Synthesis and antioxidant activity of a new class of bis and tris heterocycles

Article abstract of DOI:10.1002/ardp.201100361

A series of novel heterocycles, bisbenzoxazolyl/benzothiazolyl/ benzimidazolyl pyrazoles/isoxazoles/pyrimidines were synthesized and evaluated for their antioxidant activity. The bisbenzoxazolylisoxazole 10 exhibited good antioxidant activity when compared with the standard ascorbic acid.

Full text of DOI:10.1002/ardp.201100361

Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
1
Full Paper
Synthesis and Antioxidant Activity of a New Class of Bis
and Tris Heterocycles
Venkatapuram Padmavathi, Bhumireddy Chinnachennaiahgari Venkatesh, Akkarapalli
Muralikrishna, and Adivireddy Padmaja
Department of Chemistry, Sri Venkateswara University, Tirupati, Andhra Pradesh, India
A series of novel heterocycles, bisbenzoxazolyl/benzothiazolyl/benzimidazolyl pyrazoles/isoxazoles/
pyrimidines were synthesized and evaluated for their antioxidant activity. The bisbenzoxazolyl-
isoxazole 10 exhibited good antioxidant activity when compared with the standard ascorbic acid.
Keywords: Antioxidant activity / Benzimidazolyl pyrazoles / Benzothiazolyl / Bisbenzoxazolyl / Cyclocondensation /
Isoxazoles / Ketenedithiolates / Pyrimidines
Received: October 10, 2011; Revised: March 31, 2012; Accepted: April 12, 2012
DOI 10.1002/ardp.201100361
Introduction
etc. Thus the literature reflects that there is a constant strive
to develop a variety of heterocycles of pharmacological
potency. In this context, we prepared a new class of tris
heterocycles viz., bisbenzoxazolyl/benzothiazolyl/benzimid-
azolyl pyrazoles/isoxazoles/pyrimidines exploiting ketene
dithiolates as synthetic intermediates and studied their
antioxidant properties.
Heterocycles are well known for their wide range of bio-
logical properties. Pyrimidine derivatives gained importance
in medicinal chemistry for their therapeutic applications
[1, 2]. In fact pyrimidine forms an integral part of a large
number of pharmocologically important compounds like
thymine, riboflavin, purine bases and sulfadiazine [3–7],
etc. Pyrazole and isoxazole derivatives show a wide range Results and discussion
of activities including antiinflammatory [8], anticancer [9],
antibacterial [10], antiviral [11], antidiabetic [12], and anti-
microbial [13]. Besides, isoxazole analogs of curcuminoids
exhibit antioxidant activity [14]. They are therefore attractive
building blocks for pharmaceutical research (e.g., Celebrex,
Viagra, Acomplia, Valdecoxib, Celecoxib). The benzoxazole
ring is one of the most common heterocycles in medicinal
chemistry and plays an important role in designing new
drugs. Substituted benzoxazoles possess diverse chemother-
apeutic activities viz., antimicrobial [15–19], antiviral [20],
and antitumor [21, 22]. Benzothiazole derivatives have indus-
trial applications as antioxidants [23], vulcanization acceler-
ators, etc. [24]. The benzimidazole moiety exists in many
biologically active natural products and synthetic com-
pounds [25, 26]. Some of them exhibit clinical value toward
breast cancer [27–30], leukemia [31, 32], tumor cells [33, 34],
Chemistry
The general synthetic pathway for the synthesis of bis and
tris heterocycles is depicted in Scheme 1. The gem dicyano
compounds 2-(bis((benzo[d]oxazol-20-yl)methylthio)methylene)-
malononitrile (4), 2-(bis((benzo[d]thiazol-20-yl)methylthio)-
methylene)malononitrile (5), and 2-(bis((10H-benzo[d]imidazol-
20-yl)methylthio)methylene)malononitrile (6) were prepared
by a one pot reaction of malononitrile, carbon disulfide,
and 2-(chloromethyl)benzooxazole (1)/2-(chloromethyl)ben-
zothiazole (2)/2-(chloromethyl)-1H-benzimidazole (3) in the
presence of K2CO3 in DMF (Scheme 1). The compounds 1 and
2 were obtained by the irradiation of 2-aminophenol/2-amino-
thiophenol and chloroacetyl chloride for 10 min at a power
of 500 W [35, 36]. However, 3 was prepared by treating o-
phenylenediamine with chloroacetic acid in the presence of
1
5 N HCl [37]. The H NMR spectra of 4, 5, and 6 displayed a
singlet at d 4.41, 4.37, and 4.35 ppm due to methylene pro-
tons. The 13C NMR spectra of 4 exhibited signals at d 29.4,
83.5, 111.4, 182.8; 5 at 29.0, 83.8, 112.7, 183.5; and 6 at
Correspondence: Venkatapuram Padmavathi, Department of Chemistry,
Sri Venkateswara University, Tirupati 517 502, Andhra Pradesh, India.
E-mail: vkpuram2001@yahoo.com
–
–
2
28.9, 82.9, 111.8, 183.0 ppm due to CH , ((NC) C C), CN,
2
–
and (C CS(S)), respectively.
Fax: þ91-877-2249532
–
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2
V. Padmavathi et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
NC
NC
N
X
CS2
+
+
Cl
1 / 2 / 3
N
X
X
N
N
NH2
NH
S
S
S
X
i
N1
N2
O1
N2
5
4
3
5
3
4
X
S
4'
8'
5'
NH2
NH2
9'
N
iii
ii
N3'
2'
6'
7 / 8 / 9
10 / 11 / 12
1'
X
7'
NC
S
1
2
3
X
NC
S
N
N
N
vi
iv
N
NH2
Me
Me
NH
S
4 / 5 / 6
N
S
N
X
X
X
6
4
1
2
6
1
3
2
5
O
5
O
3
N
4
X
S
N
S
NH2
NH
v
N
19 / 20 / 21
13 / 14 / 15
N
NH2
N
S
S
X
X
1
2
6
4
5
S
3
N
NH2
N
16 / 17 / 18
(i) 1 Eq. K2CO3 / DMF/ °C to rt
.
(ii) NH2NH2 H2O / Piperidine / EtOH
(iii) NH2OH.HCl / Piperidine / EtOH
(iv) NH2CONH2 / Piperidine / EtOH
(v) NH2CSNH2 / Piperidine / EtOH
1 / 4 / 7 / 10 / 13 / 16 / 19; X = O
2 / 5 / 8 / 11 / 14 / 17 / 20; X = S
3 / 6 / 9 / 12 / 15 / 18 / 21; X = NH
(vi) MeNHCONHMe / Piperidine / EtOH
Scheme 1. Synthesis of bis and tris heterocycles.
The reaction of 4/5/6 with hydrazine hydrate in the pres-
ence of piperidine and ethanol resulted in 4-(bis((benzo[d]-
oxazol-20-yl)methylthio)methylene)-4H-pyrazole-3,5-diamine
(7), 4-(bis((benzo[d]thiazol-20-yl)methylthio)methylene)-4H-
pyrazole-3,5-diamine (8), and 4-(bis((10H-benzo[d]imidazol-
20-yl)methylthio)methylene)-4H-pyrazole-3,5-diamine (9). The
1H NMR spectra of 7, 8, and 9 displayed a singlet at d 4.37,
4.42, and 4.39 due to methylene protons and another broad
singlet at 5.74, 5.76, and 5.81 ppm due to NH2. In addition, 9
exhibited a broad singlet at 11.87 ppm due to NH of benz-
imidazole. The signals due to NH2 and NH disappeared
when D2O was added. Similarly, 4-(bis((benzo[d]oxazol-20-yl)-
methylthio)methylene)-4,5-dihydro-5-iminoisoxazol-3-amine
(10), 4-(bis((benzo[d]thiazol-20-yl)methylthio)methylene)-4,5-
dihydro-5-iminoisoxazol-3-amine (11), and 4-(bis((10H-benzo-
[d]imidazol-20-yl)methylthio)methylene)-4,5-dihydro-5-imino-
isoxazol-3-amine (12) were obtained by treating 4/5/6 with
hydroxylamine hydrochloride. The 1H NMR spectra of 10, 11,
and 12 displayed a singlet at d 4.40, 4.36, and 4.43 due to
methylene protons. Two broad singlets were observed at 5.77,
9.86 in 10, at 5.65, 9.72 in 11, and at 5.80, 9.98 ppm in 12,
–
which were accounted for NH2 and NH and disappeared
–
when D2O was added. Likewise, the reaction of 4/5/6
with urea produced 4,6-diamino-5-(bis((benzo[d]oxazol-20-yl)-
methylthio)methylene)pyrimidin-2(5H)-one (13), 4,6-diamino-
5-(bis((benzo[d]thiazol-20-yl)methylthio)methylene)pyrimidin-
2(5H)-one (14), and 4,6-diamino-5-(bis((10H-benzo[d]imidazol-20-
yl)methylthio)methylene)pyrimidin-2(5H)-one (15). Adopting
similar methodology, 4,6-diamino-5-(bis((benzo[d]oxazol-20-
yl)methylthio)methylene)pyrimidine-2(5H)-thione (16), 4,6-
diamino-5-(bis((benzo[d]thiazol-20-yl)methylthio)methylene)
pyrimidine-2(5H)-thione (17), and 4,6-diamino-5-(bis((10H-
benzo[d]imidazol-20-yl)methylthio)methylene)pyrimidine-
2(5H)-thione (18) were prepared by the reaction of 4/5/6
with thiourea. The 1H NMR spectra of 13–18 showed a
singlet ꢀ4.35 due to methylene protons and a broad singlet
ꢀ5.80 ppm due to NH2. The compounds 15 and 18 presented
another broad singlet ꢀ12.90 due to NH of benzimidazole.
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
Synthesis and Antioxidant Activity of Bis and Tris Heterocycles
3
Table 1. The in vitro antioxidant activity of 4–21 in DPPH method
Compound
Concentration
50 mg/mL
75 mg/mL
100 mg/mL
IC50 mmol/mL
4
5
52.43 ꢁ 1.42
54.31 ꢁ 1.21
58.71 ꢁ 1.38
0.117 ꢁ 1.29
–
–
–
–
6
–
–
–
–
7
8
9
64.10 ꢁ 0.94
66.12 ꢁ 0.86
67.42 ꢁ 1.01
0.089 ꢁ 0.46
49.32 ꢁ 1.75
50.92 ꢁ 1.42
51.23 ꢁ 1.84
0.108 ꢁ 1.80
–
–
–
–
10
11
12
13
14
15
16
17
18
19
20
21
75.40 ꢁ 0.37
76.31 ꢁ 0.65
79.12 ꢁ 0.71
0.075 ꢁ 0.16
53.45 ꢁ 1.31
56.32 ꢁ 1.87
58.81 ꢁ 1.55
0.097 ꢁ 1.13
–
–
–
–
57.31 ꢁ 1.03
59.14 ꢁ 1.41
61.24 ꢁ 1.32
0.094 ꢁ 0.78
–
–
–
–
–
–
–
–
56.71 ꢁ 0.89
58.30 ꢁ 1.26
61.10 ꢁ 1.06
0.092 ꢁ 0.69
–
–
–
–
–
–
–
–
68.23 ꢁ 0.37
69.18 ꢁ 0.16
71.31 ꢁ 0.25
0.074 ꢁ 0.20
–
–
–
–
–
–
–
–
Ascorbic acid 77.15 ꢁ 0.15
80.98 ꢁ 0.38
83.82 ꢁ 0.54
0.183 ꢁ 0.06
Blank
–
–
–
–
(ꢂ) Showed no scavenging activity. Values were the means of three replicates ꢁ SD.
The signals of NH2 and NH disappeared when D2O was added.
In the same manner, 5-(bis((benzo[d]oxazol-20-yl)methylthio)-
methylene)-tetrahydro-4,6-diimino-1,3-dimethylpyrimidin-
2(1H)-one (19), 5-(bis((benzo[d]thiazol-20-yl)methylthio)methyl-
ene)-tetrahydro-4,6-diimino-1,3-dimethylpyrimidin-2(1H)-one
(20), and 5-(bis((10H-benzo[d]-imidazol-20-yl)methylthio)methyl-
ene)-tetrahydro-4,6-diimino-1,3-dimethylpyrimidin-2(1H)-one
(21) were obtained by treating 4/5/6 with N,N0-dimethylurea
pyrazolyl and isoxazolyl derivatives, 7 and 10 showed good
radical scavenging activity in all the three methods when
compared with the standard ascorbic acid. On the other
hand, compounds 8 and 11 showed moderate activity
Table 2. The in vitro antioxidant activity of 4–21 in NO method
Compound
Concentration
1
50 mg/mL
75 mg/mL
100 mg/mL
(Scheme 1). The H NMR spectra of 19, 20, and 21 displayed
two singlets at d 4.37, 4.32, 4.45 and 2.74, 2.68, 2.70 due to
4
5
6
7
8
9
59.57 ꢁ 1.89
61.54 ꢁ 1.54
64.93 ꢁ 1.66
methylene and N-Me protons. A broad singlet was observed at
–
–
–
–
–
–
–
9.78, 9.81, and 9.89 ppm due to NH which disappeared
–
when D2O was added.
72.00 ꢁ 1.01
74.10 ꢁ 1.04
78.44 ꢁ 1.12
56.21 ꢁ 1.67
57.57 ꢁ 1.42
59.95 ꢁ 1.74
–
–
–
Biological results
10
11
12
13
14
15
16
17
18
19
20
21
84.22 ꢁ 1.86
87.51 ꢁ 1.54
89.85 ꢁ 1.71
61.13 ꢁ 1.24
62.20 ꢁ 1.02
65.15 ꢁ 1.08
–
–
–
Antioxidant activity
63.09 ꢁ 1.02
65.41 ꢁ 1.42
68.34 ꢁ 1.32
The compounds 4–21 were tested for antioxidant property
by 2,2,-diphenyl-1-picrylhydrazyl (DPPH) [38, 39], nitric oxide
(NO) [40, 41], and 2,20-azino-bis(3-ethylbenzthiazoline-6-
sulfonic acid) (ABTS) [42] methods.
–
–
–
–
–
–
61.19 ꢁ 1.34
63.32 ꢁ 1.15
65.26 ꢁ 1.23
–
–
–
–
–
–
The observed data on the antioxidant activity of the com-
pounds and control drug are shown in Tables 1–3. In this study
our goal is to identify the efficient heterocyclic moiety for
antioxidant activity. Amongst the gem dicyano compounds,
bisbenzoxazolyl derivative 4 was active while bisbenzothia-
zolyl (5) and bisbenzimidazolyl (6) compounds were inactive.
However, in the tris heterocyclic systems, compounds having
75.29 ꢁ 0.79
77.34 ꢁ 1.12
80.05 ꢁ 0.96
–
–
–
–
–
–
Ascorbic acid 86.02 ꢁ 0.91
89.46 ꢁ 1.31
91.53 ꢁ 1.22
Blank
–
–
–
(ꢂ) Showed no scavenging activity. Values were the means of
three replicates ꢁ SD.
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4
V. Padmavathi et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
Table 3. The in vitro antioxidant activity of 4–21 in ABTS method
200 FT-IR spectrometer as KBr pellets and the wave numbers are
given in cmꢂ1. 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 carried out by using a Shimadzu UV-2450 spectro-
photometer. The compounds 2-(chloromethyl)benzoxazole (1), 2-
(chloromethyl)benzothiazole (2), and 2-(chloromethyl)-1H-benz-
imidazole (3) were prepared by the literature procedure [35–37].
Compound
Concentration
50 mg/mL
75 mg/mL
100 mg/mL
4
5
17.21 ꢁ 1.54
18.82 ꢁ 1.87
20.53 ꢁ 1.95
–
–
–
6
–
–
–
7
8
9
25.61 ꢁ 1.54
26.17 ꢁ 1.45
27.48 ꢁ 1.75
16.31 ꢁ 1.71
17.14 ꢁ 1.85
19.39 ꢁ 1.97
–
–
–
10
11
12
13
14
15
16
17
18
19
20
21
27.40 ꢁ 1.10
28.00 ꢁ 1.54
28.74 ꢁ 1.34
17.33 ꢁ 0.89
19.42 ꢁ 0.68
20.56 ꢁ 1.02
–
–
–
19.43 ꢁ 1.35
20.93 ꢁ 1.57
21.55 ꢁ 1.79
General procedure for the synthesis of 2-(bis((benzo[d]-
oxazol-20-yl)methylthio)methylene)malononitrile (4)/2-
(bis((benzo[d]thiazol-20-yl)methylthio)methylene)-
malononitrile (5)/2-(bis-((10H-benzo[d]imidazol-20-yl)-
–
–
–
–
–
–
18.72 ꢁ 1.54
20.32 ꢁ 1.63
21.82 ꢁ 1.48
–
–
–
–
–
–
methylthio)methylene)malononitrile (6)
26.32 ꢁ 1.28
27.74 ꢁ 1.76
28.04 ꢁ 1.14
To a solution of dry potassium carbonate (1.38 g, 10 mmol) in
DMF (2 mL), malononitrile (0.66 g, 10 mmol) in DMF (1 mL)
followed by carbon disulfide (0.90 mL, 15 mmol) was added
dropwise under vigorous stirring. After 30 min, the reaction
mixture was cooled to 08C and to this 2-(chloromethyl)benzox-
azole (1)/2-(chloromethyl)benzothiazole (2)/2-(chloromethyl)-1H-
benzimidazole (3) (20 mmol) in DMF (5 mL) was added in 20–
30 min. The reaction mixture was further stirred for 1 h at room
temperature and poured into cold water. The precipitate was
collected, dried, and recrystallized from aqueous methanol.
–
–
–
–
–
–
Ascorbic acid 28.80 ꢁ 0.86
29.20 ꢁ 1.25
29.70 ꢁ 0.98
Blank
–
–
–
(ꢂ) Showed no scavenging activity. Values were the means of
three replicates ꢁ SD.
while 9 and 12 were inactive. Amongst compounds having
pyrimidine derivatives, compound 19 exhibited higher activity
when compared with compounds 13 and 16. This may be due to
the presence of electron donating methyl substituents and also
non-quinoline like heterocycle. The compounds 14, 15, 17, 18,
20, and 21 were inactive. This indicates that compounds with
benzoxazolyl unit exhibited greater activity than those having
benzothiazolyl and benzimidazolyl units. The presence of
other heterocyclic rings pyrazoles and isoxazoles enhances
the activity. Further the results exemplified that the compound
having the benzoxazolyl unit in combination with isoxazole
(10) is the most powerful antioxidant agent.
2-(Bis((benzo[d]oxazol-20-yl)methylthio)methylene)-
malononitrile 4
Yellow solid in 69%; m.p.: 169–1718C; IR (KBr) ymax (cmꢂ1): 1605
1
(C N), 1635 (C C), 2253 (C N); H NMR (DMSO-d ) d (ppm): 4.41
–
–
–
–
6
(s, 4H, CH2), 7.19–7.42 (m, 8H, Ar–H); 13C NMR (DMSO-d6) d (ppm):
0
–
–
2
29.4 (CH ), 83.5 ((NC) C C), 111.4 (CN), 163.5 (C-2 ), 182.8
2
–
(C CS(S)), 117.1, 120.6, 122.2, 124.6, 139.5, 149.0 (aromatic
–
carbons); MS (m/z): 404.33 [Mþꢃ]. Anal. Calcd. for C20H12N4O2S2:
C 59.39, H 2.99, N 13.85; Found: C 59.44, H 2.95, N 13.93%.
2-(Bis((benzo[d]thiazol-20-yl)methylthio)methylene)-
malononitrile 5
Yellow solid in 66%; m.p.: 186–1888C; IR (KBr) ymax (cmꢂ1): 1610
1
(C N), 1631 (C C), 2248 (C N); H NMR (DMSO-d ) d (ppm): 4.37
Conclusion
–
–
–
–
6
(s, 4H, CH2), 7.46–8.01 (m, 8H, Ar–H); 13C NMR (DMSO-d6) d (ppm):
0
–
–
2
29.0 (CH ), 83.8 ((NC) C C), 112.7 (CN), 169.1 (C-2 ), 183.5
2
In summary, we prepared a novel series of bisbenzoxazolyl/
benzothiazolyl/benzimidazolyl pyrazoles/isoxazoles/pyr-
imidines adopting simple and versatile synthetic methodo-
logies and identified bis benzoxazolyl isoxazole derivative as
potential antioxidant agent.
–
(C CS(S)), 120.4, 121.8, 124.3, 126.1, 135.2, 151.4 (aromatic
–
carbons); MS (m/z): 436.51 [Mþꢃ]. Anal. Calcd. for C20H12N4S4: C
55.02, H 2.77, N 12.83; Found: C 55.09, H 2.78, N 12.78%.
2-(Bis((10H-benzo[d]imidazol-20-yl)methylthio)methylene)-
malononitrile 6
Yellow solid in 74%; m.p.: 200–2028C; IR (KBr) ymax (cmꢂ1): 1603
Experimental
(C N), 1633 (C C), 2245 (C N), 3280 (NH); 1H NMR (DMSO-d6) d
(ppm): 4.35 (s, 4H, CH2), 7.28–7.53 (m, 8H, Ar–H), 12.78 (bs, 2H,
–
–
–
–
13
NH); C NMR (DMSO-d ) d (ppm): 28.9 (CH ), 82.9 ((NC) C C),
Chemistry
–
–
6
2
2
0
–
–
Melting points were determined in open capillaries on a Mel-
Temp apparatus and are uncorrected. The purity of the com-
pounds was checked by TLC (silica gel H, BDH, ethyl acetate/
hexane, 1:3). The IR spectra were recorded on a Thermo Nicolet IR
111.8 (CN), 150.4 (C-2 ), 183.0 (C CS(S)), 119.1, 121.4, 122.6,
127.9, 131.7, 137.5 (aromatic carbons); MS (m/z): 402.32 [Mþꢃ].
Anal. Calcd. for C20H14N6S2: C 59.68, H 3.51, N 20.88; Found: C
59.65, H 3.49, N 20.97%.
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
Synthesis and Antioxidant Activity of Bis and Tris Heterocycles
5
General procedure for the synthesis of 4-(bis((benzo[d]-
oxazol-20-yl)methylthio)methylene)-4H-pyrazole-3,5-
diamine (7)/4-(bis((benzo[d]thiazol-20-yl)methylthio)-
methylene)-4H-pyrazole-3,5-diamine (8)/4-(bis((10H-
benzo[d]imidazol-20-yl)methylthio)methylene)-4H-
4-(Bis((benzo[d]oxazol-20-yl)methylthio)methylene)-4,5-
dihydro-5-iminoisoxazol-3-amine 10
Pale yellow solid in 85%; m.p.: 191–1938C; IR (KBr) ymax (cmꢂ1):
1612 (C N), 1628 (C C), 3312 (NH), 3320, 3418 (NH ); 1H NMR
–
–
–
–
2
(DMSO-d6) d (ppm): 4.40 (s, 4H, CH2), 5.77 (bs, 2H, NH2), 7.18–7.52
(m, 8H, Ar–H), 9.86 (bs, 1H, NH); 13C NMR (DMSO-d6) d (ppm): 28.9
(CH2), 104.2 (C-4), 162.1 (C-20), 165.5, 167.2 (C-3, C-5), 176.0
pyrazole-3,5-diamine (9)
A solution of 4/5/6 (1 mmol), hydrazine hydrate (0.05 mL,
1.2 mmol), and piperidine (3 mL) in ethanol (10 mL) was heated
to reflux for 6–8 h. After completion of the reaction, it was
cooled and poured into ice-cold water containing conc. HCl.
The solid obtained was filtered, dried and recrystallized from
2-propanol.
–
(C CS(S)), 118.1, 122.8, 124.5, 126.7, 139.1, 149.6 (aromatic
–
carbons); MS (m/z): 437.28 [Mþꢃ]. Anal. Calcd. for C20H15N5O3S2:
C 54.91, H 3.46, N 16.01; Found: C 54.98, H 3.44, N 15.96%.
4-(Bis((benzo[d]thiazol-20-yl)methylthio)methylene)-4,5-
dihydro-5-iminoisoxazol-3-amine 11
Pale yellow solid in 84%; m.p.: 218–2208C; IR (KBr) ymax (cmꢂ1):
4-(Bis((benzo[d]oxazol-20-yl)methylthio)methylene)-4H-
pyrazole-3,5-diamine 7
1608 (C N), 1626 (C C), 3315 (NH), 3331, 3426 (NH ); 1H NMR
–
–
–
–
2
(DMSO-d6) d (ppm): 4.36 (s, 4H, CH2), 5.65 (bs, 2H, NH2), 7.67–8.14
(m, 8H, Ar–H), 9.72 (bs, 1H, NH); 13C NMR (DMSO-d6) d (ppm): 29.4
(CH2), 103.7 (C-4), 164.5, 166.0 (C-3, C-5), 167.4 (C-20), 175.6
Pale yellow solid in 80%; m.p.: 194–1968C; IR (KBr) ymax (cmꢂ1):
1610 (C N), 1625 (C C), 3320, 3415 (NH ); 1H NMR (DMSO-d6) d
(ppm): 4.37 (s, 4H, CH2), 5.74 (bs, 4H, NH2), 7.23–7.46 (m, 8H,
–
–
–
–
2
–
(C CS(S)), 120.9, 122.3, 125.9, 127.8, 134.3, 151.7 (aromatic
–
Ar–H); 13C NMR (DMSO-d6) d (ppm): 28.6 (CH2), 102.4 (C-4), 163.1
carbons); MS (m/z): 469.37 [Mþꢃ]. Anal. Calcd. for C20H15N5OS4:
C 51.15, H 3.22, N 14.91; Found: C 51.21, H 3.23, N 14.97%.
0
–
–
(C-2 ), 164.2 (C-3 & C-5), 174.8 (C CS(S)), 117.5, 121.4, 123.1, 125.6,
138.6, 149.8 (aromatic carbons); MS (m/z): 436.32 [Mþꢃ]. Anal.
Calcd. for C20H16N6O2S2: C 55.03, H 3.69, N 19.25; Found: C
55.09, H 3.73, N 19.34%.
4-(Bis((10H-benzo[d]imidazol-20-yl)methylthio)methylene)-
4,5-dihydro-5-iminoisoxazol-3-amine 12
Pale yellow solid in 89%; m.p.: 226–2288C; IR (KBr) ymax (cmꢂ1):
4-(Bis((benzo[d]thiazol-20-yl)methylthio)methylene)-4H-
pyrazole-3,5-diamine 8
1603 (C N), 1630 (C C), 3298 (NH), 3327, 3434 (NH ); 1H NMR
–
–
–
–
2
(DMSO-d6) d (ppm): 4.43 (s, 4H, CH2), 5.80 (bs, 2H, NH2), 7.25–7.76
(m, 8H, Ar–H), 9.98 (bs, 1H, NH), 12.74 (bs, 2H, NH); 13C NMR
(DMSO-d6) d [ppm]: 28.6 (CH2), 103.4 (C-4), 150.5 (C-20), 165.8, 167.9
Pale yellow solid in 88%; m.p.: 214–2168C; IR (KBr) ymax (cmꢂ1):
1612 (C N), 1630 (C C), 3325, 3419 (NH ); 1H NMR (DMSO-d6) d
(ppm): 4.42 (s, 4H, CH2), 5.76 (bs, 4H, NH2), 7.51–8.18 (m, 8H,
–
–
–
–
2
–
–
(C-3, C-5), 175.8 (C CS(S)), 117.2, 120.5, 122.3, 126.1, 131.1, 136.9
Ar–H); 13C NMR (DMSO-d6) d (ppm): 29.2 (CH2), 101.8 (C-4), 163.5
(aromatic carbons); MS (m/z): 435.39 [Mþꢃ]. Anal. Calcd.
for C20H17N7OS2: C 55.16, H 3.93, N 22.51; Found: C 55.20, H
3.96, N 22.59%.
0
–
–
(C-3 & C-5), 168.6 (C-2 ), 175.2 (C CS(S)), 121.9, 122.4, 124.9, 127.2,
134.7, 152.1 (aromatic carbons); MS (m/z): 468.49 [Mþꢃ]. Anal.
Calcd. for C20H16N6S4: C 51.26, H 3.44, N 17.93; Found: C
51.33, H 3.43, N 18.00%.
General procedure for the synthesis of 4,6-diamino-5-
(bis((benzo[d]oxazol-20-yl)methylthio)methylene)-
pyrimidin-2(5H)-one (13)/4,6-diamino-5-(bis((benzo[d]-
thiazol-20-yl)methylthio)methylene)pyrimidin-2(5H)-one
(14)/4,6-diamino-5-(bis((10H-benzo[d]imidazol-20-yl)-
4-(Bis((10H-benzo[d]imidazol-20-yl)methylthio)methylene)-
4H-pyrazole-3,5-diamine 9
Pale yellow solid in 82%; m.p.: 225–2278C; IR (KBr) ymax (cmꢂ1):
1609 (C N), 1631 (C C), 3295 (NH), 3331, 3428 (NH ); 1H NMR
–
–
–
–
2
methylthio)methylene)pyrimidin-2(5H)-one (15)
To an equimolar (1 mmol) mixture of compound 4/5/6 and urea,
piperidine (3 mL) and ethanol (10 mL) were added and heated to
reflux for 8–10 h. The contents of the flask were cooled and
poured into ice-cold water containing conc. HCl. The solid
separated was filtered, dried, and purified by recrystallization
from 2-propanol.
(DMSO-d6) d (ppm): 4.39 (s, 4H, CH2), 5.81 (bs, 4H, NH2), 7.26–7.60
(m, 8H, Ar–H), 11.87 (bs, 2H, NH); 13C NMR (DMSO-d6) d (ppm): 29.5
0
–
(CH ), 102.6 (C-4), 151.2 (C-2 ), 163.9 (C-3 & C-5), 174.5 (C CS(S)),
2
–
119.9, 122.0, 123.9, 128.7, 131.4, 136.3 (aromatic carbons); MS
(m/z): 434.51 [Mþꢃ]. Anal. Calcd. for C20H18N8S2: C 55.28, H 4.18,
N 25.79; Found: C 55.23, H 4.21, N 25.90%.
General procedure for the synthesis of 4-(bis((benzo[d]-
oxazol-20-yl)methylthio)methylene)-4,5-dihydro-5-
iminoisoxazol-3-amine (10)/4-(bis((benzo[d]thiazol-20-
yl)methylthio)methylene)-4,5-dihydro-5-iminoisoxazol-3-
amine (11)/4-(bis((10H-benzo[d]imidazol-20-yl)methylthio)-
4,6-Diamino-5-(bis((benzo[d]oxazol-20-yl)-
methylthio)methylene)pyrimidin-2(5H)-one 13
Yellow solid in 83%; m.p.: 210–2128C; IR (KBr) ymax (cmꢂ1):
–
–
1612 (C N), 1626 (C C), 1675 (CO–N), 3334, 3447 (NH2);
–
–
1H NMR (DMSO-d6) d (ppm): 4.32 (s, 4H, CH2), 5.78 (bs, 4H,
NH2), 7.18–7.58 (m, 8H, Ar–H); 13C NMR (DMSO-d6) d (ppm):
30.1 (CH2), 101.2 (C-5), 159.3 (C-2), 162.6 (C-20), 164.3 (C-4 &
methylene)-4,5-dihydro-5-iminoisoxazol-3-amine (12)
A mixture of 4/5/6 (1 mmol), hydroxylamine hydrochloride
(0.07 g, 1.1 mmol), piperidine (3 mL), and ethanol (10 mL) was
heated to reflux for 7–9 h. It was cooled and poured into ice-cold
water containing conc. HCl. The solid separated was collected,
dried, and recrystallized from 2-propanol.
–
C-6), 174.4 (C CS(S)), 119.8, 123.4, 125.0, 127.2, 139.2, 148.9
–
(aromatic carbons); MS (m/z): 464.43 [Mþꢃ]. Anal. Calcd.
for C21H16N6O3S2: C 54.30, H 3.47, N 18.09; Found: C 54.27, H
3.46, N, 18.14%.
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

6
V. Padmavathi et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
4,6-Diamino-5-(bis((benzo[d]thiazol-20-yl)-
methylthio)methylene)pyrimidin-2(5H)-one 14
4,6-Diamino-5-(bis((10H-benzo[d]imidazol-20-yl)-
methylthio)methylene)pyrimidine-2(5H)-thione 18
Yellow solid in 76%; m.p.: 235–2378C; IR (KBr) ymax (cmꢂ1): 1608
Pale yellow solid in 86%; m.p.: 266–2688C; IR (KBr) ymax (cmꢂ1):
1
(C N), 1628 (C C), 1664 (CO–N), 3329, 3427 (NH ); H NMR (DMSO-
–
–
– –
1495 (C S), 1607 (C N), 1626 (C C), 3282 (NH), 3323, 3443 (NH );
– –
2
–
–
d6) d (ppm): 4.40 (s, 4H, CH2), 5.89 (bs, 4H, NH2), 7.55–8.03 (m, 8H,
–
–
2
1H NMR (DMSO-d6) d (ppm): 4.39 (s, 4H, CH2), 5.69 (bs, 4H, NH2),
7.27–7.59 (m, 8H, Ar–H), 12.83 (bs, 2H, NH); 13C NMR (DMSO-d6) d
(ppm): 31.9 (CH2), 102.5 (C-5), 151.5 (C-20), 164.1 (C-4 & C-6), 173.2
Ar–H); 13C NMR (DMSO-d6) d (ppm): 30.6 (CH2), 102.3 (C-5), 160.2
(C-2), 167.5 (C-2 ), 165.5 (C-4 & C-6), 174.7 (C CS(S)), 120.4, 121.8,
0
–
–
–
124.3, 126.1, 134.9, 151.6 (aromatic carbons); MS (m/z): 496.61
[Mþꢃ]. Anal. Calcd. for C21H16N6OS4: C 50.79, H 3.25, N 16.92;
Found: C 50.85, H 3.26, N 16.99%.
(C-2), 173.9 (C CS(S)), 119.9, 123.9, 124.6, 127.3, 131.1, 136.9
–
(aromatic carbons); MS (m/z): 478.47 [Mþꢃ]. Anal. Calcd.
for C21H18N8S3: C 52.70, H 3.79, N 23.41; Found: C 52.74, H
3.82, N 23.49%.
4,6-Diamino-5-(bis((10H-benzo[d]imidazol-20-yl)-
methylthio)methylene)pyrimidin-2(5H)-one 15
General procedure for the synthesis of 5-(bis((benzo[d]-
oxazol-20-yl)methylthio)methylene)-tetrahydro-4,6-
diimino-1,3-dimethylpyrimidin-2(1H)-one (19)/5-
(bis((benzo[d]thiazol-20-yl)methylthio)methylene)-
tetrahydro-4,6-diimino-1,3-dimethylpyrimidin-2(1H)-one
(20)/5-(bis((10H-benzo[d]imidazol-20-yl)methylthio)-
methylene)-tetrahydro-4,6-diimino-1,3-dimethyl-
Yellow solid in 80%; m.p.: 246–2488C; IR (KBr) ymax (cmꢂ1): 1604
–
–
(C N), 1631 (C C), 1668 (CO–N), 3305 (NH), 3331, 3446 (NH );
–
–
2
1H NMR (DMSO-d6) d (ppm): 4.34 (s, 4H, CH2), 5.80 (bs, 4H, NH2),
7.28–7.67 (m, 8H, Ar–H), 12.93 (bs, 2H, NH); 13C NMR (DMSO-d6) d
(ppm): 29.8 (CH2), 101.2 (C-5), 149.9 (C-20), 159.8 (C-2), 164.9 (C-4 &
C-6), 173.8 (C ¼ CS(S)), 119.7, 121.4, 123.5, 127.9, 131.9, 136.7
(aromatic carbons); MS (m/z): 462.45 [Mþꢃ]. Anal. Calcd. for
C21H18N8OS2: C 54.53, H 3.92, N 24.23; Found: C 54.58, H 3.94,
N, 24.34%.
pyrimidin-2(1H)-one (21)
The compound 4/5/6 (1 mmol), N,N0-dimethylurea (0.08 g,
1 mmol), piperidine (3 mL), and ethanol (10 mL) were heated
to reflux for 9–11 h. The contents of the flask were cooled and
poured into ice-cold water containing conc. HCl. The solid sep-
arated was filtered, dried and purified by recrystallization from
2-propanol.
General procedure for the synthesis of 4,6-diamino-5-
(bis((benzo[d]oxazol-20-yl)methylthio)methylene)-
pyrimidine-2(5H)-thione (16)/4,6-diamino-5-(bis((benzo[d]-
thiazol-20-yl)methylthio)methylene)pyrimidine-2(5H)-
thione (17)/4,6-diamino-5-(bis((10H-benzo[d]imidazol-20-
yl)methylthio)methylene)pyrimidine-2(5H)-thione (18)
5-(Bis((benzo[d]oxazol-20-yl)methylthio)methylene)-
tetrahydro-4,6-diimino-1,3-dimethylpyrimidin-2(1H)-
one 19
A
mixture of 4/5/6 (2 mmol), thiourea (0.15 g, 2 mmol),
piperidine (4 mL), and ethanol (15 mL) was heated to reflux
for 12–15 h. The reaction mixture was cooled and poured into
ice-cold water containing conc. HCl. The solid separated was
filtered on a Buchner funnel, dried, and recrystallized from
2-propanol.
Yellow solid in 70%; m.p.: 200–2028C; IR (KBr) ymax (cmꢂ1): 1605
1
(C N), 1628 (C C), 1665 (CO–N), 3293 (NH); H NMR (DMSO-d ) d
–
–
–
–
6
(ppm): 2.74 (s, 6H, N–CH3), 4.37 (s, 4H, CH2), 7.21–7.39 (m, 8H,
Ar–H), 9.78 (bs, 2H, NH); 13C NMR (DMSO-d6) d (ppm): 27.2 (N–CH3),
30.5 (CH2), 101.2 (C-5), 155.2 (C-4 & C-6), 158.4 (C-2), 163.1 (C-20),
–
174.2 (C CS(S)), 119.6, 123.8, 124.5, 125.9, 139.5, 149.7 (aromatic
–
4,6-Diamino-5-(bis((benzo[d]oxazol-20-yl)methylthio)-
methylene)pyrimidine-2(5H)-thione 16
carbons); MS (m/z): 492.35 [Mþꢃ]. Anal. Calcd. for C23H20N6O3S2: C
56.08, H 4.09, N 17.06; Found: C 56.14, H 4.11, N 17.02%.
Pale yellow solid in 73%; m.p.: 215–2178C; IR (KBr) ymax (cmꢂ1):
1
–
–
5-(Bis((benzo[d]thiazol-20-yl)methylthio)methylene)-
tetrahydro-4,6-diimino-1,3-dimethylpyrimidin-2(1H)-
one 20
1487 (C S), 1611 (C N), 1629 (C ¼ C), 3319, 3437 (NH ); H NMR
–
(DMSO-d6) d (ppm): 4.42 (s, 4H, CH2), 5.72 (bs, 4H, NH2), 7.24–7.46
–
2
(m, 8H, Ar–H); 13C NMR (DMSO-d6) d (ppm): 31.3 (CH2), 102.1 (C-5),
162.8 (C-2 ), 164.3 (C-4 & C-6), 172.1 (C-2), 173.5 (C CS(S)), 119.2,
0
–
–
Yellow solid in 72%; m.p.: 228–2308C; IR (KBr) ymax (cmꢂ1): 1608
122.6, 123.9, 125.7, 139.9, 148.7 (aromatic carbons); MS (m/z):
480.51 [Mþꢃ]. Anal. Calcd. for C21H16N6O2S3: C 52.48, H 3.36, N
17.49; Found: C 52.45, H 3.33, N 17.45%.
1
(C N), 1625 (C C), 1662 (CO–N), 3276 (NH); H NMR (DMSO-d ) d
–
–
–
–
6
(ppm): 2.68 (s, 6H, N–CH3), 4.32 (s, 4H, CH2), 7.46–7.98 (m, 8H,
Ar–H), 9.81 (bs, 2H, NH); 13C NMR (DMSO-d6) d (ppm): 28.3 (N–CH3),
29.7 (CH2), 101.7 (C-5), 154.7 (C-4 & C-6), 157.6 (C-2), 168.5 (C-20),
4,6-Diamino-5-(bis((benzo[d]thiazol-20-yl)methylthio)-
methylene)pyrimidine-2(5H)-thione 17
–
173.8 (C CS(S)), 119.5, 123.1, 125.2, 126.8, 135.1, 151.7 (aromatic
–
carbons); MS (m/z): 524.46 [Mþꢃ]. Anal. Calcd. for C23H20N6OS4: C
52.65, H 3.84, N 16.02; Found: C 52.62, H 3.83, N 16.08%.
Pale yellow solid in 77%; m.p.: 240–2428C; IR (KBr) ymax (cmꢂ1):
1490 (C S), 1613 (C N), 1632 (C C), 3324, 3441 (NH ); 1H NMR
(DMSO-d6) d (ppm): 4.36 (s, 4H, CH2), 5.83 (bs, 4H, NH2), 7.49–8.08
–
–
–
–
–
–
2
5-(Bis((10H-benzo[d]imidazol-20-yl)methylthio)methylene)-
tetrahydro-4,6-diimino-1,3-dimethylpyrimidin-2(1H)-
one 21
(m, 8H, Ar–H); 13C NMR (DMSO-d6) d (ppm): 32.5 (CH2), 101.8
(C-5), 163.7 (C-4
&
C-6), 168.7 (C-20), 172.6 (C-2), 174.4
(C ¼ CS(S)), 119.2, 122.6, 124.3, 126.5 134.7, 151.2 (aromatic
carbons); MS (m/z): 512.63 [Mþꢃ]. Anal. Calcd. for C21H16N6S5:
Yellow solid in 75%; m.p.: 251–2538C; IR (KBr) ymax (cmꢂ1): 1611
–
–
C 49.19,
16.46%.
H
3.15,
N
16.39; Found:
C
49.25,
H
3.17,
N
(C N), 1627 (C C), 1667 (CO–N), 3285 (NH), 3318 (NH); 1H NMR
–
–
(DMSO-d6) d (ppm): 2.70 (s, 6H, N–CH3), 4.45 (s, 4H, CH2), 7.25–7.42
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
Synthesis and Antioxidant Activity of Bis and Tris Heterocycles
7
(m, 8H, Ar–H), 9.89 (bs, 2H, NH), 12.88 (bs, 2H, NH); 13C NMR
(DMSO-d6) d (ppm): 27.8 (N–CH3), 31.0 (CH2), 102.1 (C-5), 150.8
of the test compound (containing all reagents and test com-
pound), and Ablank is the absorbance of the blank (containing
only reagents).
0
–
(C-2 ), 155.3 (C-4 & C-6), 156.9 (C-2), 175.1 (C CS(S)), 120.2, 122.5,
–
125.3, 127.7, 132.1, 137.2 (aromatic carbons); MS (m/z): 490.39
[Mþꢃ]. Anal. Calcd. for C23H22N8OS2: C 56.31, H 4.52, N 22.84;
Found: C 56.35, H 4.55, N 22.93%.
ABTS radical scavenging activity
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
Biological assays
þ
ABTSꢃ solution was prepared by mixing 0.02 mol of ABTS
Antioxidant activity
The compounds 4–21 were evaluated for antioxidant
property by DPPH, NO, and ABTS methods.
salt with 0.01 mol of potassium persulfate in 25 mL of dis-
tilled water. The solution was kept at room tþemperature in
the dark for 16 h before use. Then the ABTSꢃ solution was
diluted with methanol in order to obtain an absorbance
between 0.7þand 0.9 at 734 nm using the spectrophotometer.
Fresh ABTSꢃ solutions were prepared for each assay. To 50,
75, and 100 mg/mL of each test compounds and standard,
1 mL of ABTSꢃþ 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 aþbsorbance decrease at 734 nm
and the absorbance of ABTSꢃ solution in the absence of
test compounds.
DPPH radical scavenging activity
The hydrogen atom or electron donation ability of the com-
pounds was measured from the bleaching of the purple
colored methanol solution of DPPH radical. The spectropho-
tometric 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 incu-
bation period at room temperature, the absorbance was read
against blank at 517 nm. Ascorbic acid was used as the stand-
ard. The percent of inhibition (I%) of free radical production
from DPPH was calculated by the following equation
The authors are grateful to University Grants Commission (UGC),
New Delhi, for financial assistance under major research project.
ÂÀ
Áꢀ
Ã
I% ¼ Acontrol ꢂ Asample Ablank ꢄ 100
where Acontrol is the absorbance of the control reaction (con-
taining methanolic DPPH and Ascorbic acid), Asample 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.
The authors have declared no conflict of interest.
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8
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