, whereas the compounds 8b and 14b showed
activity equal to the standard ascorbic acid.
numbers were given in cmꢁ1. The 1H NMR spectra were recorded
in DMSO-d6 on a Bruker-400 spectrometer (400 MHz). The 13C NMR
spectra were recorded in DMSO-d6 on a Bruker spectrometer
operating at 100 MHz. All chemical shifts are reported in d (ppm)
using TMS as an internal standard. The mass spectra were
recorded on Jeol JMS-D 300 and Finnigan Mat 1210 B at 70 eV
with an emission current of 100 mA. The microanalyses were
performed on a Perkin-Elmer 240C elemental analyzer. The
antioxidant property was assessed by using Shimadzu UV-2450
spectrophotometer. The synthetic intermediates 2-((4-aryloxazol-
2-ylcarbamoyl)methylsulfonyl)acetohydrazide (1), 2-((4-arylthia-
zol-2-ylcarbamoyl)methylsulfonyl)acetohydrazide (2), and 2-((4-
aryl-1H-imidazol-2-ylcarbamoyl)methylsulfonyl) acetohydrazide
(3) were prepared as per the literature procedure [29].
Experimental
Chemistry
Melting points were determined in open capillaries on a Mel-
Temp apparatus and are uncorrected. The purity of the
compounds was checked by TLC (silica gel H, BDH, ethyl
acetate/hexane, 1:3). The IR spectra were recorded on a Thermo
Nicolet IR 200 FT-IR spectrometer as KBr pellets and the wave
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

60
N. Mahaboob Basha et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 54–67
Table 3. The in vitro antioxidant activity of 5–16 in ABTS method.
Concentration
Compound
50 mg/mL
75 mg/mL
100 mg/mL
5a
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
8c
9a
9b
9c
24.35 ꢂ 0.44
26.83 ꢂ 0.97
20.65 ꢂ 1.04
22.73 ꢂ 0.53
24.51 ꢂ 0.28
18.77 ꢂ 1.36
16.24 ꢂ 0.48
18.82 ꢂ 0.22
14.06 ꢂ 0.56
19.33 ꢂ 1.39
23.86 ꢂ 0.87
15.91 ꢂ 0.45
18.04 ꢂ 0.68
20.66 ꢂ 1.23
16.41 ꢂ 1.08
–
25.03 ꢂ 0.92
27.91 ꢂ 1.53
22.38 ꢂ 0.68
23.46 ꢂ 0.82
25.05 ꢂ 0.67
20.02 ꢂ 0.46
17.38 ꢂ 1.04
19.65 ꢂ 1.77
15.23 ꢂ 0.91
21.17 ꢂ 0.55
24.64 ꢂ 0.24
16.75 ꢂ 0.86
19.14 ꢂ 1.18
21.32 ꢂ 0.23
17.28 ꢂ 0.63
–
26.54 ꢂ 1.32
29.10 ꢂ 0.41
23.18 ꢂ 0.35
24.82 ꢂ 1.15
26.11 ꢂ 1.02
21.63 ꢂ 0.76
19.47 ꢂ 0.26
20.40 ꢂ 0.92
16.15 ꢂ 0.17
22.09 ꢂ 0.68
25.42 ꢂ 1.04
17.49 ꢂ 1.44
21.00 ꢂ 0.16
23.14 ꢂ 0.98
18.05 ꢂ 0.33
–
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
14a
14b
14c
15a
15b
15c
16a
16b
16c
Ascorbic acid
Blank
15.02 ꢂ 0.78
–
16.37 ꢂ 1.47
–
17.41 ꢂ 0.15
–
–
–
–
14.69 ꢂ 0.92
–
15.53 ꢂ 0.26
–
16.31 ꢂ 1.27
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
20.34 ꢂ 0.63
23.12 ꢂ 0.29
16.52 ꢂ 1.12
18.45 ꢂ 0.84
21.02 ꢂ 0.71
15.23 ꢂ 0.32
–
22.18 ꢂ 1.18
24.82 ꢂ 1.47
17.25 ꢂ 0.22
19.04 ꢂ 0.16
22.14 ꢂ 0.86
16.48 ꢂ 0.57
–
23.76 ꢂ 0.27
25.38 ꢂ 0.92
18.63 ꢂ 0.83
21.15 ꢂ 0.75
23.43 ꢂ 1.08
17.06 ꢂ 1.21
–
14.78 ꢂ 0.96
–
15.42 ꢂ 0.33
–
16.12 ꢂ 1.36
–
23.80 ꢂ 0.38
–
24.20 ꢂ 0.46
–
25.70 ꢂ 0.28
–
(–) Showed no scavenging activity.
Values were the means of three replicates ꢂ SD.
General procedure for the synthesis of 2-((5 0-
ate solution and then with water, dried, and recrystallized from
2-propanol.
((styrylsulfonyl)methyl)-1 0,3 0,4 0-oxadiazol-20-yl)-
methylsulfonyl)-N-(4-aryloxazol-2-yl)acetamide (5a–c)/2-
((5 0-((styrylsulfonyl)-methyl)-1 0,3 0,4 0-oxadiazol-2 0-yl)-
methylsulfonyl)-N-(4-arylthiazol-2-yl)acetamide (6a–c)/2-
((5 0-((styrylsulfonyl)methyl)-1 0,3 0,4 0-oxadiazol-20-yl)-
2-((5 0-((Styrylsulfonyl)methyl)-1 0,3 0,4 0-oxadiazol-20-yl)-
methylsulfonyl)-N-(4-phenyloxazol-2-yl)acetamide
(5a):
White solid in 68%; m.p.: 135–137°C; IR (KBr) nmax (cmꢁ1):
–
–
1122, 1322 (SO ), 1565 (C N), 1616 (C C), 1668 (NHCO), 3246 (NH);
–
–
2
1H NMR (DMSO-d6) d (ppm): 4.37 (s, 2H, CH2-(C-2 0)), 4.69 (s, 2H, CH2-
(C-5 0)), 4.95 (s, 2H, CO–CH2), 6.71 (d, 1H, HB, J ¼ 9.7 Hz), 7.28–7.53
(m, 12H, Ar–H, C5-H, and HA), 11.22 (bs, 1H, NH–CO); 13C NMR
methylsulfonyl)-N-(4-aryl-1H-imidazol-2-yl)acetamide (7a–c)
A mixture of 1/2/3 (10 mmol), Z-styrylsulfonylacetic acid (4)
(10 mmol), and POCl3 (7 mL) was heated under reflux for 7–9 h.
The excess POCl3 was removed under reduced pressure and
the residue was poured onto crushed ice. The resulting
precipitate was filtered, washed with saturated sodium bicarbon-
(DMSO-d6)
d
(ppm): 46.9 (CH2-(C-2 0)), 50.2 (CH2-(C-5 0)), 54.1
(CO–CH2), 111.6 (C-HB), 127.2 (C-HA), 137.4 (C-5), 140.8 (C-4),
148.0 (C-2), 158.7 (C-2 0), 165.7 (C-5 0), 168.7 (CO), 125.9, 127.0,
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2014, 347, 54–67
Synthesis and Antioxidant Activity of Bis and Tris Heterocycles
61
Table 4. Antioxidant activity of the compounds 5a, 5b, 6b, 8b, 9b, 14a, 14b, and 15b at 10 min.
Compound
10 min
20 min
30 min
5a
5b
6b
8b
72.17
79.34
73.42
76.05
70.14
70.98
77.07
72.05
72.35
79.65
73.57
76.34
70.25
71.16
77.45
72.34
72.94
79.88
73.88
76.59
70.46
71.32
77.82
72.58
9b
14a
14b
15b
Time intervals by DPPH scavenging method.
128.2, 130.5, 131.7, 132.6, 134.2, 136.7 (aromatic carbons);
MS (m/z): 528.57 [Mþ]. Anal. calcd. for C23H20N4O7S2: C 52.26,
H 3.81, N 10.60; Found: C 52.38, H 3.84, N 10.76%.
(m/z): 544.64 [Mþ]. Anal. calcd. for C23H20N4O6S3: C 50.72, H 3.70,
N 10.29; Found: C 50.67, H 3.69, N 10.41%.
2-((5 0-((Styrylsulfonyl)methyl)-1 0,3 0,4 0-oxadiazol-20-yl)-
2-((5 0-((Styrylsulfonyl)methyl)-1 0,3 0,4 0-oxadiazol-20-yl)-
methylsulfonyl)-N-(4-p-tolylthiazol-2-yl)acetamide
(6b):
White solid in 67%; m.p.: 154–156°C; IR (KBr) nmax (cmꢁ1):
methylsulfonyl)-N-(4-p-tolyloxazol-2-yl)acetamide
(5b):
White solid in 66%; m.p.: 126–128°C; IR (KBr) nmax (cmꢁ1):
–
–
–
1123, 1315 (SO ), 1572 (C N), 1618 (C C), 1674 (NHCO), 3245 (NH);
–
2
1H NMR (DMSO-d6) d (ppm): 2.34 (s, 3H, Ar–CH3), 4.30 (s, 2H, CH2-(C-
2 0)), 4.60 (s, 2H, CH2-(C-5 0)), 4.90 (s, 2H, CO–CH2), 6.44 (d, 1H, HB,
J ¼ 9.6 Hz), 6.54 (s, 1H, C5-H), 7.19–7.42 (m, 10H, Ar–H, and HA),
10.84 (bs, 1H, NH–CO); 13C NMR (DMSO-d6) d (ppm): 23.4 (Ar–CH3),
46.2 (CH2-(C-2 0)), 49.7 (CH2-(C-5 0)), 53.2 (CO–CH2), 102.5 (C-5), 109.8
(C-HB), 126.2 (C-HA), 146.5 (C-4), 154.2 (C-2 0), 162.5 (C-2), 166.5 (C-
5 0), 168.5 (CO), 128.4, 130.0, 131.3, 132.8, 134.7, 135.3, 137.1,
138.3 (aromatic carbons); MS (m/z): 558.66 [Mþ]. Anal. calcd. for
–
–
–
1120, 1316 (SO ), 1562 (C N), 1610 (C C), 1664 (NHCO), 3242 (NH);
–
2
1H NMR (DMSO-d6) d (ppm): 2.37 (s, 3H, Ar–CH3), 4.33 (s, 2H, CH2-(C-
2 0)), 4.64 (s, 2H, CH2-(C-5 0)), 4.92 (s, 2H, CO–CH2), 6.69 (d, 1H, HB,
J ¼ 9.1 Hz), 7.20–7.35 (m, 11H, Ar–H, C5-H, and HA), 10.82 (bs, 1H,
NH–CO); 13C NMR (DMSO-d6) d (ppm): 24.6 (Ar–CH3), 46.7 (CH2-(C-
2 0)), 49.4 (CH2-(C-5 0)), 53.8 (CO–CH2), 109.5 (C-HB), 126.6 (C-HA),
136.8 (C-5), 139.4 (C-4), 147.5 (C-2), 157.2 (C-2 0), 164.8 (C-5 0), 168.4
(CO), 128.3, 129.1, 129.8, 131.5, 132.2, 134.8, 135.6, 137.3
(aromatic carbons); MS (m/z): 542.59 [Mþ]. Anal. calcd. for
C24H22N4O7S2: C 53.13, H 4.09, N 10.33; Found: C 53.21,
H 4.08, N 10.46%.
C24H22N4O6S3: C 51.60, H 3.97, N 10.03; Found: C 51.67, H 4.00,
N 10.13%.
2-((5 0-((Styrylsulfonyl)methyl)-1 0,3 0,4 0-oxadiazol-20-yl)-
methylsulfonyl)-N-(4-(4-chloro-phenyl)thiazol-2-yl)acet-
amide (6c): White solid in 70%; m.p.: 173–175°C; IR (KBr) nmax
2-((5 0-((Styrylsulfonyl)methyl)-1 0,3 0,4 0-oxadiazol-20-yl)-
methylsulfonyl)-N-(4-(4-chloro-phenyl)oxazol-2-yl)acet-
amide (5c): White solid in 72%; m.p.: 152–154°C; IR (KBr) nmax
(cmꢁ1): 1132, 1323 (SO ), 1587 (C N), 1615 (C C), 1679 (NHCO),
–
–
–
–
2
1
(cmꢁ1): 1127, 1324 (SO ), 1575 (C N), 1622 (C C), 1672 (NHCO),
–
–
–
–
3262 (NH); H NMR (DMSO-d6) d (ppm): 4.35 (s, 2H, CH2-(C-2 0)),
4.66 (s, 2H, CH2-(C-5 0)), 4.95 (s, 2H, CO–CH2), 6.57 (s, 1H, C5-H),
6.85 (d, 1H, HB, J ¼ 9.9 Hz), 7.28–7.47 (m, 10H, Ar–H, and HA),
10.95 (bs, 1H, NH–CO); 13C NMR (DMSO-d6) d (ppm): 46.8 (CH2-
(C-2 0)), 50.3 (CH2-(C-5 0)), 53.8 (CO-CH2), 104.4 (C-5), 111.2 (C-HB),
127.5 (C-HA), 147.2 (C-4), 155.6 (C-2 0), 163.0 (C-2), 164.8 (C-5 0), 169.2
(CO), 127.6, 128.2, 129.6, 130.4, 131.3, 132.2, 132.3, 135.4
(aromatic carbons); MS (m/z): 579.08 [Mþ]. Anal. calcd. for
C23H19ClN4O6S3: C 47.70, H 3.31, N 9.68; Found: C 47.79,
H 3.36, N 9.84%.
2
3257 (NH); 1H NMR (DMSO-d6) d (ppm): 4.39 (s, 2H, CH2-(C-2 0)), 4.72
(s, 2H, CH2-(C-5 0)), 4.98 (s, 2H, CO–CH2), 6.76 (d, 1H, HB, J ¼ 9.8 Hz),
7.23–7.62 (m, 11H, Ar–H, C5-H, and HA), 11.27 (bs, 1H, NH–CO); 13
C
NMR (DMSO-d6) d (ppm): 47.5 (CH2-(C-2 0)), 50.8 (CH2-(C-5 0)), 54.7
(CO–CH2), 111.8 (C-HB), 127.8 (C-HA), 137.6 (C-5), 141.6 (C-4), 148.3
(C-2), 158.2 (C-2 0), 166.7 (C-5 0), 169.8 (CO), 127.5, 128.4, 129.5,
131.4, 132.6, 133.8, 135.2, 137.8 (aromatic carbons); MS (m/z):
563.01 [Mþ]. Anal. calcd. for C23H19ClN4O7S2: C 49.07, H 3.04,
N 9.95; Found: C 49.17, H 3.44, N 10.09%.
2-((5 0-((Styrylsulfonyl)methyl)-1 0,3 0,4 0-oxadiazol-20-yl)-
methylsulfonyl)-N-(4-phenyl-1H-imidazol-2-yl)acetamide
(7a): White solid in 69%; m.p.: 140–142°C; IR (KBr) nmax (cmꢁ1):
2-((5 0-((Styrylsulfonyl)methyl)-1 0,3 0,4 0-oxadiazol-20-yl)-
methylsulfonyl)-N-(4-phenylthiazol-2-yl)acetamide
(6a):
White solid in 65%; m.p.: 147–149°C; IR (KBr) nmax (cmꢁ1):
–
–
–
1128, 1320 (SO ), 1570 (C N), 1626 (C C), 1657 (NHCO), 3249 (NH);
–
2
–
1126, 1318 (SO ), 1578 (C N), 1624 (C C), 1667 (NHCO), 3248 (NH);
–
–
–
2
1H NMR (DMSO-d6) d (ppm): 4.32 (s, 2H, CH2-(C-2 0)), 4.62 (s, 2H, CH2-
(C-5 0)), 4.92 (s, 2H, CO–CH2), 6.56 (s, 1H, C5-H), 6.59 (d, 1H, HB,
J ¼ 9.7 Hz), 7.23–7.54 (m, 11H, Ar–H, and HA), 10.92 (bs, 1H,
NH–CO); 13C NMR (DMSO-d6) d (ppm): 46.6 (CH2-(C-2 0)), 50.4 (CH2-(C-
5 0)), 53.6 (CO–CH2), 103.4 (C-5), 111.4 (C-HB), 126.4 (C-HA), 147.3 (C-
4), 156.4 (C-2 0), 162.9 (C-2), 164.7 (C-5 0), 168.9 (CO), 127.6, 128.1,
130.3, 132.7, 134.5, 136.0, 137.9, 139.5 (aromatic carbons); MS
1H NMR (DMSO-d6) d (ppm): 4.44 (s, 2H, CH2-(C-2 0)), 4.64 (s, 2H, CH2-
(C-5 0)), 4.94 (s, 2H, CO–CH2), 6.75 (d, 1H, HB, J ¼ 9.3 Hz), 7.22–7.51
(m, 12H, Ar–H, C5-H, and HA), 10.98 (bs, 1H, NH–CO), 12.47 (bs, 1H,
NH); 13C NMR (DMSO-d6) d (ppm): 46.5 (CH2-(C-2 0)), 50.1 (CH2-(C-5 0)),
54.5 (CO–CH2), 111.0 (C-HB), 119.5 (C-5), 126.8 (C-HA), 136.3 (C-2),
143.4 (C-4), 154.8 (C-2 0), 165.5 (C-5 0), 169.9 (CO), 126.5, 128.1,
129.6, 130.0, 132.5, 134.9, 136.3, 137.6 (aromatic carbons); MS
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

62
N. Mahaboob Basha et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 54–67
(m/z): 527.58 [Mþ]. Anal. calcd. for C23H21N5O6S2: C 52.36, H 4.01, N
13.27; Found: C 52.41, H 4.02, N 13.42%.
(C-500), 118.0 (C-200), 127.0 (C-400), 137.4 (C-5), 140.8 (C-4), 150.2 (C-2),
158.7 (C-2 0), 165.7 (C-5 0), 170.4 (CO), 127.3, 128.1, 128.9, 129.2,
131.2, 132.4, 134.7, 135.6 (aromatic carbons); MS (m/z): 567.61
[Mþ]. Anal. calcd. for C25H21N5O7S2: C 52.90, H 3.73, N 12.34;
Found: C 52.94, H 3.75, N 12.43%.
2-((5 0-((Styrylsulfonyl)methyl)-1 0,3 0,4 0-oxadiazol-20-yl)-
methylsulfonyl)-N-(4-p-tolyl-1H-imidazol-2-yl)acetamide
(7b): White solid in 72%; m.p.: 135–137°C; IR (KBr) nmax (cmꢁ1):
2-((5 0-((400-Phenyl-100H-pyrrol-300-ylsulfonyl)methyl)-
1 0,3 0,4 0-oxadiazol-20-yl)methylsulfonyl)-N-(4-p-tolyloxa-
zol-2-yl)acetamide (8b): White solid in 71%; m.p.: 152–154°C;
–
–
–
1125, 1317 (SO ), 1566 (C N), 1630 (C C), 1656 (NHCO), 3244 (NH);
–
2
1H NMR (DMSO-d6) d (ppm): 2.36 (s, 3H, Ar–CH3), 4.42 (s, 2H, CH2-(C-
2 0)), 4.62 (s, 2H, CH2-(C-5 0)), 4.91 (s, 2H, CO–CH2), 6.66 (d, 1H, HB,
J ¼ 9.1 Hz), 7.23–7.46 (m, 11H, Ar–H, C5-H, and HA), 10.96 (bs, 1H,
NH–CO), 12.45 (bs, 1H, NH); 13C NMR (DMSO-d6) d (ppm) 24.8
(Ar–CH3), 46.3 (CH2-(C-2 0)), 49.8 (CH2-(C-5 0)), 53.6 (CO–CH2), 109.8
(C-HB), 119.0 (C-5), 126.4 (C-HA), 136.1 (C-2), 142.2 (C-4), 153.7 (C-2 0),
165.3 (C-5 0), 168.3 (CO), 125.4, 128.5, 129.0, 130.4, 131.5, 134.1,
135.2, 138.5 (aromatic carbons); MS (m/z): 541.60 [Mþ]. Anal. calcd.
for C24H23N5O6S2: C 53.22, H 4.28, N 12.93; Found: C 53.16, H 4.32,
N 13.04%.
IR (KBr) nmax (cmꢁ1): 1138, 1326 (SO ), 1564 (C N), 1611 (C C),
–
–
–
–
2
1
1671 (NHCO), 3235 (NH); H NMR (DMSO-d6) d (ppm): 2.40 (s, 3H,
Ar–CH3), 4.30 (s, 2H, CH2-(C-2 0)), 4.62 (s, 2H, CH2-(C-5 0)), 4.69 (s, 2H,
CO–CH2), 6.48 (s, 1H, C500-H), 6.92–7.52 (m, 11H, Ar–H, C5-H, and
C200-H), 8.61 (bs, 1H, NH-C200), 11.12 (bs, 1H, NH–CO); 13C NMR
(DMSO-d6) d (ppm): 24.6 (Ar–CH3), 47.1 (CH2-(C-2 0)), 50.1 (CH2-(C-5 0)),
53.8 (CO–CH2), 105.7 (C-300), 110.6 (C-500), 118.2 (C-200), 126.8 (C-400),
138.0 (C-5), 140.4 (C-4), 150.5 (C-2), 157.2 (C-2 0), 164.8 (C-5 0), 169.8
(CO), 127.6, 128.3, 128.6, 129.3, 129.7, 130.5, 131.8, 134.3 (aromatic
carbons); MS (m/z): 581.63 [Mþ]. Anal. calcd. for C26H23N5O7S2:
C 53.69, H 3.99, N 12.04; Found: C 53.81, H 4.03, N 12.16%.
2-((5 0-((Styrylsulfonyl)methyl)-1 0,3 0,4 0-oxadiazol-20-yl)-
methylsulfonyl)-N-(4-(4-chloro-phenyl)-1H-imidazol-2-yl)-
acetamide (7c): White solid in 68%; m.p.: 163–165°C; IR (KBr)
2-((5 0-((400-Phenyl-100H-pyrrol-300-ylsulfonyl)methyl)-
1 0,3 0,4 0-oxadiazol-20-yl)methylsulfonyl)-N-(4-(4-chloro-
phenyl)oxazol-2-yl)acetamide (8c): White solid in 68%; m.p.:
nmax (cmꢁ1): 1134, 1328 (SO ), 1579 (C N), 1622 (C C), 1667
–
–
–
–
2
(NHCO), 3257 (NH); 1H NMR (DMSO-d6) d (ppm): 4.48 (s, 2H, CH2-(C-
2 0)), 4.69 (s, 2H, CH2-(C-5 0)), 4.96 (s, 2H, CO–CH2), 6.79 (d, 1H, HB,
J ¼ 9.7 Hz), 7.24–7.58 (m, 11H, Ar–H, C5-H, and HA), 11.06 (bs, 1H,
NH–CO), 12.52 (bs, 1H, NH); 13C NMR (DMSO-d6) d (ppm): 47.8 (CH2-
(C-2 0)), 50.6 (CH2-(C-5 0)), 54.2 (CO–CH2), 111.5 (C-HB), 119.8 (C-5),
127.2 (C-HA), 137.6 (C-2), 143.8 (C-4), 155.4 (C-2 0), 166.7 (C-5 0), 170.2
(CO), 125.3, 127.3, 128.2, 128.8, 129.5, 130.2, 133.4, 134.6 (aromatic
carbons); MS (m/z): 562.02 [Mþ]. Anal. calcd. for C23H20ClN5O6S2: C
49.15, H 3.59, N 12.46; Found: C 49.25, H 3.57, N 12.39%.
165–167°C; IR (KBr) nmax (cmꢁ1): 1144, 1334 (SO ), 1574 (C N),
–
–
2
1
–
1628 (C C), 1685 (NHCO), 3252 (NH); H NMR (DMSO-d ) d (ppm):
–
6
4.37 (s, 2H, CH2-(C-2 0)), 4.68 (s, 2H, CH2-(C-5 0)), 4.85 (s, 2H, CO–CH2),
6.55 (s, 1H, C500-H), 6.94–7.56 (m, 11H, Ar–H, C5-H, and C200-H), 8.65
(bs, 1H, NH-C200), 11.20 (bs, 1H, NH–CO); 13C NMR (DMSO-d6) d
(ppm): 47.6 (CH2-(C-2 0)), 50.4 (CH2-(C-5 0)), 54.7 (CO–CH2), 106.9 (C-
300), 111.3 (C-500), 119.1 (C-200), 127.2 (C-400), 138.3 (C-5), 140.7 (C-4),
151.3 (C-2), 158.2 (C-2 0), 166.7 (C-5 0), 171.8 (CO), 124.3, 125.6,
126.8, 128.5, 129.7, 130.4, 132.3, 134.5 (aromatic carbons); MS
(m/z): 602.05 [Mþ]. Anal. calcd. for C25H20ClN5O7S2: C 49.88, H 3.35,
N 11.63; Found: C 50.02, H 3.41, N 11.81%.
General procedure for the synthesis of 2-((50-((400-phenyl-
100H-pyrrol-300-ylsulfonyl)-methyl)-10,30,40-oxadiazol-20-yl)-
methylsulfonyl)-N-(4-aryloxazol-2-yl)acetamide (8a–c)/2-
((50-((400-phenyl-100H-pyrrol-300-ylsulfonyl)methyl)-10,30,40-
oxadiazol-20-yl)methylsulfonyl)-N-(4-arylthiazol-2-yl)-
acetamide (9a–c)/2-((50-((400-phenyl-100H-pyrrol-300-
ylsulfonyl)methyl)-10,30,40 -oxadiazol-20-yl)methylsulfonyl)-
2-((5 0-((400-Phenyl-100H-pyrrol-300-ylsulfonyl)methyl)-
1 0,3 0,4 0-oxadiazol-20-yl)methylsulfonyl)-N-(4-phenylthia-
zol-2-yl)acetamide (9a): White solid in 70%; m.p.: 153–155°C;
IR (KBr) nmax (cmꢁ1): 1131, 1333 (SO ), 1586 (C N), 1626 (C C),
–
–
–
–
2
1
N-(4-aryl-1H-imidazol-2-yl)acetamide (10a–c)
1670 (NHCO), 3245 (NH); H NMR (DMSO-d6) d (ppm): 4.42 (s, 2H,
CH2-(C-2 0)), 4.57 (s, 2H, CH2-(C-5 0)), 4.64 (s, 2H, CO–CH2), 6.48 (s, 1H,
C500-H), 6.58 (s, 1H, C5-H), 6.83–7.66 (m, 11H, Ar–H, and C200-H),
8.32 (bs, 1H, NH-C200), 11.05 (bs, 1H, NH–CO); 13C NMR (DMSO-d6) d
(ppm): 46.2 (CH2-(C-2 0)), 49.4 (CH2-(C-5 0)), 54.6 (CO–CH2), 104.4 (C-5),
107.6 (C-300), 110.5 (C-500), 117.7 (C-200), 126.9 (C-400), 148.3 (C-4),
156.4 (C-2 0), 163.9 (C-2), 164.7 (C-5 0), 168.0 (CO), 129.1, 130.2,
130.9, 131.2, 132.7, 133.5, 135.4, 138.2 (aromatic carbons);
MS (m/z): 583.68 [Mþ]. Anal. calcd. for C25H21N5O6S3: C 51.45,
H 3.63, N 12.00; Found: C 51.51, H 3.60, N 12.12%.
To a suspension of NaH (0.05 g) in Et2O (20 mL), 5/6/7 (1 mmol) and
TosMIC (2 mmol) in Et2O/DMSO (2:1) was added while stirring at
room temperature and continued for 6–8 h. Then, water was
added and the reaction mass was extracted with Et2O. The
ethereal layer was dried over anhydrous Na2SO4 and filtered.
Evaporation of the solvent in vacuo gave a crude product, which
was purified by passing through a column of silica gel using ethyl
acetate and hexane (1:4) as eluent.
2-((5 0-((400-Phenyl-100H-pyrrol-300-ylsulfonyl)methyl)-
1 0,3 0,4 0-oxadiazol-20-yl)methylsulfonyl)-N-(4-phenyloxa-
zol-2-yl)acetamide (8a): White solid in 69%; m.p.: 146–148°C;
2-((5 0-((400-Phenyl-100H-pyrrol-300-ylsulfonyl)methyl)-
1 0,3 0,4 0-oxadiazol-20-yl)methylsulfonyl)-N-(4-p-tolylthia-
zol-2-yl)acetamide (9b): White solid in 72%; m.p.: 158–160°C;
IR (KBr) nmax (cmꢁ1): 1140, 1330 (SO ), 1562 (C N), 1620 (C C),
–
–
–
–
2
1
IR (KBr) nmax (cmꢁ1): 1129, 1330 (SO ), 1582 (C N), 1613 (C C),
1677 (NHCO), 3240 (NH); H NMR (DMSO-d6) d (ppm): 4.36 (s, 2H,
CH2-(C-2 0)), 4.64 (s, 2H, CH2-(C-5 0)), 4.78 (s, 2H, CO–CH2), 6.51 (s,
1H, C500-H), 6.95–7.72 (m, 12H, Ar–H, C5-H, and C200-H), 8.62 (bs,
1H, NH-C200), 11.24 (bs, 1H, NH–CO); 13C NMR (DMSO-d6) d (ppm):
47.4 (CH2-(C-2 0)), 50.2 (CH2-(C-5 0)), 53.8 (CO–CH2), 106.5 (C-300), 110.8
–
–
–
–
2
1
1674 (NHCO), 3236 (NH); H NMR (DMSO-d6) d (ppm): 2.32 (s, 3H,
Ar–CH3), 4.37 (s, 2H, CH2-(C-2 0)), 4.54 (s, 2H, CH2-(C-5 0)), 4.62 (s, 2H,
CO–CH2), 6.44 (s, 1H, C500-H), 6.55 (s, 1H, C5-H), 6.81–7.55 (m, 10H,
Ar–H, and C200-H), 8.26 (bs, 1H, NH-C200), 10.98 (bs, 1H, NH–CO);
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2014, 347, 54–67
Synthesis and Antioxidant Activity of Bis and Tris Heterocycles
63
1
13C NMR (DMSO-d6) d (ppm): 23.6 (Ar–CH3), 46.0 (CH2-(C-2 0)), 49.2
(CH2-(C-5 0)), 53.2 (CO–CH2), 105.5 (C-5), 107.0 (C-300), 110.2 (C-500),
117.2 (C-200), 126.3 (C-400), 147.5 (C-4), 154.2 (C-2 0), 163.5 (C-2), 166.5
(C-5 0), 167.8 (CO), 128.5, 130.7, 131.2, 131.9, 132.5, 133.7, 134.1,
134.5 (aromatic carbons); MS (m/z): 597.67 [Mþ]. Anal. calcd. for
C26H23N5O6S3: C 52.25, H 3.88, N 11.72; Found: C 52.21, H 3.90, N
11.79%.
(C N), 1629 (C C), 1677 (NHCO), 3250 (NH); H NMR (DMSO-d ) d
–
–
–
–
6
(ppm): 4.38 (s, 2H, CH2-(C-2 0)), 4.63 (s, 2H, CH2-(C-5 0)), 4.80 (s, 2H,
CO–CH2), 6.51 (s, 1H, C500-H), 6.91–7.56 (m, 11H, Ar–H, C5-H, and
C200-H), 8.60 (bs, 1H, NH-C200), 11.18 (bs, 1H, NH–CO), 12.50 (bs, 1H,
NH-(C-5)); 13C NMR (DMSO-d6) d (ppm): 47.3 (CH2-(C-2 0)), 50.5 (CH2-
(C-5 0)), 54.0 (CO–CH2), 107.8 (C-300), 112.0 (C-500), 119.2 (C-200), 123.6
(C-5), 127.8 (C-400), 138.0 (C-2), 141.2 (C-4), 155.4 (C-2 0), 166.7 (C-5 0),
171.2 (CO), 126.7, 129.5, 130.5, 131.2, 132.8, 133.5, 134.0, 135.1
(aromatic carbons); MS (m/z): 601.07 [Mþ]. Anal. calcd. for
2-((5 0-((400-Phenyl-100H-pyrrol-300-ylsulfonyl)methyl)-
1 0,3 0,4 0-oxadiazol-20-yl)methylsulfonyl)-N-(4-(4-chloro-
phenyl)thiazol-2-yl)acetamide (9c): White solid in 65%; m.p.:
C
25H21ClN6O6S2: C 49.96, H 3.52, N 13.98; Found: C 50.06, H
3.50, N 13.90%.
184–186°C; IR (KBr) nmax (cmꢁ1): 1138, 1340 (SO ), 1590 (C N),
–
–
2
General procedure for the synthesis of 2-((50-((400,500-
dihydro-400-phenyl-100H-pyrazol-300-ylsulfonyl)methyl)-
10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-(4-aryloxazol-2-
yl)acetamide (11a–c)/2-((50-((400,500-dihydro-400-phenyl-
100H-pyrazol-300-ylsulfonyl)methyl)-10,30,40-oxadiazol-20-yl)
methylsulfonyl)-N-(4-arylthiazol-2-yl)acetamide (12a–c)/2-
((50-((400,500-dihydro-400-phenyl-100H-pyrazol-300-ylsulfonyl)-
methyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-(4-aryl-
1
–
1611 (C C), 1682 (NHCO), 3254 (NH); H NMR (DMSO-d ) d (ppm):
–
6
4.45 (s, 2H, CH2-(C-2 0)), 4.60 (s, 2H, CH2-(C-5 0)), 4.77 (s, 2H, CO–CH2),
6.53 (s, 1H, C500-H), 6.60 (s, 1H, C5-H), 6.88–7.48 (m, 10H, Ar–H, and
C200-H), 8.34 (bs, 1H, NH-C200), 11.11 (bs, 1H, NH–CO); 13C NMR
(DMSO-d6)
d
(ppm): 46.8 (CH2-(C-2 0)), 50.2 (CH2-(C-5 0)), 54.8
(CO–CH2), 106.0 (C-5), 108.2 (C-300), 110.9 (C-500), 118.7 (C-200),
127.2 (C-400), 148.6 (C-4), 155.5 (C-2 0), 164.3 (C-2), 165.8 (C-5 0), 168.2
(CO), 124.7, 125.6, 126.4, 128.5, 128.9, 129.4, 130.2, 131.1
(aromatic carbons); MS (m/z): 618.12 [Mþ]. Anal. calcd. for
C25H20ClN5O6S3: C 48.58, H 3.26, N 11.33; Found: C 48.65, H
1H-imidazol-2-yl)acetamide (13a–c)
3.31, N 11.46%.
An ethereal solution of diazomethane (40 mL, 0.4 M) and
triethylamine (0.12 g) were added to a cooled solution of 5/6/7
(5 mmol) in dichloromethane (20 mL). The reaction mixture was
kept at ꢁ20 to ꢁ15°C for 42–46 h. The solvent was removed under
reduced pressure. The resultant solid was purified by passing
through a column of silica gel using ethyl acetate and hexane (1:3)
as eluent.
2-((5 0-((400-Phenyl-100H-pyrrol-300-ylsulfonyl)methyl)-
1 0,3 0,4 0-oxadiazol-20-yl)methylsulfonyl)-N-(4-phenyl-1H-
imidazol-2-yl)acetamide (10a): White solid in 66%; m.p.: 145–
147°C; IR (KBr) nmax (cmꢁ1): 1134, 1332 (SO ), 1566 (C N), 1627
–
–
2
1
–
(C C), 1674 (NHCO), 3246 (NH); H NMR (DMSO-d ) d (ppm): 4.36 (s,
–
6
2H, CH2-(C-2 0)), 4.62 (s, 2H, CH2-(C-5 0)), 4.71 (s, 2H, CO–CH2), 6.49 (s,
1H, C500-H), 6.86–7.64 (m, 12H, Ar–H, C5-H, and C200-H), 8.57 (bs,
1H, NH-C200), 11.09 (bs, 1H, NH–CO), 12.48 (bs, 1H, NH-(C-5)); 13C
NMR (DMSO-d6) d (ppm): 47.1 (CH2-(C-2 0)), 50.1 (CH2-(C-5 0)), 53.7
(CO–CH2), 107.4 (C-300), 111.7 (C-500), 118.9 (C-200), 123.5 (C-5), 127.5
(C-400), 137.3 (C-2), 140.4 (C-4), 154.8 (C-2 0), 165.5 (C-5 0), 169.9 (CO),
124.4, 129.5, 131.2, 131.8, 132.9, 133.3, 134.1, 134.9 (aromatic
carbons); MS (m/z): 566.62 [Mþ]. Anal. calcd. for C25H22N6O6S2: C
52.99, H 3.91, N 14.83; Found: C 53.08, H 3.94, N, 14.98%.
2-((5 0-((400,500-Dihydro-400-phenyl-100H-pyrazol-300-ylsul-
fonyl)methyl)-1 0,3 0,4 0-oxadiazol-2 0-yl)methylsulfonyl)-N-
(4-phenyloxazol-2-yl)acetamide (11a): White solid in
78%; m.p.: 155–157°C; IR (KBr) nmax (cmꢁ1): 1145, 1331 (SO2),
1570 (C N), 1617 (C C), 1666 (NHCO), 3248 (NH); 1H NMR
–
–
–
–
(DMSO-d6) d (ppm): 3.63 (dd, 1H, HX, JAX ¼ 6.4 Hz, JMX ¼ 10.5 Hz),
4.10 (dd, 1H, HM, JAM ¼ 12.2 Hz), 4.36 (s, 2H, CH2-(C-2 0)), 4.54
(dd, 1H, HA), 4.58 (s, 2H, CH2-(C-5 0)), 4.62 (s, 2H, CO–CH2), 6.65
(bs, 1H, N–NH), 7.20–7.52 (m, 11H, Ar–H, and C5-H), 11.23
2-((5 0-((400-Phenyl-100H-pyrrol-300-ylsulfonyl)methyl)-
1 0,3 0,4 0-oxadiazol-20-yl)methylsulfonyl)-N-(4-p-tolyl-1H-
imidazol-2-yl)acetamide (10b): White solid in 68%; m.p.: 152–
13
(bs, 1H, NH–CO); C NMR (DMSO-d6) d (ppm): 40.4 (C-400), 46.8
(CH2-(C-2 0)), 49.2 (CH2-(C-5 0)), 52.2 (C-500), 54.1 (CO–CH2), 138.3
(C-5), 140.8 (C-4), 150.2 (C-2), 158.7 (C-2 0), 158.8 (C-300), 165.7
(C-5 0), 170.4 (CO), 125.6, 126.1, 127.4, 128.5, 129.7, 130.1, 130.4,
132.3 (aromatic carbons); MS (m/z): 570.60 [Mþ]. Anal. calcd. for
C24H22N6O7S2: C 50.52, H 3.89, N 14.73; Found: C 50.40, H 3.93,
N 14.77%.
154°C; IR (KBr) nmax (cmꢁ1): 1130, 1325 (SO ), 1564 (C N), 1625
–
–
2
1
–
(C C), 1672 (NHCO), 3241 (NH); H NMR (DMSO-d ) d (ppm): 2.42 (s,
–
6
3H, Ar–CH3), 4.33 (s, 2H, CH2-(C-2 0)), 4.59 (s, 2H, CH2-(C-5 0)), 4.66 (s,
2H, CO–CH2), 6.40 (s, 1H, C500-H), 6.85–7.52 (m, 11H, Ar–H, C5-H,
and C200-H), 8.48 (bs, 1H, NH-C200), 11.06 (bs, 1H, NH–CO), 12.46 (bs,
1H, NH-(C-5)); 13C NMR (DMSO-d6) d (ppm): 24.2 (Ar–CH3), 46.8 (CH2-
(C-2 0)), 49.7 (CH2-(C-5 0)), 53.4 (CO–CH2), 107.1 (C-300), 110.8 (C-500),
118.5 (C-200), 123.0 (C-5), 127.0 (C-400), 137.1 (C-2), 140.2 (C-4), 153.7
(C-2 0), 165.3 (C-5 0), 168.3 (CO), 128.7, 130.4, 131.5, 131.9, 132.2,
133.7, 134.5, 135.7 (aromatic carbons); MS (m/z): 580.65 [Mþ]. Anal.
calcd. for C26H24N6O6S2: C 53.78, H 4.17, N 14.47; Found: C 53.83,
H 4.18, N 14.56%.
2-((5 0-((400,500-Dihydro-400-phenyl-100H-pyrazol-300-ylsul-
fonyl)methyl)-1 0,3 0,4 0-oxadiazol-2 0-yl)methylsulfonyl)-N-
(4-p-tolyloxazol-2-yl)acetamide (11b): White solid in
75%; m.p.: 164–166°C; IR (KBr) nmax (cmꢁ1): 1138, 1326 (SO2),
1
–
–
1577 (C N), 1615 (C C), 1663 (NHCO), 3234 (NH); H NMR (DMSO-
–
–
d6) d (ppm): 2.35 (s, 3H, Ar–CH3), 3.54 (dd, 1H, HX, JAX ¼ 6.2 Hz,
JMX ¼ 10.2 Hz), 4.04 (dd, 1H, HM, JAM ¼ 12.0 Hz), 4.32 (s, 2H, CH2-(C-
2 0)), 4.57 (dd, 1H, HA), 4.52 (s, 2H, CH2-(C-5 0)), 4.59 (s, 2H, CO–CH2),
6.60 (bs, 1H, N–NH), 7.24–7.46 (m, 10H, Ar–H, and C5-H), 11.20 (bs,
1H, NH–CO); 13C NMR (DMSO-d6) d (ppm): 22.9 (Ar–CH3), 39.8 (C-
400), 46.2 (CH2-(C-2 0)), 48.9 (CH2-(C-5 0)), 51.9 (C-500), 53.8 (CO–CH2),
137.8 (C-5), 140.2 (C-4), 149.5 (C-2), 157.2 (C-2 0), 158.4 (C-300), 164.8
2-((5 0-((400-Phenyl-100H-pyrrol-300-ylsulfonyl)methyl)-
1 0,3 0,4 0-oxadiazol-20-yl)methylsulfonyl)-N-(4-(4-chloro-
phenyl)-1H-imidazol-2-yl)acetamide (10c): White solid in
67%; m.p.: 175–177°C; IR (KBr) nmax (cmꢁ1): 1136, 1336 (SO2), 1569
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

64
N. Mahaboob Basha et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 54–67
(C-5 0), 169.8 (CO), 127.2, 128.7, 129.5, 130.7, 131.6, 132.5, 133.1,
133.9 (aromatic carbons); MS (m/z): 584.64 [Mþ]. Anal. calcd. for
C25H24N6O7S2: C, 51.36, H 4.14, N 14.38; Found: C 51.56, H 4.22, N
14.69%.
d6) d (ppm): 3.59 (dd, 1H, HX, JAX ¼ 6.0 Hz, JMX ¼ 10.1 Hz), 4.28 (dd,
1H, HM, JAM ¼ 12.0 Hz), 4.33 (s, 2H, CH2-(C-2 0)), 4.58 (s, 2H, CH2-(C-
5 0)), 4.64 (dd, 1H, HA), 4.73 (s, 2H, CO–CH2), 6.45 (bs, 1H, N–NH),
6.58 (s, 1H, C5-H), 7.25–7.42 (m, 9H, Ar–H), 11.21 (bs, 1H, NH–CO);
13C NMR (DMSO-d6) d (ppm): 39.2 (C-400), 46.9 (CH2-(C-2 0)), 50.2 (CH2-
(C-5 0)), 53.5 (C-500), 53.8 (CO–CH2), 106.0 (C-5), 148.6 (C-4), 155.2 (C-
2 0), 158.3 (C-300), 164.2 (C-2), 165.7 (C-5 0), 168.2 (CO), 125.6, 126.3,
127.7, 128.3, 129.4, 130.3, 132.5, 134.8 (aromatic carbons); MS
(m/z): 621.12 [Mþ]. Anal. calcd. for C24H21ClN6O6S3: C 46.41, H 3.41,
N 13.53; Found: C 46.51, H 3.44, N 13.68%.
2-((50-((400,500-Dihydro-400-phenyl-100H-pyrazol-300-ylsul-
fonyl)-methyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-
(4-(4-chlorophenyl)oxazol-2-yl)acetamide (11c): White sol-
id in 77%; m.p.: 178–180°C; IR (KBr) nmax (cmꢁ1): 1150, 1338 (SO2),
1
–
–
1585 (C N), 1620 (C C), 1676 (NHCO), 3253 (NH); H NMR (DMSO-
–
–
d6) d (ppm): 3.67 (dd, 1H, HX, JAX ¼ 6.7 Hz, JMX ¼ 10.8 Hz), 4.20 (dd,
1H, HM, JAM ¼ 12.6 Hz), 4.39 (s, 2H, CH2-(C-2 0)), 4.58 (dd, 1H, HA),
4.60 (s, 2H, CH2-(C-5 0)), 4.71 (s, 2H, CO–CH2), 6.67 (bs, 1H, N–NH),
7.29–7.59 (m, 10H, Ar–H, and C5-H), 11.24 (bs, 1H, NH–CO); 13C
NMR (DMSO-d6) d (ppm): 40.6 (C-400), 47.2 (CH2-(C-2 0)), 50.1 (CH2-(C-
5 0)), 52.6 (C-500), 54.7 (CO–CH2), 138.3 (C-5), 140.2 (C-4), 151.3 (C-2),
158.2 (C-2 0), 159.0 (C-300), 166.7 (C-5 0), 171.8 (CO), 126.4, 127.2,
128.3, 129.1, 130.4, 131.4, 132.0, 137.4 (aromatic carbons); MS (m/
z): 605.05 [Mþ]. Anal. calcd. for C24H21ClN6O7S2: C 47.64, H 3.50, N
13.89; Found: C 47.75, H 3.55, N 14.05%.
2-((50-((400,500-Dihydro-400-phenyl-100H-pyrazol-300-ylsulfonyl)-
methyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-(4-
phenyl-1H-imidazol-2-yl)acetamide (13a): White solid in
78%; m.p.: 157–159°C; IR (KBr) nmax (cmꢁ1): 1134, 1332 (SO2),
1
–
–
1572 (C N), 1624 (C C), 1680 (NHCO), 3252 (NH); H NMR (DMSO-
–
–
d6) d (ppm): 3.60 (dd, 1H, HX, JAX ¼ 6.4 Hz, JMX ¼ 10.4 Hz), 4.19 (dd,
1H, HM, JAM ¼ 12.2 Hz), 4.34 (s, 2H, CH2-(C-2 0)), 4.56 (dd, 1H, HA),
4.59 (s, 2H, CH2-(C-5 0)), 4.70 (s, 2H, CO–CH2), 6.61 (bs, 1H, N–NH),
7.18–7.56 (m, 11H, Ar–H, and C5-H), 11.23 (bs, 1H, NH–CO), 12.46
(bs, 1H, NH-(C-5)); 13C NMR (DMSO-d6) d (ppm): 40.2 (C-400), 47.5 (CH2-
(C-2 0)), 49.4 (CH2-(C-5 0)), 52.3 (C-500), 53.7 (CO–CH2), 123.5 (C-5), 137.3
(C-2), 140.4 (C-4), 154.8 (C-2 0), 157.7 (C-300), 165.5 (C-5 0), 169.9 (CO),
127.3, 128.1, 128.9, 129.2, 131.2, 132.4, 134.7, 135.6 (aromatic
carbons); MS (m/z): 569.62 [Mþ]. Anal. calcd. for C24H23N7O6S2: C
50.61, H 4.07, N 17.21; Found: C 50.68, H 4.06, N 17.33%.
2-((5 0-((400,500-Dihydro-400-phenyl-100H-pyrazol-300-ylsulfonyl)-
methyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-(4-
phenylthiazol-2-yl)acetamide (12a): White solid in 76%; m.p.:
159–161°C; IR (KBr) nmax (cmꢁ1): 1132, 1332 (SO ), 1574 (C N),
–
–
2
1
–
1624 (C C), 1677 (NHCO), 3256 (NH); H NMR (DMSO-d ) d (ppm):
–
6
3.55 (dd, 1H, HX, JAX ¼ 5.9Hz, JMX ¼ 9.8 Hz), 4.25 (dd, 1H, HM,
JAM ¼ 11.8 Hz), 4.33 (s, 2H, CH2-(C-2 0)), 4.54 (s, 2H, CH2-(C-5 0)), 4.61
(dd, 1H, HA), 4.68 (s, 2H, CO–CH2), 6.46 (bs, 1H, N–NH), 6.54 (s, 1H,
C5-H), 7.21–7.50 (m, 10H, Ar–H), 11.18 (bs, 1H, NH–CO); 13C NMR
(DMSO-d6) d (ppm): 38.6 (C-400), 46.5 (CH2-(C-2 0)), 49.3 (CH2-(C-5 0)),
52.8 (C-500), 53.6 (CO–CH2), 105.4 (C-5), 148.3 (C-4), 155.4 (C-2 0), 157.4
(C-300), 163.9 (C-2), 165.7 (C-5 0), 167.5 (CO), 127.7, 128.4, 129.7,
130.6, 131.2, 132.0, 132.9, 135.1 (aromatic carbons); MS (m/z):
586.67 [Mþ]. Anal. calcd. for C24H22N6O6S3: C 49.13, H 3.78, N
14.32; Found: C 49.07, H 3.80, N 14.42%.
2-((50-((400,500-Dihydro-400-phenyl-100H-pyrazol-300-ylsulfonyl)-
methyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-(4-
p-tolyl-1H-imidazol-2-yl)acetamide (13b): White solid in
80%; m.p.: 166–168°C; IR (KBr) nmax (cmꢁ1): 1132, 1326 (SO2),
1
–
–
1565 (C N), 1612 (C C), 1678 (NHCO), 3245 (NH); H NMR (DMSO-
–
–
d6) d (ppm): 2.32 (s, 3H, Ar–CH3), 3.52 (dd, 1H, HX, JAX ¼ 6.0 Hz,
JMX ¼ 10.1 Hz), 4.13 (dd, 1H, HM, JAM ¼ 12.1 Hz), 4.30 (s, 2H, CH2-(C-
2 0)), 4.48 (dd, 1H, HA), 4.55 (s, 2H, CH2-(C-5 0)), 4.63 (s, 2H, CO–CH2),
6.57 (bs, 1H, N–NH), 7.28–7.53 (m, 10H, Ar–H, and C5-H), 11.16 (bs,
1H, NH–CO), 12.39 (bs, 1H, NH-(C-5)); 13C NMR (DMSO-d6) d (ppm):
24.4 (Ar–CH3), 39.4 (C-400), 46.8 (CH2-(C-2 0)), 49.2 (CH2-(C-5 0)), 51.7 (C-
500), 53.4 (CO–CH2), 123.0 (C-5), 137.1 (C-2), 140.2 (C-4), 153.7 (C-2 0),
156.1 (C-300), 165.3 (C-5 0), 168.3 (CO), 128.7, 129.2, 130.6, 131.2
132.6, 133.1, 133.9, 134.7 (aromatic carbons); MS (m/z): 583.66 [Mþ].
Anal. calcd. for C25H25N7O6S2: C 51.45, H 4.32, N 16.80; Found: C
51.50, H 4.34, N 16.89%.
2-((50-((400,500-Dihydro-400-phenyl-100H-pyrazol-300-ylsulfonyl)-
methyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-(4-p-
tolylthiazol-2-yl)acetamide (12b): White solid in 78%; m.p.:
166–168°C; IR (KBr) nmax (cmꢁ1): 1130, 1329 (SO ), 1568 (C N),
–
–
2
1
–
1628 (C C), 1669 (NHCO), 3248 (NH); H NMR (DMSO-d ) d (ppm):
–
6
2.30 (s, 3H, Ar–CH3), 3.47 (dd, 1H, HX, JAX ¼ 5.7 Hz, JMX ¼ 9.5 Hz),
4.14 (dd, 1H, HM, JAM ¼ 11.6 Hz), 4.29 (s, 2H, CH2-(C-2 0)), 4.52 (dd,
1H, HA), 4.56 (s, 2H, CH2-(C-5 0)), 4.62 (s, 2H, CO–CH2), 6.41 (bs, 1H,
N–NH), 6.52 (s, 1H, C5-H), 7.18–7.58 (m, 9H, Ar–H), 11.15 (bs, 1H,
2-((50-((400,500-Dihydro-400-phenyl-100H-pyrazol-300-ylsulfonyl)-
methyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-(4-
(4-chlorophenyl)-1H-imidazol-2-yl)acetamide (13c): White
13
NH–CO); C NMR (DMSO-d6) d (ppm): 24.5 (Ar–CH3), 38.4 (C-400),
solid in 79%; m.p.: 188–190°C; IR (KBr) nmax (cmꢁ1): 1138, 1336
46.0 (CH2-(C-2 0)), 48.9 (CH2-(C-5 0)), 52.4 (C-500), 53.2 (CO–CH2), 105.5
(C-5), 148.0 (C-4), 154.6 (C-2 0), 156.8 (C-300), 163.5 (C-2), 164.9 (C-50),
166.8 (CO), 126.3, 127.5, 128.3, 128.6, 129.5, 131.6, 132.3, 135.0
(aromatic carbons); MS (m/z): 600.71 [Mþ]. Anal. calcd. for
C25H24N6O6S3: C 49.99, H 4.03, N 13.99; Found: C 50.08, H 4.07,
N 14.12%.
1
–
–
(SO ), 1581 (C N), 1628 (C C), 1682 (NHCO), 3253 (NH); H NMR
–
–
2
(DMSO-d6) d (ppm): 3.65 (dd, 1H, HX, JAX ¼ 6.6 Hz, JMX ¼ 10.4 Hz),
4.22 (dd, 1H, HM, JAM ¼ 12.6 Hz), 4.37 (s, 2H, CH2-(C-2 0)), 4.58 (s, 2H,
CH2-(C-5 0)), 4.60 (dd, 1H, HA), 4.68 (s, 2H, CO–CH2), 6.63 (bs, 1H,
N–NH), 7.25–7.62 (m, 10H, Ar–H, and C5-H), 11.24 (bs, 1H, NH–CO),
13
12.48 (bs, 1H, NH-(C-5)); C NMR (DMSO-d6) d (ppm): 40.6 (C-400),
47.8 (CH2-(C-2 0)), 49.6 (CH2-(C-5 0)), 52.8 (C-500), 54.0 (CO–CH2), 123.6
(C-5), 138.0 (C-2), 141.2 (C-4), 155.4 (C-2 0), 157.8 (C-300), 166.7 (C-50),
171.2 (CO), 125.3, 126.2, 127.0, 127.8, 128.6, 129.3, 131.5, 132.0
(aromatic carbons); MS (m/z): 604.06 [Mþ]. Anal. calcd. for
C24H22ClN7O6S2: C 47.72, H 3.67, N 16.23; Found: C 47.80, H
3.70, N 16.34%.
2-((5 0-((400,500-Dihydro-400-phenyl-100H-pyrazol-300-ylsul-
fonyl)methyl)-1 0,3 0,4 0-oxadiazol-2 0-yl)methylsulfonyl)-N-
(4-(4-chlorophenyl)thiazol-2-yl)acetamide (12c): White sol-
id in 79%; m.p.: 193–195°C; IR (KBr) nmax (cmꢁ1): 1138, 1341 (SO2),
1
–
–
–
–
1585 (C N), 1620 (C C), 1682 (NHCO), 3257 (NH); H NMR (DMSO-
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2014, 347, 54–67
Synthesis and Antioxidant Activity of Bis and Tris Heterocycles
65
General procedure for the synthesis of 2-((50-((400-phenyl-
100H-pyrazol-300-ylsulfonyl)methyl)-10,30,40-oxadiazol-2 0-yl)-
methylsulfonyl)-N-(4-aryloxazol-2-yl)acetamide (14a–c)/2-
((50-((400-phenyl-100H-pyrazol-300-ylsulfonyl)methyl)-1 0,30,4 0-
oxadiazol-20-yl)methylsulfonyl)-N-(4-arylthiazol-2-yl)-
acetamide (15a–c)/2-((50-((400-phenyl-100H-pyrazol-300-
ylsulfonyl)methyl)-10,30,40-oxadiazol-2 0-yl)methylsulfonyl)-
carbons); MS (m/z): 603.03 [Mþ]. Anal. calcd. for C24H19ClN6O7S2:
C 47.80, H 3.18, N 13.94; Found: C 47.89, H 3.14, N 14.10%.
2-((5 0-((400-Phenyl-100H-pyrazol-300-ylsulfonyl)methyl)-
1 0,3 0,4 0-oxadiazol-20-yl)methylsulfonyl)-N-(4-phenylthia-
zol-2-yl)acetamide (15a): White solid in 66%; m.p.: 210–
212°C; IR (KBr) nmax (cmꢁ1): 1143, 1330 (SO ), 1577 (C N), 1625
–
–
2
1
–
(C C), 1671 (NHCO), 3250 (NH); H NMR (DMSO-d ) d (ppm): 4.34
–
6
N-(4-aryl-1H-imidazol-2-yl)acetamide (16a–c)
(s, 2H, CH2-(C-2 0)), 4.81 (s, 2H, CH2-(C-5 0)), 4.88 (s, 2H, CO–CH2), 6.58
(s, 1H, C5-H), 7.33–8.10 (m, 11H, Ar–H, and C500-H), 9.80 (bs, 1H,
N–NH), 11.06 (bs, 1H, NH–CO); 13C NMR (DMSO-d6) d (ppm): 47.2
(CH2-(C-2 0)), 49.6 (CH2-(C-5 0)), 53.6 (CO–CH2), 103.4 (C-5), 122.3
(C-400), 129.5 (C-300), 134.7 (C-500), 148.3 (C-4), 156.4 (C-2 0), 163.9 (C-2),
164.7 (C-5 0), 168.9 (CO), 127.3, 128.1, 128.9, 129.2, 131.2, 132.4,
134.7, 135.6 (aromatic carbons); MS (m/z): 584.66 [Mþ]. Anal. calcd.
for C24H20N6O6S3: C 49.30, H 3.45, N 14.37; Found: C 49.45, H 3.51,
N 14.17%.
A solution of 11/12/13 (1 mmol) and chloranil (1.4 mmol) in xylene
(10 mL) was refluxed for 21–24 h. Then, the reaction mixture was
treated with a 5% NaOH solution. The organic layer was separated
and repeatedly washed with water. It was then dried over
anhydrous Na2SO4 and the solvent was removed on a rotary
evaporator. The resultant solid was recrystallized from 2-
propanol.
2-((5 0-((400-Phenyl-100H-pyrazol-300-ylsulfonyl)methyl)-
1 0,3 0,4 0-oxadiazol-20-yl)methylsulfonyl)-N-(4-phenyloxa-
zol-2-yl)acetamide (14a): White solid in 69%; m.p.: 193–
2-((5 0-((400-Phenyl-100H-pyrazol-300-ylsulfonyl)methyl)-
1 0,3 0,4 0-oxadiazol-20-yl)methylsulfonyl)-N-(4-p-tolylthia-
zol-2-yl)acetamide (15b): White solid in 69%; m.p.: 205–
195°C; IR (KBr) nmax (cmꢁ1): 1134, 1334 (SO ), 1573 (C N), 1616
–
–
2
1
–
207°C; IR (KBr) nmax (cmꢁ1): 1140, 1324 (SO ), 1575 (C N), 1620
(C C), 1675 (NHCO), 3254 (NH); H NMR (DMSO-d ) d (ppm): 4.36
–
6
–
–
2
(s, 2H, CH2-(C-2 0)), 4.83 (s, 2H, CH2-(C-5 0)), 4.92 (s, 2H, CO–CH2),
7.31–8.18 (m, 12H, Ar–H, C5-H, and C500-H), 9.85 (bs, 1H, N–NH),
11.32 (bs, 1H, NH–CO); 13C NMR (DMSO-d6) d (ppm): 47.2 (CH2-
(C-2 0)), 50.4 (CH2-(C-5 0)), 54.1 (CO–CH2), 122.9 (C-400), 131.1 (C-300),
135.5 (C-500), 137.4 (C-5), 140.8 (C-4), 150.2 (C-2), 158.7 (C-2 0), 165.7
(C-5 0), 170.4 (CO), 125.8, 126.7, 127.5, 128.9, 129.2, 130.3, 131.4,
132.5 (aromatic carbons); 568.59 [Mþ]. Anal. calcd. for
C24H20N6O7S2: C 50.70, H 3.55, N 14.78; Found: C 50.60, H
3.60, N 14.96%.
1
–
(C C), 1668 (NHCO), 3235 (NH); H NMR (DMSO-d ) d (ppm): 2.88
–
6
(s, 3H, Ar–CH3), 4.32 (s, 2H, CH2-(C-2 0)), 4.74 (s, 2H, CH2-(C-5 0)), 4.79
(s, 2H, CO–CH2), 6.51 (s, 1H, C5-H), 7.27–8.06 (m, 10H, Ar–H, and
C500-H), 9.73 (bs, 1H, N–NH), 10.98 (bs, 1H, NH–CO); 13C NMR
(DMSO-d6) d (ppm): 22.5 (Ar–CH3), 46.7 (CH2-(C-2 0)), 49.4 (CH2-
(C-5 0)), 53.2 (CO–CH2), 102.5 (C-5), 121.9 (C-400), 129.4 (C-300), 134.0
(C-500), 148.0 (C-4), 154.2 (C-2 0), 163.5 (C-2), 166.5 (C-5 0), 168.0 (CO),
126.8, 128.5, 130.3, 132.9, 133.5, 134.9, 135.7, 137.2 (aromatic
carbons); MS (m/z): 598.69 [Mþ]. Anal. calcd. for C25H22N6O6S3: C
50.16, H 3.70, N 14.04; Found: C 50.27, H 3.74, N 14.18%.
2-((5 0-((400-Phenyl-100H-pyrazol-300-ylsulfonyl)methyl)-
1 0,3 0,4 0-oxadiazol-20-yl)methylsulfonyl)-N-(4-p-tolyloxa-
zol-2-yl)acetamide (14b): White solid in 68%; m.p.: 187–
2-((5 0-((400-Phenyl-100H-pyrazol-300-ylsulfonyl)methyl)-
1 0,3 0,4 0-oxadiazol-20-yl)methylsulfonyl)-N-(4-(4-chloro-
189°C; IR (KBr) nmax (cmꢁ1): 1131, 1328 (SO ), 1565 (C N), 1622
–
–
2
phenyl)thiazol-2-yl)acetamide (15c): White solid
in
1
73%; m.p.: 223–225°C; IR (KBr) nmax (cmꢁ1): 1144, 1332 (SO2),
–
–
(C C), 1667 (NHCO), 3249 (NH); H NMR (DMSO-d ) d (ppm): 2.43
6
(s, 3H, Ar–CH3), 4.35 (s, 2H, CH2-(C-2 0)), 4.84 (s, 2H, CH2-(C-5 0)),
4.89 (s, 2H, CO–CH2), 7.40–8.11 (m, 11H, Ar–H, C5-H, and C500-H),
9.82 (bs, 1H, N–NH), 11.26 (bs, 1H, NH–CO); 13C NMR (DMSO-d6)
d (ppm): 23.6 (Ar–CH3), 46.9 (CH2-(C-2 0)), 50.0 (CH2-(C-5 0)),
53.8 (CO–CH2), 122.4 (C-400), 130.8 (C-300), 135.0 (C-500), 138.0
(C-5), 140.4 (C-4), 150.5 (C-2), 157.2 (C-2 0), 164.8 (C-5 0), 169.8
(CO), 128.5, 129.8, 130.7, 131.2, 132.8, 133.1, 134.2, 135.8
(aromatic carbons); MS (m/z): 582.62 [Mþ]. Anal. calcd. for
C25H22N6O7S2: C 51.54, H 3.81, N 14.42; Found: C 51.84, H 3.71,
N 14.74%.
1
–
–
1576 (C N), 1622 (C C), 1674 (NHCO), 3258 (NH); H NMR (DMSO-
–
–
d6) d (ppm): 4.36 (s, 2H, CH2-(C-2 0)), 4.82 (s, 2H, CH2-(C-5 0)), 4.91
(s, 2H, CO–CH2), 6.61 (s, 1H, C5-H), 7.26–8.15 (m, 10H, Ar–H, and
C500-H), 9.84 (bs, 1H, N–NH), 11.15 (bs, 1H, NH–CO); 13C NMR
(DMSO-d6)
d
(ppm): 47.8 (CH2-(C-2 0)), 50.2 (CH2-(C-5 0)), 53.8
(CO–CH2), 104.0 (C-5), 122.8 (C-400), 129.7 (C-300), 135.4 (C-500),
148.6 (C-4), 155.6 (C-2 0), 164.3 (C-2), 164.8 (C-5 0), 168.2 (CO), 125.7,
126.9, 127.4, 128.8, 130.2, 131.5, 133.6, 134.2 (aromatic carbons);
MS (m/z): 619.10 [Mþ]. Anal. calcd. for C24H19ClN6O6S3: C 46.56,
H 3.09, N 13.57; Found: C 46.63, H 3.06, N 13.73%.
2-((50-((400-Phenyl-100H-pyrazol-300-ylsulfonyl)methyl)-
10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-(4-(4-chloro-
phenyl)oxazol-2-yl)acetamide (14c): White solid in 71%; m.p.:
2-((5 0-((400-Phenyl-100H-pyrazol-300-ylsulfonyl)methyl)-
1 0,3 0,4 0-oxadiazol-20-yl)methylsulfonyl)-N-(4-phenyl-1H-
imidazol-2-yl)acetamide (16a): White solid in 68%; m.p.: 198–
200–202°C; IR (KBr) nmax (cmꢁ1): 1137, 1336 (SO ), 1582 (C N), 1628
200°C; IR (KBr) nmax (cmꢁ1): 1141, 1330 (SO ), 1574 (C N), 1616
–
–
–
–
2
2
1
1
–
–
–
–
(C C), 1684 (NHCO), 3256 (NH); H NMR (DMSO-d ) d (ppm): 4.38 (s,
(C C), 1678 (NHCO), 3254 (NH); H NMR (DMSO-d ) d (ppm): 4.35 (s,
6
6
2H, CH2-(C-2 0)), 4.90 (s, 2H, CH2-(C-5 0)), 4.97 (s, 2H, CO–CH2), 7.48–
8.19 (m, 11H, Ar–H, C5-H, and C500-H), 9.91 (bs, 1H, N–NH), 11.34 (bs,
2H, CH2-(C-2 0)), 4.83 (s, 2H, CH2-(C-5 0)), 4.90 (s, 2H, CO–CH2), 7.28–
8.04 (m, 12H, Ar–H, C5-H, and C500-H), 9.78 (bs, 1H, N–NH), 11.30
(bs, 1H, NH–CO), 12.50 (bs, 1H, NH-(C-5)); 13C NMR (DMSO-d6) d
(ppm): 47.5 (CH2-(C-2 0)), 50.1 (CH2-(C-5 0)), 54.5 (CO–CH2), 122.9 (C-
400), 123.5 (C-5), 130.1 (C-300), 135.0 (C-500), 137.3 (C-2), 140.4 (C-4),
154.8 (C-2 0), 165.5 (C-5 0), 169.7 (CO), 127.3, 128.1, 128.9, 129.2,
13
1H, NH–CO); C NMR (DMSO-d6) d (ppm): 47.6 (CH2-(C-2 0)), 50.9
(CH2-(C-5 0)), 54.7 (CO–CH2), 123.0 (C-400), 131.7 (C-300), 135.9 (C-500),
138.3 (C-5), 140.2 (C-4), 151.3 (C-2), 158.2 (C-20), 166.7 (C-5 0), 171.8
(CO), 127.1, 128.4, 129.6, 130.2, 130.8, 132.2, 133.8, 136.2 (aromatic
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

66
N. Mahaboob Basha et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 54–67
131.2, 132.4, 134.7, 135.6 (aromatic carbons); MS (m/z): 567.61
[Mþ]. Anal. calcd. for C24H21N7O6S2: C 50.78, H 3.73, N 17.27;
Found: C 50.90, H 3.76, N 17.44%.
Nitric oxide (NO) scavenging activity
Nitric oxide scavenging activity was measured by slightly
modified methods of Green et al. [38] and Marcocci et al. [39].
Nitric oxide (NO) radicals were generated from sodium nitro-
prusside. One milliliter of sodium nitroprusside (10 mM) and
1.5 mL of phosphate buffer saline (0.2 M, pH 7.4) were added to
different concentrations (50, 75, and 100 mg/mL) of the test
compounds and incubated for 150 min at 25°C. After incubation,
1 mL of the reaction mixture was treated with 1 mL of Griess
reagent (1% sulfanilamide, 2% H3PO4 and 0.1% naphthylethyl-
enediamine dihydrochloride). The absorbance of the chromato-
phore was measured at 546 nm. Ascorbic acid was used as
standard. Nitric oxide scavenging activity was calculated by the
following equation
2-((5 0-((400-Phenyl-100H-pyrazol-300-ylsulfonyl)methyl)-
1 0,3 0,4 0-oxadiazol-20-yl)methylsulfonyl)-N-(4-p-tolyl-1H-
imidazol-2-yl)acetamide (16b): White solid in 72%; m.p.: 209–
211°C; IR (KBr) nmax (cmꢁ1): 1139, 1325 (SO ), 1572 (C N), 1613
–
–
2
1
–
(C C), 1676 (NHCO), 3242 (NH); H NMR (DMSO-d ) d (ppm): 2.38 (s,
–
6
3H, Ar–CH3), 4.33 (s, 2H, CH2-(C-2 0)), 4.80 (s, 2H, CH2-(C-5 0)), 4.87 (s,
2H, CO–CH2), 7.22–8.01 (m, 11H, Ar–H, C5-H, and C500-H), 9.75 (bs,
1H, N–NH), 11.24 (bs, 1H, NH–CO), 12.48 (bs, 1H, NH-(C-5)); 13C
NMR (DMSO-d6) d (ppm): 23.8 (Ar–CH3), 46.9 (CH2-(C-2 0)), 49.8 (CH2-
(C-5 0)), 53.7 (CO–CH2), 122.4 (C-400), 123.0 (C-5), 129.6 (C-300), 134.8
(C-500), 137.1 (C-2), 139.6 (C-4), 153.7 (C-2 0), 164.8 (C-5 0), 168.3 (CO),
129.7, 131.6, 132.5, 132.8, 133.5, 133.8, 134.6, 135.7 (aromatic
carbons); MS (m/z): 581.64 [Mþ]. Anal. calcd. for C25H23N7O6S2: C
51.63, H 3.99, N 16.86; Found: C 51.54, H 4.00, N 16.98%.
ꢀ
ꢁ
Acontrol ꢁ Asample
% of scavenging ¼
ꢃ 100
Ablank
where Acontrol is the absorbance of the control reaction
(containing all reagents and ascorbic acid), Asample is the
absorbance of the test compound (containing all reagents and
test compound), and Ablank is the absorbance of the blank
(containing only reagents). Tests were carried out in triplicate.
2-((5 0-((400-Phenyl-100H-pyrazol-300-ylsulfonyl)methyl)-
1 0,3 0,4 0-oxadiazol-20-yl)methylsulfonyl)-N-(4-(4-chloro-
phenyl)-1H-imidazol-2-yl)acetamide (16c): White solid in
74%; m.p.: 227–229°C; IR (KBr) nmax (cmꢁ1): 1142, 1334 (SO2), 1578
ABTS radical scavenging activity
1
–
–
(C N), 1625 (C C), 1682 (NHCO), 3256 (NH); H NMR (DMSO-d ) d
–
–
6
The antioxidant activity of the test compounds and standard
(ascorbic acid) were assessed on the basis of the radical scavenging
effect of the stable ABTS free radical. The ABTS•þ solution was
prepared by mixing 0.02 mol of ABTS salt with 0.01 mol of
potassium persulfate in 25 mL of distilled water. The solution
was kept at room temperature in the dark for 16 h before use.
Then the ABTS•þ solution was diluted with methanol in order
to obtain an absorbance between 0.7 and 0.9 at 734 nm using
the spectrophotometer. Fresh ABTS•þ solutions were prepared for
each assay. To 50, 75, and 100 mg/mL of each test compound and
standard, 1 mL of ABTS•þ solution was added and allowed to react
for 2 h in dark condition. Then the absorbance was taken at
734 nm using the spectrophotometer. The corresponding blank
reading was also taken and the results in percentage were
expressed as the ratio of absorbance decrease at 734 nm and
the absorbance of ABTS•þ solution in the absence of test
compounds.
(ppm): 4.37 (s, 2H, CH2-(C-2 0)), 4.85 (s, 2H, CH2-(C-5 0)), 4.94 (s, 2H,
CO–CH2), 7.31–8.06 (m, 11H, Ar–H, C5-H, and C500-H), 9.87 (bs, 1H,
N–NH), 11.32 (bs, 1H, NH–CO), 12.54 (bs, 1H, NH-(C-5)); 13C NMR
(DMSO-d6)
d
(ppm): 47.8 (CH2-(C-2 0)), 50.4 (CH2-(C-5 0)), 54.8
(CO–CH2), 123.7 (C-400), 124.2 (C-5), 130.5 (C-300), 135.5 (C-500),
138.0 (C-2), 141.2 (C-4), 155.4 (C-2 0), 166.1 (C-5 0), 170.2 (CO), 128.6,
130.4, 129.8, 130.2, 131.6, 132.0, 132.3, 135.3 (aromatic carbons);
MS (m/z): 602.05 [Mþ]. Anal. calcd. for C24H20ClN7O6S2: C 47.88, H
3.35, N 16.29; Found: C 47.94, H 3.40, N 16.39%.
Biological assays
Antioxidant activity
The compounds 5–16 were tested for antioxidant property by
DPPH, NO, and ABTS methods.
DPPH radical scavenging activity
The hydrogen atom or electron donation ability of the
compounds was measured from the bleaching of the purple
colored methanol solution of 2,2,-diphenyl-1-picrylhydrazyl
radical (DPPH). The spectrophotometric assay uses the stable
radical DPPH as a reagent. To 4 mL of 0.004% w/v methanol
solution of DPPH, 1 mL of various concentrations of the test
compounds (50, 75, and 100 mg/mL) in methanol were added.
After a 30 min incubation period at room temperature, the
absorbance was read against blank at 517 nm. Ascorbic acid was
used as the standard. The percent of inhibition (I%) of free radical
production from DPPH was calculated by the following equation
The authors are grateful to Council of Scientific and Industrial
Research (CSIR), New Delhi for financial assistance under major
research project. One of the authors, N. Mahaboob Basha, is grate
to University Grants Commission, New Delhi for the sanction of
UGC-BSR fellowship.
The authors have declared no conflict of interest.
References
ꢀ
ꢁ
Acontrol ꢁ Asample
[1] S. D. Joshi, H. M. Vagdevi, V. P. Vaidya, G. S. Gadaginamath,
I% ¼
ꢃ 100
Ablank
Eur. J. Med. Chem. 2008, 43, 1989–1996.
[2] M. Z. Wang, H. Xu, T. W. Liu, Q. Feng, S. J. Yu, S. H. Wang,
where Acontrol is the absorbance of the control reaction (containing
methanolic DPPH and ascorbic acid), Asample is the absorbance
of the test compound (containing methanolic DPPH and test
compound), and Ablank is the absorbance of the blank (containing
only methanolic DPPH). Tests were carried out in triplicate.
Z. M. Li, Eur. J. Med. Chem. 2011, 46, 1463–1472.
[3] A. Goel, N. Agarwal, F. V. Singh, A. Sharon, P. Tiwari, M. Dixit,
R. Pratap, A. K. Srivastava, P. R. Maulik, V. J. Ram, Bioorg. Med.
Chem. Lett. 2004, 14, 1089–1092.
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2014, 347, 54–67
Synthesis and Antioxidant Activity of Bis and Tris Heterocycles
67
[4] Y. Harrak, G. Rosell, G. Daidone, S. Plescia, D. Schillaci,
[20] Y. Li, Y. Luo, Y. Hu, D. D. Zhu, S. Zhang, Z. J. Liu, H. B. Gong,
M. D. Pujol, Bioorg. Med. Chem. 2007, 15, 4876–4890.
H. L. Zhu, Bioorg. Med. Chem. 2012, 20, 4316–4322.
[5] K. Starcevic, M. Kralj, K. Ester, I. Sabol, M. Grce, K. Pavelic,
[21] S. H. Lee, S. Kim, M. H. Yun, Y. S. Lee, S. N. Cho, T. Oh, P. Kim,
G. Karminski-Zamola, Bioorg. Med. Chem. 2007, 15, 4419–4426.
Bioorg. Med. Chem. Lett. 2011, 21, 1515–1518.
[6] D. Bandyopadhyay, S. Mukherjee, J. C. Granados, J. D. Short,
[22] E. Hernandez-Nunez, H. Tlahuext, R. Moo-Puc, H. Torres-
Gomez, R. Reyes-Martinez, R. Cedillo-Rivera, C. Nava-Zuazo,
G. Navarrete-Vazquez, Eur. J. Med. Chem. 2009, 44, 2975–2984.
B. K. Banik, Eur. J. Med. Chem. 2012, 50, 209–215.
[7] P. C. Lv, H. Q. Li, J. Sun, Y. Zhou, H. Y. Zhu, Bioorg. Med. Chem.
2010, 18, 4606–4614.
[23] K. Liu, H. L. Zhu, Anticancer Agents Med. Chem. 2011, 11, 687–
691.
[8] S. Bondock, W. Fadaly, M. A. Metwally, Eur. J. Med. Chem. 2010,
45, 3692–3701.
[24] Y. Hu, X. Lu, K. Chen, R. Yan, Q. S. Li, H. L. Zhu, Bioorg. Med.
Chem. 2012, 20, 903–909.
[9] F. F. Barsoum, A. S. Girgis, Eur. J. Med. Chem. 2009, 44, 2172–
2177.
[25] D. Kumar, S. Sundaree, E. O. Johnson, K. Shah, Bioorg. Med.
Chem. Lett. 2009, 19, 4492–4494.
[10] O. I. El-Sabbagh, M. M. Baraka, S. M. Ibrahim, C. Pannecouque,
G. Andrei, R. Snoeck, J. Balzarini, A. A. Rashad, Eur. J. Med. Chem.
2009, 44, 3746–3753.
[26] R. Kumar, A. Kumar, S. Jain, D. Kaushik, Eur. J. Med. Chem.
2011, 46, 3543–3550.
[11] M. Abdel-Aziz, G. E.-D. A. Abuo-Rahma, A. A. Hassan, Eur. J.
Med. Chem. 2009, 4, 3480–3487.
[27] A. Rauf, S. Sharma, S. Gangal, Chin. Chem. Lett. 2008, 19,
5–8.
[12] D. Clemett, K. L. Goa, Drugs 2000, 59, 957–980.
[28] M. Amir, K. Shikha, Eur. J. Med. Chem. 2004, 39, 535–
545.
[13] a) R. A. Hughes, C. J. Moody, Angew. Chem. Int. Ed. 2007, 46,
7930–7954; b) M. Inuoe, Org. Chem. 2008, 5, 77–84. Mini-Rev.
[29] S. V. Bhandari, K. G. Bothara, M. K. Raut, A. A. Patil,
A. P. Sarkate, V. J. Mokale, Bioorg. Med. Chem. 2008, 16, 1822–
1831.
[14] a) G. Crank, M. J. Foulis, J. Med. Chem. 1971, 14, 1075–1077; b)
G. Crank, M. Neville, R. Ryden, J. Med. Chem. 1973, 16, 1402–
1405; c) A. C. Giddens, H. I. M. Boshoff, S. G. Franzblau,
C. E. Barry, B. R. Copp, Tetrahedron Lett. 2005, 46, 7355–7357; d)
K. A. Z. Siddiquee, P. T. Gunning, M. Glenn, W. P. Katt,
S. Zhang, C. Schroeck, S. M. Sebti, R. Jove, A. D. Hamilton,
J. Turkson, ACS Chem. Biol. 2007, 2, 787–798; e) M. Kaspady,
V. K. Narayanaswamy, M. Raju, G. K. Rao, Lett. Drug Des. Discov.
2009, 6, 21–28.
[30] A. Husan, M. Ajmal, Acta Pharm. 2009, 59, 223–233.
[31] T. M. C. Tan, Y. Chen, K. H. Kong, J. Bai, Y. Li, S. G. Lim,
T. H. Ang, Y. Lam, Antiviral Res. 2006, 71, 7–14.
[32] G. Mallikarjuna Reddy, P. Ramachandra Reddy, V. Padmavathi,
A. Padmaja, Arch. Pharm. Chem. Life Sci. 2013, 346, 154–
162.
[33] A. Padmaja, C. Rajasekhar, A. Muralikrishan, V. Padmavathi,
[15] V. Zaharia, A. Ignat, N. Palibroda, B. Ngameni, V. Kuete,
C. N. Fokunang, M. L. Moungang, B. T. Ngadjui, Eur. J. Med.
Chem. 2010, 45, 5080–5085.
J. Chem. Pharm. Res. 2012, 4, 294–302.
[34] N. Mahaboob Basha, G. Lavanya, A. Padmaja, V. Padmavathi,
Arch. Pharm. Chem. Life Sci. 2013, 346, 511–520.
[16] A. Kamal, M. N. A. Khan, K. S. Reddy, K. Rohini, Bioorg. Med.
Chem. 2007, 15, 1004–1013.
[35] R. Maheshwari, P. Chawla, S. A. Saraf, Med. Chem. Res. 2011, 20,
1650–1655.
[17] K. J. Wilson, C. R. Illig, N. Subasinghe, J. B. Hoffman,
M. J. Rudolph, R. Soll, C. J. Molloy, R. Bone, D. Green,
T. Randall, M. Zhang, F. A. Lewandowski, Z. Zhou, C. Sharp,
D. Maguire, B. Grasberger, R. L. DesJarlais, J. Spurlino, Bioorg.
Med. Chem. Lett. 2001, 11, 915–918.
[36] M. Burits, F. Bucar, Phytother. Res. 2000, 14, 323–328.
[37] M. Cuendet, K. Hostettmann, O. Potterat, Helv. Chim. Acta
1997, 80, 1144–1152.
[38] L. C. Green, D. A. Wagner, J. Glogowski, P. L. Skipper, J. K.
S. R. Wishnok, Anal. Biochem. 1982, 126, 131–138.
[18] R. N. Sharma, F. P. Xavier, K. K. Vasu, S. C. Chaturvedi,
S. S. Pancholi, J. Enzyme Inhib. Med. Chem. 2009, 24, 890–897.
[39] L. Marcocci, J. J. Maguire, M. T. Droy-Lefaix, L. Packer, Biochem.
Biophys. Res. Commun. 1994, 201, 748–755.
[19] A. Khalaj, M. Nakhjiri, A. S. Negahbani, M. Samadizadeh,
L. Firoozpour, S. Rajabalian, N. Samadi, M. A. Faramarzi,
N. Adibpour, A. Shafiee, A. Foroumadi, Eur. J. Med. Chem. 2011,
46, 65–70.
[40] C. C. Teow, V. D. Truong, R. F. McFeeters, R. L. Thompson,
K. V. Pecota, G. C. Yencho, Food Chem. 2007, 103, 829–
838.
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com