Synthesis and antioxidant evaluation of some new pyrazolopyridine derivatives

Article abstract of DOI:10.1002/ardp.201100171

4,6-Dimethyl-1H-pyrazolo[3,4-b]pyridine-3-amine (1) was used as a key intermediate for the synthesis of imidazolopyrazole derivatives 7-11 upon interaction with 3-(2-bromoacetyl)-2H-chromen-2-one (2), 2-(benzothiazol-2-yl)- 4-chloro-3-oxobutanenitrile (3), 2,3-dibromonaphthalene-1,4-dione (4), naphtha[2,3-b]oxirene-2,7-dione (5), 2,5-dichloro-3,6-dihydroxyhexa-2,5-diene-1, 4-dione (6), respectively. Acetylation of 11 afforded the bis-acetyl 12. Also, the imidazolopyrimidine 15 was prepared via treatment of 1 with sodium 3,4-dioxo-3,4-dihydronaphthalene-1-sulfonate (13) in DMF followed by cyclization of the bis-pyrazolopyrimidine 14 with glacial acetic acid. On the other hand, compound 1 was reacted with (E)-1-(4-methoxyphenyl)-5-(piperidin-1-yl)pent-1-en- 3-one hydrochloride (16), 2-hydroxy-3-((piperidin-1-yl)-methyl)-naphthalene-1,4- dione (17), 2-styryl-2H-indene-1,3-dione (18), enaminone 22, chloroquinoline-3-carbaldehyde 27a, chloroquinoline-(6-methyl)-3-carbaldehyde 27b and 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (28) to afford pyrazolo[3,4-a]pyrimidines 19-21, 23, 29a, 29b and 30, respectively. Also, the pyrazolopyrimidinone 33 was obtained via treatment of 1 with 1-cyanoacetyl-3,5-dimethylpyrazole (31) followed by cyclization of the formed intermediate 32 with glacial acetic acid. Finally, treatment of 1 with o-terephthalaldehyde in glacial acetic acid afforded diazepine 34. The newly synthesized compounds were screened for their antioxidant properties in which some of them exhibited promising activities. Compounds 1, 14, 15, 23, 26, 29a, 30 and 32 have the ability to protect DNA from the damage induced by bleomycin. New synthesized pyrazolopyridine derivatives were screened for their antioxidant properties. Some of the tested compounds as 1, 14, 15, 23, 26, 29a, 30 and 32 have the ability to protect DNA from the damage induced by bleomycin.

Full text of DOI:10.1002/ardp.201100171

Arch. Pharm. Chem. Life Sci. 2012, 345, 155–162
155
Full Paper
Synthesis and Antioxidant Evaluation of Some New
Pyrazolopyridine Derivatives
Moustafa A. Gouda
Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt
4,6-Dimethyl-1H-pyrazolo[3,4-b]pyridine-3-amine (1) was used as a key intermediate for the synthesis of
imidazolopyrazole derivatives 7–11 upon interaction with 3-(2-bromoacetyl)-2H-chromen-2-one (2), 2-
(benzothiazol-2-yl)-4-chloro-3-oxobutanenitrile (3), 2,3-dibromonaphthalene-1,4-dione (4), naphtha[2,3-
b]oxirene-2,7-dione (5), 2,5-dichloro-3,6-dihydroxyhexa-2,5-diene-1,4-dione (6), respectively.
Acetylation of 11 afforded the bis-acetyl 12. Also, the imidazolopyrimidine 15 was prepared via
treatment of 1 with sodium 3,4-dioxo-3,4-dihydronaphthalene-1-sulfonate (13) in DMF followed by
cyclization of the bis-pyrazolopyrimidine 14 with glacial acetic acid. On the other hand, compound 1
was reacted with (E)-1-(4-methoxyphenyl)-5-(piperidin-1-yl)pent-1-en-3-one hydrochloride (16), 2-
hydroxy-3-((piperidin-1-yl)-methyl)-naphthalene-1,4-dione (17), 2-styryl-2H-indene-1,3-dione (18),
enaminone 22, chloroquinoline-3-carbaldehyde 27a, chloroquinoline-(6-methyl)-3-carbaldehyde 27b
and 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (28) to afford pyrazolo[3,4-a]pyrimidines
19–21, 23, 29a, 29b and 30, respectively. Also, the pyrazolopyrimidinone 33 was obtained via treatment
of 1 with 1-cyanoacetyl-3,5-dimethylpyrazole (31) followed by cyclization of the formed intermediate
32 with glacial acetic acid. Finally, treatment of 1 with o-terephthalaldehyde in glacial acetic acid
afforded diazepine 34. The newly synthesized compounds were screened for their antioxidant
properties in which some of them exhibited promising activities. Compounds 1, 14, 15, 23, 26,
29a, 30 and 32 have the ability to protect DNA from the damage induced by bleomycin.
Keywords: Antioxidant activity / Imidazolopyrazole / Pyrazolopyridine / Pyrazolopyrimidine
Received: May 6, 2011; Revised: June 15, 2011; Accepted: June 20, 2011
DOI 10.1002/ardp.201100171
Introduction
Results and discussion
Chemistry
Pyrazole derivatives have attracted continued interest over the
years due to use of this ring system as an important core
structure in many drug substances, having a wide range of
pharmacological applications [1–6]. Furthermore, the use of
the pyrazolopyridine nucleus has pronounced pharmacologi-
cal applications in anxiolytic [7], antiviral [8, 9], antileishma-
nial [10] and anti-inflammatory agents [11]. In continuation of
our efforts [12–15] to identify new candidates that may be of
value in designing new, potent, selective and less toxic anti-
oxidant agents, we report herein the synthesis of some new
fused heterocycles containing pyrazolopyridine systems start-
ing from 4,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-3-amine (1).
The synthetic procedures adopted to obtain the target
compounds are depicted in Schemes 1–6. Compound 1
was prepared according to the previously reported method
[16].
Condensation of 1 with 3-(2-bromoacetyl)-2H-chromen-2-
one (2) [17], 2-(benzothiazol-2-yl)-4-chloro-3-oxobutanenitrile
(3) [18], 2,3-dibromonaphthalene-1,4-dione (4) [19], naph-
tha[2,3-b]oxirene-2,7-dione (5) [20] or 2,5-dichloro-3,6-dihy-
droxyhexa-2,5-diene-1,4-dione (6) in DMF/AcOH afforded the
corresponding imidazo[1,2-b]pyrazole derivatives 7–11,
respectively. Acetylation of 11 with acetic anhydride afforded
the bis-acetyl derivative 12 (Schemes 1 and 2).
Furthermore, the reactivity of aminopyrazole 1 towards
sodium 3,4-dihydro-3,4-dioxonaphthalene-1-sulfonate (13)
with the aim of preparing imidazo[1,2-b]pyrazole 15 was
investigated. Thus, treatment of 1 with two equivalent
Correspondence: Moustafa Ahmed Gouda, Faculty of Science,
Mansoura University, Mansoura, 35516, Egypt.
E-mail: dr_mostafa_chem@yahoo.com
Fax: (þ2050)2246781
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

156
M. A. Gouda
Arch. Pharm. Chem. Life Sci. 2012, 345, 155–162
O
N
CH3
N
O
O
O
H
N
O
Br
CH3
N
N
CH3
CH3
N
N
H
CH3
N
O
O
NH2
SO3Na
13
2
N
H3C
N
H
N
N
H3C
N
N
H
H3C
N
H
DMF/ AcOH
O
N
1
CH3
7
14a
NH2
N
O
CH3
CH3
N
N
N
H3C
N
CN
CH3
N
N
N
H
S
Cl
3
N
N
N
1
N
CH3
N
H
N
CH3
N
CH3
AcOH/DMF
O
NH
N
CH3
H3C
N
H
8
S
N
DMF/ AcOH
CN
H3C
N
N
H
N
H3C
N
N
14
H
15
Scheme 1. Reactions of 1 with a-halo ketones.
Scheme 3. Reaction of 1 with 1,2-naphthoquinone derivative 13
followed by cyclocondensation.
amounts of sodium 3,4-dihydro-3,4-dioxonaphthalene-1-sul-
fonate (13) through modification of the previously reported
method for the synthesis of analogs [21] afforded the bis-
pyrazolopyridine which upon treatment with acetic acid
under reflux afforded the imidazopyrazole 15 (Scheme 3).
Pyrazolo[3,4-a]pyrimidines are of considerable chemical
and pharmacological importance as purine analogues
[22, 23]. Various related compounds of these also have anti-
tumor, anti-leukemic activities. Several biological activities
have been established for some pyrazolo derivatives [24, 25].
Also, the insecticidal activities have been investigated for
some pyrazolo derivatives [26, 27]. We report herein the
synthesis of some pyrazolo[1,5-a]pyrimidines from 4,6-
dimethyl-1H-pyrazolo[3,4-b]pyridine-3-amine (1). Thus, com-
pound 1 was reacted with (E)-1-(4-methoxyphenyl)-5-(piperi-
din-1-yl)-pent-1-en-3-one hydrochloride (16) [28], 2-hydroxy-3-
((piperidin-1-yl)-methyl)-naphthalene-1,4-dione (17) [29] and 2-
styryl-2H-indene-1,3-dione (18) [30] in acetic acid to give the
pyrazolo[3,4-a]pyrimidines 19–21 (Scheme 4), respectively.
Moreover, treatment of 1 with the enaminone 22 in glacial
acetic acid afforded the pyrazolopyrimidine 23. Furthermore,
attempted preparation of the aminopyrazolopyrimidine 25
via treatment of 1 with (benzo[d]thiazol-2-yl)-3-(dimethyl-
amino)-acrylonitrile (24) [31] in glacial acetic acid failed
but instead gave the acrylonitrile 26 (Scheme 5).
Furthermore, treatment of 1 with 2-chloroquinoline-3-
carbaldehydes 27a and b and 5-chloro-3-methyl-1-phenyl-
1H-pyrazole-4-carbaldehyde (28) [32] in DMF afforded pyrazo-
lopyridine derivatives 29a,b and 30 (Scheme 6), respectively.
Cyanoacetylation of 1 with 1-cyanoacetyl-3,5-dimethylpyr-
azole (31) [33] in dioxane afforded the corresponding cyano-
acetamide derivative 32 which cyclized to the desired
pyrazolopyridine under the influence of glacial acetic acid
33. Finally, the reactivity of 1 towards o-terephthalaldehyde
(34) was also studied in order to synthesize the diazepine
derivative 35. Thus, o-terephthalaldehyde (34) was refluxed in
glacial acetic acid with 1 to afford 35.
Assignment of the newly synthesized compounds was
1
based on elemental analyses, IR, H-NMR and mass spectral
data (c.f. Experimental part).
O
O
.HCl
N
Br
CH3
N
H
N
CH3
Br
H3CO
N
O
N
O
O
O
16
OCH3
N
O
H3C
N
N
4
Cl
OH
Cl
H3C
N
N
AcOH
CH3
N
DMF/ AcOH
19
Br
HO
O
O
N
O
9
CH3
OH
N
N
OH
Cl
H
N
O
6
H3C
N
CH3
1
AcOH
NH2
HO
CH3
N
N
O
O
O
17
H3C
N
N
N
11
H3C
N
N
H
AcOH
O
5
N
H3C
N
1
20
Ac2O
DMF/ AcOH
O
HO
CH3
N
CH3
10
H
N
N
O
COCH3
O
O
18
N
N
O
H3C
N
H3C
N
N
AcOH
H3COCO
Cl
12
21
Scheme 2. Reactions of 1 with p-quinone derivatives ‘‘1,4-
diketones’’.
Scheme 4. Reactions of 1 with Mannich bases and arylidene
derivatives.
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Arch. Pharm. Chem. Life Sci. 2012, 345, 155–162
Pyrazolopyridines, Synthesis and Biological Studies
157
CH3
N
O
O
the free radical by the antioxidant material is measured calori-
metrically at a specific wavelength. The assay employs the
radical cation derived from 2,20-azino-bis-(3-ethyl benzthiazo-
line-6-sulfonic acid) (ABTS) as stable free radical to assess the
antioxidant potential of the investigated compounds.
N
CH3
N
N
O
CH3
H3C
N
O
O
22
dioxane/ POCl3
23
Some of the pyrazolopyridine derivatives exhibited
an antioxidant effect as shown in Table 1. Compared
with the control (ascorbic acid), the antioxidant potency
of compounds 1 and 8 was found to be highest, while
compounds 10, 11, 19 and 35 showed a moderate antioxidant
activity and the rest of the compounds tested showed
weak antioxidant activity. Compound 1 exhibited a high anti-
oxidant activity compared to the new synthesized compounds.
CH3
N
1
N
N
S
N
CN
CH3
N
H3C
N
S
NH2
N
25
24
CH3
CH3
N
AcOH
H
N
NH
Bleomycin-dependent DNA damage assay
H3C
N
N
NC
The compounds pyrazolopyridines were also to test for bleo-
mycin-dependent DNA damage (Table 1) and showed that
compounds 1, 14, 15, 23, 26, 29a, 30 and 32 have an ability
to protect DNA from damage induced by bleomycin. Also,
compound 1 exhibited a high antioxidant activity compared
to the new synthesized compounds. By comparing the results
obtained for the antioxidant properties of the compounds
reported in this study with their structures (Fig. 1), the
following structure activity relationships (SARs) were postu-
lated: (i) 3-Aminopyrazolopyridines 1 and 33 are more potent
than ascorbic acid which may be attributable to presence of
NH and pyrazolopyridine moieties. (ii) Compounds 29a,b, 30
and 32 are more potent or of similar potency as ascorbic acid
which may be due to presence of pyrazolopyridopyrimidine
moiety. (iii) Compound 23 has good antioxidant activity
which may be due to presence of coumarin and pyrazolopyri-
dopyrimidine moieties (Fig. 1).
S
26
Scheme 5. Reactions of
derivatives.
1
with N,N-dimethyletheneamine
CH3
N
N
CH3
H3C
H
N
CN
CN
O
CH3
N
CHO
Cl
R
N
O
31
dioxane
N
N
H3C
N
N
H
N
32
N
27a, b
H3C
N
DMF
AcOH
29a; R= H
29b; R= CH3
R
CH3
H
N
O
1
N
H3C
N
N
CH3
H3
C
CHO
Cl
NH2
N
N
33
N
O
N
Ph
CH3
N
28
CH3
H
H
H3C
N
N
N
N
DMF
Ph
O
34
30
N
H3C
N
N
EtOH/ AcOH
3:1
HO
35
Scheme 6. Reactions of 1 with different aldehyde and ketones.
Conclusion
Some of the tested compounds gave good activity by bleomycin-
dependent DNA damage assay than ABTS antioxidant assay
because the addition of aqueous buffer solution (pH 7)
re-precipitated the compound, so the antioxidant activity
decreased compared to that in case of bleomycin-dependent
DNA damage.
Biological activity
ABTS Antioxidant assay
The antioxidant activity of the synthesized compounds was
evaluated by the method of Lissi et al. [34]. The antioxidant
activity assay employed here is one of the several assays that
depend on measuring the consumption of stable free
radicals, i.e. they evaluate the free radical scavenging activity
of the investigated component. The methodology assumes
that the consumption of the stable free radical (X0) will be
determined by reactions as follows:
Experimental
All melting points are recorded on Gallenkamp electric melt-
ing point apparatus and are uncorrected. The IR spectra n
(cmꢀ1) (KBr) were recorded on a Perkin Elmer infrared
1
spectrophotometer Model 157. The H-NMR spectra of com-
XH þ Y0 ! X0 þ YH
(1)
pounds 7, 12, 20, 26 and 29a were recorded on a Bruker
The rate and/or the extent of the process measured in terms of
the decrease in X0 concentration would be related to the ability
of the added compounds to trap free radicals. The decrease in
color intensity of the free radical solution due to scavenging of
400 MHz spectrometer and were carried out at the Georgia
1
State University, Atlanta, GA, while the H-NMR spectra for
the rest of the compounds were obtained on a JEOL spectro-
photometer at 500 MHz, using TMS as an internal reference
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158
M. A. Gouda
Arch. Pharm. Chem. Life Sci. 2012, 345, 155–162
Table 1. Assay for ABTS antioxidant activity and bleomycin-dependent DNA damage
Compound No.
ABTS
Bleomycin-dependent DNA damage
Absorbance
Absorbance
%Inhibition
Control
Ascorbic acid
1
7
8
0.498
0.057
0.065
0.333
0.128
0.342
0.178
0.230
0.426
0.368
0.387
0.298
0.358
0.426
0.324
0.384
0.372
0.310
0.384
0.320
0.369
0.283
0.0
–
88.55
86.94
33.31
74.29
31.32
64.25
53.81
14.41
26.10
22.28
40.16
28.11
14.41
34.93
22.89
25.30
37.75
22.89
35.74
25.90
43.17
0.098
0.059
0.120
0.134
0.152
0.156
0.122
0.111
0.101
0.100
0.250
0.120
0.134
0.102
0.096
0.097
0.096
0.099
0.098
0.099
0.160
9
10
11
12
14
15
19
20
21
23
26
29a
29b
30
32
33
35
% Inhibition ¼ ðAcontrol ꢀ Atest=AcontrolÞ ꢁ 100 Eq: ð2Þ
Acontrol: Absorbance for ascorbic acid
Atest: Absorbance for the tested samples
Control: Ascorbic acid
CH3
2,3-dibromonaphthalene-1,4-dione (4) (0.63 g, 2 mmol), naphtha[2,3-
b]oxirene-2,7-dione (5) (0.63 g, 2 mmol) or 2,5-dichloro-3,6-
dihydroxyhexa-2,5-diene-1,4-dione (6) (0.42 g, 2 mmol) were
added. The reaction mixture was heated under reflux for 6–
12 h. The mixture was poured into ice cold-water and
neutralized by adding sodium bicarbonate solution. The
resulting precipitate was filtered off, dried and crystallized
from EtOH/DMF to afford imidazo[1,2-b]pyrazole derivatives
7–11.
CH3
N
NHR
N
O
H3C
N
N
O
N
H3C
N
N
H
1, R= H
32, R= COCH2CN
23
CH3
N
CH3
N
CH3
H
N
N
N
N
O
N
CH3
N
N
H3C
N
H3C
N
H3C
N
N
N
N
NH2
33
Ph
29a, R= H
29b, R= CH3
30
R
2,4-Dimethyl-6-(2H-chromen-2-on-3-yl)imidazo[10,20;2,3]-
pyrazolo[5,4-b]pyridine (7)
Figure 1. Structure activity relationships of the more potent
compounds.
Reddish brown crystals, reaction time 7 h, yield, 80%, mp:
>3208C, IR (KBr): nmax, cmꢀ1: 3255 (NH), 1724 (CO), 1615
–
–
and DMSO-d6 as solvent, carried out in the National Research
Center, Dokki, Giza, Egypt. The mass spectra (EI) were
recorded at 70 eV with JEOL JMS600 equipment at the
Central Laboratory, Assiut University. Elemental analyses
(C, H and N) were carried out at the Microanalytical
Center of Cairo University, Giza, Egypt.
(C N); 1H-NMR (DMSO-d6): d 2.77 (s, 3H, CH3), 2.79 (s, 3H,
CH3), 6.98–8.10 (m, 6H, Ar–H), 8.47 (s, 1H, C-H4, coumarin),
9.65 (br, s, 1H, NH); MS (EI): m/z (%) 330 (Mþ, 100%), 313 (3.9),
261 (0.8), 2.28 (0.9), 169 (16.6), 145 (13.3), 100 (13.0), 77 (3.2),
72 (100). Anal. calcd. for C19H14N4O2 (330.34): C, 69.08; H,
4.27; N, 16.96%. Found: C, 69.12; H, 4.20; N, 16.99%.
Synthesis of imidazo[1,2-b]pyrazoles 7–11
2-(Benzo[d]thiazol-2-yl)2-(2,4-dimethyl-imidazo-
[10,20;2,3]pyrazolo[5,4-b]pyridin-6-yl-acetonitrile (8)
To a suspension of 1 (0.32 g, 2 mmol) in DMF/AcOH (11 mL,
10:1), 3-(2-bromoacetyl)-2H-chromen-2-one (2) (0.53 g, 2 mmol),
2-(benzothiazol-2-yl)-4-chloro-3-oxobutanenitrile (3) (0.47 g, 2 mmol),
Brown powder, reaction time 9 h, yield, 77%, mp: >2108C, IR
1
(KBr): nmax, cmꢀ1: 3255 (NH), 2170 (CN), 1620 (C N); H-NMR
–
–
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Arch. Pharm. Chem. Life Sci. 2012, 345, 155–162
Pyrazolopyridines, Synthesis and Biological Studies
159
(DMSO-d6): d 2.69 (s, 3H, CH3), 2.84 (s, 3H, CH3), 6.54 (s, 1H,
CHCN), 7.01–8.03 (m, 6H, Ar–H), 9.59 (br, s, 1H, NH); MS (EI):
m/z (%) 358 (Mþ, 1.3), 323 (0.8), 299 (0.4), 232 (23.3), 212 (14.9),
174 (53.1), 162 (100), 135 (11.6), 107 (11.8), 82 (19.3). Anal.
calcd. for C19H14N6S (358.42): C, 63.67; H, 3.94; N, 23.45%.
Found: C, 63.69; H, 3.91; N, 23.5%.
(10.2), 134 (5.7), 109 (22.2),75 (13.8), 70 (1.3). Anal. calcd.
for C18H13ClN4O5 (400.77): C, 53.94; H, 3.27; N, 13.98%.
Found: C, 53.89; H, 3.30; N, 14.02%.
N-[2-(4,6-Dimethyl-pyrazolo[3,4-b]pyridin-3-yl-imino)-
naphthalen-1-oxo-4-yl]-4,6-dimethyl-pyrazolo-
[3,4-b]pyridin-3-amine (14)
1-Bromo-2,4-dimethyl-10H-naphthol[100,200;40,50]-
To a suspension of 1 (1.27 g, 8 mmol) in DMF (15 mL), a
solution of 3,4-dihydro-3,4-dioxonaphthalene-1-sulfonate
(13) (1.04 g, 4 mmol) in H2O (10 mL) was added. The reaction
mixture was heated under reflux for 6 h. The resulting
precipitate was filtered off, dried and recrystallized from
EtOH/DMF to afford compound 14.
imidazo[10,20;2,3]pyrazolo[5,4-b]pyridine-10-one (9)
Reddish brown crystals, reaction time 11 h, yield, 90%, mp:
1
>3208C, IR (KBr): nmax, cmꢀ1: 1666 (CO), 1606 (C N); H-NMR
–
–
(DMSO-d6): d 2.68 (s, 3H, CH3), 2.82 (s, 3H, CH3), 7.05–8.11
(m, 5H, Ar–H); MS (EI): m/z (%) 381 (Mþþ2, 0.2), 379 (Mþ, 0.2),
282 (100), 239 (0.5), 206 (0.4), 173 (6.1), 108 (18.6), 72 (34.9).
Anal. calcd. for C18H11BrN4O (379.21): C, 57.01; H, 2.92;
N, 14.77%. Found: C, 57.08; H, 2.93; N, 14.75%.
Red powder, reaction time 6 h, yield, 90%, mp: >3208C, IR
(KBr): nmax, cmꢀ1: 3434, 3357, 3145 (3NH), 1660 (CO), 1598
1
(C N); H-NMR (DMSO-d ): d 2.67 (br, s, 6H, 2CH ), 2.82 (br, s,
–
–
6
3
6H, 2CH3), 7.18–7.94 (m, 6H, Ar–H), 8.81 (br, s, 1H, NH), 9.99
(br, s, 1H, NH, pyrazole), 13.04 (br, s, 1H, NH, pyrazole); MS
(EI): m/z (%) 463 (Mþþ1, 1.3), 452 (1.7), 387 (100), 358 (75.5), 313
(65.7), 278 (22.6), 262 (18.7), 228 (37.7), 194 (23.4), 161 (40.0),
96 (24.4), 72 (62.3). Anal. calcd. for C26H22N8O (462.51):
C, 67.52; H, 4.79; N, 24.23%. Found: C, 67.50; H, 4.75;
N, 24.20%.
2,4,-Dimethyl-11-hydroxy-10H-naphthol[100,200;40,50]-
imidazo[10,20;2,3]pyrazolo[5,4-b]pyridine-10-one (10)
Black powder, reaction time 8 h, yield, 80%, mp: >3208C, IR
1
(KBr): nmax, cmꢀ1: 3415 (OH), 1660 (CO), 1613 (C N); H-NMR
–
–
(DMSO-d6): d 2.56 (s, 3H, CH3), 2.69 (s, 3H, CH3), 7.03–8.30
(m, 6H, OH, Ar–H); MS (EI): m/z (%) 316 (Mþ, 4.0), 314 (22.2), 278
(30.3), 186 (100),162 (47.5), 129 (47.5), 90 (39.4), 79 (65.7), 69
(99.0), 59 (38.4). Anal. calcd. for C18H12N4O2 (316.31): C, 68.35;
H, 3.82; N, 17.71%. Found: C, 68.30; H, 3.69; N, 17.76%.
2,4-Dimethyl-10-(4,6-dimethyl-pyrazolo[3,4-b]pyridin-3-yl-
imino)-10H-naphthol[100,200;40,50]imidazo[10,20;2,3]-
pyrazolo[5,4-b]pyridine (15)
7-Chloro-6,9-dihydroxy-2,4-dimethyl-8H-naphthol-
[100,200;40,50]imidazo[10,20;2,3] pyrazolo[5,4-b]pyridine-8-
one (11)
A suspension of 14 (0.463 g, 1 mmol) in a mixture of DMF/
AcOH (16 mL, 1:1) was refluxed for 12 h. The resulting pre-
cipitate was filtered off, dried and recrystallized from DMF to
afford compound 15.
Black powder, reaction time 13 h, yield, 80%, mp: >3208C, IR
(KBr): nmax, cmꢀ1: 3239-3199 (br, 2OH), 1640 (CO) and 1618
Reddish brown powder, yield, 79%, mp: >3208C, IR (KBr):
1
(C N); H-NMR (DMSO-d ): d 2.69 (s, 3H, CH ), 2.79 (s, 3H, CH ),
1
nmax, cmꢀ1: 1656 (CO), 1600 (C N); H-NMR (DMSO-d ): d 2.69
–
–
–
–
6
3
3
6
7.03 (s, 1H, Ar–H), 7.13 (br., 1H, OH), 7.23 (br., 1H, OH); MS (EI):
m/z (%) 318 (Mþþ2, 0.1), 316 (Mþ, 0.2), 282 (100), 251 (0.5), 211
(0.4), 170 (5.8), 147 (3.2), 123 (2.7), 109 (20.4), 75 (7.8), 70 (1.0).
Anal. calcd. for C14H9ClN4O3 (316.7): C, 53.09; H, 2.86;
N, 17.69%. Found: C, 53.05; H, 2.89; N, 17.64%.
(br, s, 6H, 2CH3), 2.79 (br, s, 6H, 2CH3), 6.94–8.13 (m, 6H,
Ar–H), 9.95 (br, s, 1H, NH); MS (EI): m/z (%) 444 (Mþ, 5.3), 431
(28.9), 400 (5.3), 379 (19.7), 343 (18.4), 298 (17.1), 262 (38.2),
239 (80.3), 186 (56.6), 162 (14.5), 89 (42.1), 72 (100), 56 (55.3).
Anal. calcd. for C26H20N8 (444.49): C, 70.26; H, 4.54; N, 25.21%.
Found: C, 70.34; H, 4.58; N, 25.25%.
7-Chloro-2,4-dimethyl-8H-naphthol[100,200;40,50]imidazo-
[10,20;2,3]pyrazolo[5,4-b] pyridine-8-one-6,9-diyl-
diacetate (12)
Synthesis of pyrazolopyrimidine derivatives 19–21 and 26
To a suspension of 1 (0.528 g, 4 mmol) in glacial acetic
acid (25 mL), (E)-1-(4-methoxyphenyl)-5-(piperidin-1-yl)-pent-
1-en-3-one hydrochloride (16) (1.24 g, 4 mmol), 2-hydroxy-3-
((piperidin-1-yl)-methyl)-naphthalene-1,4-dione (17) (1.08 g,
4 mmol), 2-styryl-2H-indene-1,3-dione (18) (0.97 g, 4 mmol)
or (E)-2-(benzol[d]thiazol-2-yl)-3-(dimethylamino)-acrylonitrile
(24) (0.92 g, 4 mmol) were added. The reaction mixture was
heated under reflux for 15–20 h (TLC control). The reaction
mixture was poured into ice cold-water then the resulting
precipitate was filtered off, dried and crystallized from EtOH/
DMF to afford compounds 19–21 and 26, respectively.
A suspension of 11 (0.316 g, 1 mmol) in acetic anhydride
(10 mL), was refluxed for 3 h. The reaction mixture was
poured into ice cold water and then the formed precipitate
was filtered off, dried and crystallized from DMF/EtOH to
give 12.
Black powder, yield, 84%, mp: >3208C, IR (KBr): nmax, cmꢀ1
:
1705 (br, 2CO), 1636 (CO), 1600 (C N); 1H-NMR (DMSO-d6):
–
–
d 2.27 (br, s, 6H, 2COCH3), 2.72 (s, 3H, CH3), 2.83 (s, 3H, CH3),
7.20 (s, 1H, Ar–H); MS (EI): m/z (%) 402 (Mþþ2, 0.6), 400 (Mþ,
1.6), 358 (6.8), 282 (100), 268 (0.8), 238 (1.9), 204 (1.6), 170
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M. A. Gouda
Arch. Pharm. Chem. Life Sci. 2012, 345, 155–162
5,6-Dihydro-2,4-dimethyl-8-(4-methoxy-styrenyl-1,5,8a,9-
tetrazafluorene (19)
neutralized with sodium bicarbonate solution to obtain a
yellow solid product which was filtered off, washed with
water, dried and finally crystallized from DMF/EtOH to
give 23.
Brown powder, reaction time 15 h, yield, 69%, mp: >3108C,
1
IR (KBr): nmax, cmꢀ1: 3378 (NH), 1615 (C N); H-NMR (DMSO-
–
–
d6): d 2.69 (s, 3H, CH3), 2.84 (s, 3H, CH3), 3.70–3.74 (m, 5H,
OCH3, CH2 of pyrimidine), 6.50–7.41 (m, 9H, NH, 2CH, ole-
finic, Ar–H); MS (EI): m/z (%) 332 (Mþþ2, 5.7), 330 (Mþ, 22.9),
316 (3.8), 279 (8.5), 243 (5.7), 200 (22.5), 161 (100), 120 (43.0),
90 (3.9). Anal. calcd. for C20H20N4O (332.4): C, 72.27; H, 6.06;
N, 16.86%. Found: C, 72.30; H, 6.01; N, 16.91%.
Yellow crystals, yield, 77%, mp: >3208C, IR (KBr):
nmax, cmꢀ1: 1724 (CO), 1606 (C N); 1H-NMR (DMSO-d6):
–
–
d 2.66 (s, 3H, CH3), 2.80 (s, 3H, CH3), 7.04–8.56 (m, 8H,
Ar–H, C-4 coumarin); MS (EI): m/z (%) 342 (Mþ, 100%),
315 (32.2), 271 (8.2), 212 (25.3), 162 (20.2), 101 (4.2), 75
(9.3). Anal. calcd. for C20H14N4O2 (342.35): C, 70.17; H, 4.12;
N, 16.37%. Found: C, 70.26; H, 4.17; N, 16.42%.
5,6-Dihydro-2,4-dimethyl-1,5,12a,13-tetraza-indene-
[1,2-c]phenanthrene-7,8-dione (20)
Synthesis of pyrazolopyrimidine derivatives 29a,b and 30
Black powder, reaction time 17 h, yield, 90%, mp: >3208C,
IR (KBr): nmax, cmꢀ1: 3394 (NH), 1668 (br., 2CO), 1616 (C N);
General procedure
–
–
1H-NMR (DMSO-d6): d 2.69 (s, 3H, CH3), 2.81 (s, 3H, CH3), 4.76
(br., 2H, CH2), 6.54 (br., s, 1H, NH), 7.10–8.03 (m, 5H, Ar–H); MS
(EI): m/z (%) 330 (Mþ, 5.7), 328 (8.1), 313 (35.7), 278 (24.6), 253
(15.5), 229 (25.5), 195 (17.2), 179 (23.6), 170 (34.3), 161 (100),
156 (3.7), 96 (31.0), 69 (32.7). Anal. calcd. for C19H14N4O2
(330.34): C, 69.08; H, 4.27; N, 16.96%. Found: C, 69.06;
H, 4.29; N, 17.02%.
A suspension of compound 1 (0.324 g, 2 mmol and 2-chlor-
oquinoline-3-carbaldehyde (27a) (0.382 g, 2 mmol), 6-methyl-
2-chloro-quinoline-3-carbaldehyde (27b) (0.411 g, 2 mmol) or
5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (28)
(0.442 g, 10 mmol) in DMF (15 mL) was heated under reflux
with stirring for 7–12 h (TLC control). The reaction mixture
was poured onto crushed ice, the formed precipitate filtered
off, dried and recrystallized to afford compounds 29a,b and
30, respectively.
5,6-Dihydro-2,4-dimethyl-6-phenyl-1,5,11a,12-tetraza-
indene[1,2-c]fluoren-7-one (21)
Reddish brown powder, reaction time 20 h, yield, 79%,
mp: >3208C, IR (KBr): nmax, cmꢀ1: 3255 (NH), 1724 (CO),
2,4-Dimethyl-1,5,12,12a,13-pentazaindeno[2,1-a]-
anthracene (29a)
Pale yellow powder, reaction time 12 h, crystallization from
1615 (C N); 1H-NMR (DMSO-d6): d 2.55 (s, 3H, CH3), 2.65
–
–
(s, 3H, CH3), 4.01 (d, 1H, CH, J ¼ 9.65), 7.03–7.31 (m, 5H,
Ar–H), 8.97 (br, s, 1H, NH); MS (EI): m/z (%) 330 (Mþ, 100%),
313 (3.9), 261 (0.8), 2.28 (0.9), 169 (16.6), 145 (13.3),
100 (13.0), 77 (3.2), 72 (100). Anal. calcd. for C24H18N4O
(378.43): C, 76.17; H, 4.79; N, 14.81%. Found: C, 76.15;
H, 4.84; N, 14.86%.
DMF/EtOH, yield, 90%, mp: >3208C, IR (KBr): nmax, cmꢀ1: 1608
1
(C N); H-NMR (DMSO-d ): d 2.69 (s, 3H, CH ), 2.80 (s, 3H, CH ),
–
–
6
3
3
–
7.12–8.23 (m, 6H, Ar–H), 9.25 (s, 1H, CH N). MS (EI): m/z (%)
–
299 (Mþ, 100), 269 (1.6), 257 (5.5), 230 (9.2), 197 (7.4), 175
(1.7), 140 (1.3), 79 (1.7). Anal. calcd. for C18H13N5 (299.33):
C, 72.23; H, 4.38; N, 23.40%. Found: C, 72.17; H, 4.33;
N, 23.34%.
(E)-3-(4,6-Dimethyl-2H-pyrazolo[3,4-b]pyridin-3-ylamino)-
2-(benzo[d]thiazol-2-yl) acrylonitrile (26)
2,4,9-Trimethyl-1,5,12,12a,13-pentazaindeno[2,1-a]-
anthracene (29b)
Yellow powder, reaction time 10 h, crystallization from
Yellow crystals, reaction time 20 h, yield, 82%, mp: >3208C,
IR (KBr): nmax, cmꢀ1: 3359, 3237 (2NH), 2206 (CN), 1619 (C N);
–
–
1H-NMR (DMSO-d6): d 2.69 (s, 3H, CH3), 2.80 (s, 3H, CH3), 7.10–
8.25 (m, 5H, Ar–H), 8.65 (s, 1H, CH), 8.95 (s, 1H, NH), 9.0 (s, NH,
pyrazole); MS (EI): m/z (%)¼ 346 (Mþ, 17.7), 331 (8.1), 223 (28.8),
179 (10.9), 146 (6.4), 135 (100), 107 (16.0), 88 (2.9). Anal. calcd.
for C18H14N6S (346.41): C, 62.41; H, 4.07; N, 24.26%. Found:
C, 62.47; H, 4.15; N, 24.32%.
DMF/EtOH, yield, 88%, mp: >3208C, IR (KBr): nmax, cmꢀ1
:
1612 (C N); 1H-NMR (DMSO-d6): d 2.05 (s, 3H, CH3), 2.70
–
–
(s, 3H, CH3), 2.85 (s, 3H, CH3), 7.01–8.26 (m, 5H, Ar–H), 9.43
þ
–
(br., s, 1H, CH N); MS (EI): m/z (%) 314 (M , 100), 289 (1.6), 247
–
(0.9), 230 (9.2), 197 (62.3), 162 (33.3), 97 (3.1), 72 (8.3). Anal.
calcd. for C19H15N5 (313.36): C, 72.83; H, 4.82; N, 22.35%.
Found: C, 72.89; H, 4.87; N, 22.46%.
Synthesis of 2,4-dimethyl-8-(2H-chromen-2on-3yl)-
1,5,8a,9-tetrazafluorene (23)
1,10a-Dihydro-3,6,8-trimethyl-1-phenylcyclopenta[a]-
fluorine-3,6,8-trimethyl-1-phenyl-1,2,5,9,10,10a-
hexazacyclopenta[a]fluorine (30)
A mixture of 1 (0.32 g, 2 mmol), 22 (0.46 g, 2 mmol) and
phosphorous oxychloride (0.5 mL) in dioxane (20 mL) was
refluxed for 6 h on a water bath. The reaction mixture was
left to cool and poured gradually onto crushed ice and
Pale yellow needle crystals, reaction time 7 h, crystallization
from benzene/EtOH, yield, 91%, mp: 2718C, IR (KBr):
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2012, 345, 155–162
Pyrazolopyridines, Synthesis and Biological Studies
161
1
nmax, cmꢀ1: 1625 (C N); H-NMR (DMSO-d ): d 2.60 (s, 3H, CH ), Materials and methods
–
–
6
3
2.66 (s, 3H, CH3), 2.78 (s, 3H, CH3), 7.04þ–8.19 (m, 6H, Ar–H),
–
8.53 (s, 1H, CH N); MS (EI): m/z (%) 328 (M , 1.6), 218 (21.5), 183
Antioxidant screening
–
(21.5), 183 (7.5), 141 (6.9), 124 (24.7), 76 (3.1), 72 (100). Anal.
calcd. for C19H16N6 (328.37): C, 69.50; H, 4.91; N, 25.59%.
Found: C, 69.58; H, 4.88; N, 25.57%.
Antioxidant activity screening assay; ABTS method [34]
Antioxidant activity determinations were evaluated from the
bleaching of ABTS derived radical cations. The radical cation
derived from ABTS was prepared by reaction of ABTS (60 ml)
with MnO2 (3 mL, 25 mg/mL) in (5 mL) aqueous buffer
solution (pH 7). After shaking the solution for a few minutes,
it was centrifuged and filtered. The absorbance (Acontrol) of the
resulting green-blue solution (ABTS radical solution) was
Synthesis of 2-cyano-N-(4,6-dimethyl-1H-pyrazolo[3,4-b]-
pyridin-3-yl)acetamide (32)
A mixture of 1 (1.62 g, 10 mmol) and 1-cyanoacetyl-3,4-dime-
thylpyrazole (31) (1.63 g, 10 mmol) in dioxane (30 mL) was
refluxed for 5 h. The separated precipitate was filtered off,
dried and recrystallized from DMF/ethanol to give compound
32.
recorded at lmax 734 nm. The absorbance (Atest
) was
measured upon the addition of (20 mL of 1 mg/mL) solution
of the tested sample in spectroscopic grade MeOH/buffer (1:1
v/v) to the ABTS solution. The inhibition ratio (%) was calcu-
lated using the following formula:
White crystals, yield, 90%, mp: >3208C, IR (KBr):
nmax, cmꢀ1: 3235 (NH); 2258 (CN); 1662 (C O), 1612 (C N);
–
–
–
–
1H-NMR (DMSO-d6): d 2.63 (s, 3H, CH3), 2.75 (s, 3H, CH3), 4.23
(s, 2H, CH2), 7.13 (s, 1H, Ar–H), 10.21 (s, 1H, NH), 13.22 (s, 1H,
NHCO); MS (EI): m/z (%)¼ 229 (Mþ, 0.5), 228 (MþꢀH, 100), 188
(15.2), 161 (92.3), 131 (10.4), 95 (14.6), 76 (5.2). Anal. calcd.
for C11H11N5O (229.24): C, 57.63; H, 4.84; N, 30.55%. Found: C,
57.65; H, 4.50; N, 30.53%.
% Inhibition ¼ ðAcontrol ꢀ Atest=AcontrolÞ ꢁ 100
(2)
Ascorbic acid (20 mL, 2 mM) solution was used as a stand-
ard antioxidant (positive control). Blank sample was run
using solvent without ABTS (Table 1).
Synthesis of 5,6-dihydro-2,4-dimethyl-6-oxo-1,5,8a,9-
tetrazafluorene-8-amine (33)
Bleomycin-dependent DNA damage
The assay was performed according to Aeschlach et al. [35] and
Chan & Tang [36], with minor modifications. L-Ascorbic acid
was used as a positive control. The tested compounds were
dissolved in DMSO (1 mg/mL). A mixture of DNA (0.5 mg/mL),
bleomycin sulfate (0.05 mg/mL), MgCl2 (5 mM), FeCl3 (50 mM)
and the sample (20 mL) was prepared. The previous mixture
(0.5 mL) was incubated at 378C for 1 h, then the reaction was
terminated by addition of 0.05 mL EDTA (0.1 M). The color was
developed by adding thiobarbituric acid (TBA) (0.5 mL) (1%, w/
v) and HCl (0.5 mL) (25%, v/v) followed by heating at 808C for
10 min. After centrifugation, the absorbance of the tested
compounds was measured at lmax 532 nm the extent of
DNA damage was measured by the increase in absorbance.
Compound 32 (0.6 g, 2 mmol) in glacial acetic acid (10 mL)
was heated under reflux for 12 h. The reaction mixture was
cooled and the solid product collected by filtration and
crystallized from DMF to give compound 33.
Pale yellow powder, yield, 90%, mp: >3208C, IR (KBr):
nmax, cmꢀ1: 3399, 3376, 3315 (NH , NH), 1664 (C O), 1606
–
–
(C N); H-NMR (DMSO-d ): d 2.54 (s, 3H, CH ), 2.61 (s, 3H, CH ),
2
1
–
–
6
3
3
3.95 (br, s, 2H, NH2), 6.65 (s, 1H, CH, pyrimidine ring),
6.49 (br, s, 1H, NH), 7.07 (s, 1H, Ar–H). Anal. calcd.
for C11H11N5O (229.24): C, 57.63; H, 4.84; N, 30.55%. Found:
C, 57.60; H, 4.90; N, 30.57%.
Synthesis of 11,11a-dihydro-2,4-dimethyl-1,5,11a,12-
tetraza-benzo[c]benzo[f]azulen-11-ol (35)
I would like to thank Dr. Serry A.A. El Bialy, Department of Pharmaceutical
Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura,
Egypt and Dr. Ameen A. Abu-Hashem, Photochemistry Department
(Heterocyclic Unit), National Research Centre, Dokki, Giza, Egypt, for
carrying out the spectral measurements of some of the newly prepared
samples, also, Mr. Ahmed Abbas, Faculty of Pharmacy, Mansoura
University, Mansoura, Egypt for biological activity. Their assistance is
greatly acknowledged.
A mixture of 1 (0.324 g, 2 mmol) and phthaladehyde (34)
(0.268 g, 2 mmol) was refluxed in a mixture of ethanol/acetic
acid (20 mL, 3:1) for 5 h. The product mixture was poured
gradually onto crushed ice with vigorous stirring to obtain a
yellow solid product, filtered off, washed with water, dried
and finally crystallized from DMF/EtOH to give compound 35.
Yellow crystals, yield, 89%, mp: >3008C, IR (KBr):
The author has declared no conflict of interest.
nmax, cmꢀ1: 3376 (OH), 1606 (C N); 1H-NMR (DMSO-d6):
–
–
d 2.70 (s, 3H, CH3), 2.85 (s, 3H, CH3), 6.93–8.09 (m, 7H,
References
þ
–
Ar–H, CH N, OH); MS (EI): m/z (%) 278 (M , 5.6), 261
–
(MþꢀOH, 1.7), 230 (2.5), 161 (4.6), 147 (28.1), 95 (100), 75
(65.3). Anal. calcd. for C16H14N4O (278.31): C, 69.05; H, 5.07;
N, 20.13%. Found: C, 69.09; H, 5.10; N, 20.16%.
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