Synthesis of some new biologically active sulfur compounds containing pyrazolo[3,4-d] pyrimidine moiety

Article abstract of DOI:10.1080/10426500307825

A novel series of the pyrazolo[3,4-d]pyrimidines having biologically active sulfur moieties 3-20 were prepared via reaction of 4-mercapto-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine 3 with different reagents. Identification of the new compounds was established by elemental analyses, IR, ¹H-NMR, and mass spectral data. Some of the obtained compounds showed the interesting antimicrobial activity comparable to antibiotic chloramphenicol as standard antibacterial agent and Terbinafin as a standard antifungal agent.

Full text of DOI:10.1080/10426500307825

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of Some New Biologically Active Sulfur
Compounds Containing Pyrazolo[3,4-d] pyrimidine
Moiety
Zeinab H. Ismail a , Soad M. Abdel-Gawad a , Anhar Abdel-Aziem a & M. M. Ghorab a b
a Department of Chemistry, Faculty of Science , Al-Azhar University (Girls) , Cairo, Egypt
b National Center for Radiation Research and Technology , Cairo, Egypt
Published online: 27 Oct 2010.
To cite this article: Zeinab H. Ismail , Soad M. Abdel-Gawad , Anhar Abdel-Aziem & M. M. Ghorab (2003) Synthesis of Some
New Biologically Active Sulfur Compounds Containing Pyrazolo[3,4-d] pyrimidine Moiety, Phosphorus, Sulfur, and Silicon and
the Related Elements, 178:8, 1795-1805, DOI: 10.1080/10426500307825
To link to this article: http://dx.doi.org/10.1080/10426500307825
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Phosphorus, Sulfur, and Silicon, 178:1795–1805, 2003
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print
DOI: 10.1080/10426500390221447
SYNTHESIS OF SOME NEW BIOLOGICALLY ACTIVE
SULFUR COMPOUNDS CONTAINING
PYRAZOLO[3,4-d] PYRIMIDINE MOIETY
Zeinab H. Ismail,a Soad M. Abdel-Gawad,a
Anhar Abdel-Aziem,a and M. M. Ghoraba,b
Department of Chemistry, Faculty of Science, Al-Azhar
University (Girls), Cairo, Egypt;a and National Center for
Radiation Research and Technology, Cairo, Egyptb
(Received January 8, 2003; accepted March 14, 2003)
A novel series of the pyrazolo[3,4-d]pyrimidines having biologically ac-
tive sulfur moieties 3-20 were prepared via reaction of 4-mercapto-1-
phenyl-1H-pyrazolo[3,4-d]pyrimidine 3 with different reagents. Identi-
fication of the new compounds was established by elemental analyses,
IR, 1 H-NMR, and mass spectral data. Some of the obtained compounds
showed the interesting antimicrobial activity comparable to antibiotic
chloramphenicol as standard antibacterial agent and Terbinafin as a
standard antifungal agent.
Keywords: Sulfur containing pyrazolo[3,4-d]pyrimidine and antimicro-
bial activity
Pyrazolo[3,4-d]pyrimidines are of considerable chemical and phar-
macological importance as purine analoges.1–3 Various compounds
with related structures also possess antimicrobial,4 antitumor, and
antileukemia5,6 activities. It is reported that many sulfur containing
compounds have a biologically active agents.7–12 As a continuation of
our work on azoloazines,4 we aimed to incorporate the sulfur moiety
into the 4-position of the pyrazolo[3,4-d]pyrimidine ring system to thus
obtain a new sulfur heterocyclic system which is expected to possess
notable chemical and biological activities.
Many thanks are due to Prof. Dr. A. I. El-Batal in the Department of Drug Radiation
Research, National Centre for Radiation Research and Technology for performing the
antimicrobial activity of the synthesized compounds.
Address correspondence to M. M. Ghorab, Department of Drug Radiation Research,
National Center for Radiation Research and Technology, PO Box 29, Nasr City, Cairo,
Egypt. E-mail: ghorabmoustafa@hotmail.com
1795

1796
Z. H. Ismail et al.
SCHEME 1
INVESTIGATIONS, RESULTS AND DISCUSSION
Chemistry
The synthetic strategy to synthesize the target sulfur compounds
3-20 is depicted in Schemes 1 and 2. The starting material

Synthesis of Some New Biologically Active Sulfur Compounds
1797
SCHEME 2
1-phenyl-1,5-dihydropyrazolo[3,4-d]pyrimidine 113 was treated with
phosphorus penta sulfide to afford the 4-mercapto-1-phenyl-1H-
pyrazolo[3,4-d]pyrimidine 3. Compound 3 also was obtained in quanti-
tative yield via reaction of chloro compound 214 with thiourea in ethanol.
IR spectrum of compound 3 showed the absence of (C O) band and pres-
ence bands at 3390 cm−1 (NH), 3100 cm−1 (CH arom.), 1600 cm−1 (C N),
1188 cm−1 (C S). 1H-NMR spectrum of compound (3, in DMSO-d6) re-
vealed signals at 7.0-7.8 (m, 5H, Ar-H), 8.2, 8.4 (2s, 2H, CH pyrazole +
CH pyrimidine), 9.2 (s, 1H, NH) (Scheme 1).
The 4-mercapto function 3 was alkylated using variety of alkyl
halide such as chloroacetone and ethyl bromoacetate to give the
alkylthio derivatives 4 and 6. In addition compound 3 was reacted with
chloroacetic acid to yield the corresponding 4-thioacetic acid derivative
5. IR spectrum of compound 4 exhibited bands at 2924 cm−1 (CH aliph.),

1798
Z. H. Ismail et al.
1728 cm−1 (C O). 1H-NMR spectrum of compound (4 in CDCl3) showed
signals at 2.6 (s, 3H, COCH3), 4.4 (s, 2H, SCH2CO), 7.2-8.0 (m, 5H,
Ar-H), 8.3, 8.8 (2s, 2H, CH pyrazole + CH pyrimidine). IR spectrum of
compound 6 revealed bands at 2935 cm−1 (CH aliph.), 1735 cm−1 (C O).
1H-NMR spectrum of compound (6 in DMSO-d6) exhibited signals at 1.2
(t, 3H, CH3 ester), 4.2 (q, 2H, CH2 ester), 4.4 (s, 2H, SCH2CO), 7.5-8.2
(m, 5H, Ar-H), 8.7, 8.9 (2s, 2H, CH pyrazole + CH pyrimidine). IR spec-
trum of compound 5 exhibited bands at 3417 cm−1 (OH), 3100 cm−1
(CH arom.), 2931 cm−1 (CH aliph.), 1728 cm−1 (C O), 1643 cm−1
(C N).
Interaction of compound 6 with 2-aminoethanol afforded the cor-
responding pyrazolopyrimidine derivative 7; its IR spectrum showed
bands at 3448 cm−1 (OH), 3139 cm−1 (NH), 2924 cm−1 (CH aliph.),
1597 cm−1 (C N). Mass spectrum of compound 7 showed a molecular
ion peak m/z 329 (M+, 0.86%) with a base peak at 228 (100%), and other
significant peaks appeared at 269 (5.80%), 229 (17.51%), 168 (8.84%),
142 (5.81%), 91 (5.13%), 77 (23.02%).
The strategic starting material 4-[(1-phenyl-1H-pyrazolo[3,4-d]-
pyrimidin-4-yl)thio]acetylhydrazide 8 was obtained in good yield via re-
action of the corresponding ester derivative 6 with hydrazine hydrate in
refluxing ethanol. IR spectrum of 8 exhibited bands at 3336, 3209 cm−1
(NH,NH2), 2935 cm−1 (CH aliph.), 1655 cm−1 (C O), 1593 cm−1 (C N).
1H-NMR spectrum of compound (8 in DMSO-d6) revealed signals at
4.8 (s, 2H, CH2CO), 7.3-8.2 (m, 7H, Ar-H + NH2), 8.4, 8.6 (2s, 2H, CH
pyrazole + CH pyrimidine), 10.6 (s, 1H, NH).
Interaction of compound 8 with ethyl-2-cyano-3-ethoxyacrylate in
methanol containing few drops of acetic acid yielded the pyrazole
derivative 9. IR spectrum showed bands at 3425, 3302 cm−1 (NH2),
1689, 1680 cm−1 (2C O), 1589 cm−1 (C N). 1H-NMR spectrum of
compound (9 in CDCl3) revealed signals at 1.3 (t, 3H, CH3 ester),
4.3 (q, 2H, CH2 ester), 4.8 (s, 2H, CH2CO), 7.1-8.2 (m, 7H, Ar-H
+ NH2), 8.3, 8.8, 8.9 (3s, 3H, CH pyrazole + CH pyrazoline + CH
pyrimidine).
Refluxing of compound 8 in acetic anhydride furnished the corre-
sponding monoacetyl derivative 10. IR spectrum of compound 10 re-
vealed bands at 3140 cm−1 (NH), 2931 cm−1 (CH aliph.), 1728 cm−1
(C O), 1590 cm−1 (C N). 1H-NMR spectrum of compound (10 in CDCl3)
exhibited signals at 2.6 (s, 3H, COCH3), 4.2 (s, 2H, CH2CO), 7.2-8.1 (m,
5H, Ar-H), 8.3, 8.8 (2s, 2H, CH pyrazole + CH pyrimidine), 8.5, 9.4 (2s,
2H, 2NH).
On the other hand interaction of compound 3 with benzylamino-
carbonylmethyl chloride in dimethylformamide yielded the corres-
ponding 4-(benzylaminocarbonylmethylthio)pyrazolo[3,4-d]pyrimidine

Synthesis of Some New Biologically Active Sulfur Compounds
1799
derivative 11. IR spectrum showed bands at 3278 cm−1 (NH), 3062 cm−1
1
(CH arom.), 2924 cm−1 (CH aliph.), 1643 cm−1 (C O). H-NMR spec-
trum of compound (11 in CDCl3) showed signals at 4.2 (s, 2H, CH2-
Ph), 4.5 (s, 2H, CH2CO), 7.1-8.1 (m, 10H, Ar-H), 8.4, 8.8 (2s, 2H, CH
pyrazole + CH pyrimidine), 9.2 (s, 1H, NH).
Also, reaction of compound 3 with substituted sulfamoylphenyl-
aminocarbonylmethyl chloride in dimethylformamide furnished the
corresponding 4-(substituted sulfamoylphenylaminocarbonylmethyl-
thio)-pyrazolo[3,4-d]pyrimidine 12-14 respectively (Scheme 2). IR
spectrum of compounds 12-14 revealed the presence of (NH) at 3260-
3180 cm−1 and (C O) band at 1700–1680 cm−1. Mass spectrum of com-
pound 12 showed a molecular ion peak m/z 520 (M-1, 1.14%), 519 (M-2,
0.94%) with a base peak at 228 (100%), and other significant peaks
appeared at 404 (5.83%), 385 (33.91%), 286 (3.51%), 195 (56.87%), 156
(57.74%), 77 (70.53%).
In addition 4-[N-(substitutedphenyl)carbamoylmethylthio)]pyra-
zolo[3,4-d]pyrimidines 15-16 were obtained via reaction of compound 3
with 2ꢁ-chloro-4-substituted-acetanilide. IR spectrum of compound 15
showed bands at 3317 cm−1 (NH), 2923 cm−1 (CH aliph.), 1658 cm−1
(C O). IR spectrum of compound 16 revealed bands at 3309 cm−1 (NH),
1658 cm−1 (C O). 1H-NMR spectrum of compound (15 in DMSO-d6) ex-
hibited signals at 2.2 (s, 3H, CH3), 4.3 (s, 2H, CH2CO), 7.1-8.1 (m, 9H,
Ar-H), 8.6, 8.8 (2s, 2H, CH pyrazole + CH pyrimidine), 10.4 (s, 1H,
NH). IR spectrum of compound 17 showed bands at 3448 cm−1 (NH),
2916 cm−1 (CH aliph.), 1689 cm−1 (C O), 1566 cm−1 (C N). Mass spec-
trum of compound 17 exhibited a molecular ion peak m/z 368 (M+,
0.12%), with a base peak at 269 (100%) and other significant peaks
appeared at 336 (0.32%), 250 (0.81%), 195 (12.32%), 168 (8.30%), 127
(15.13%), 77 (17.81%).
Finally, interaction of compound 3 with chloroacetonitrile, benzyl
chloride, and/or phenacylbromide gave the corresponding 4-thiomethyl
derivatives 18–20 respectively. IR spectrum of compound 18 showed
bands at 3070 cm−1 (CH arom.), 2985 cm−1 (CH aliph.), 2245 cm−1
(C N), 1558 cm−1 (C N). IR spectrum of compound 19 showed bands
at 3086 cm−1 (CH arom.), 2923 cm−1 (CH aliph.), 1550 cm−1 (C N).
1H-NMR spectrum of compound (19 in DMSO-d6) revealed signals at
4.9 (s, 2H, CH2), 7.1-8.2 (m, 10H, Ar-H), 8.4, 8.8 (2s, 2H, CH pyra-
zole + CH pyrimidine). IR spectrum of compound 20 revealed bands at
1
2923 cm−1 (CH aliph.), 1689 cm−1 (C O), 1635 cm−1 (C N). H-NMR
spectrum of compound (20 in DMSO-d6) showed signals at 4.2 (s, 2H,
CH2CO), 7.1-8.1 (m, 10H, Ar-H), 8.3, 8.6 (2s, 2H, CH pyrazole + CH
pyrimidine).

1800
Z. H. Ismail et al.
TABLE I Physical and Analytical Data of the Synthesized Compounds
Analysis Required/(Found) %
Compd.
No.
m.p.
(◦C)
Yield
(%)
Mol. Formula
(mol. wt.)
C
H
N
3
4
276–278
122–124
303–305
90–92
86
71
68
84
77
91
59
62
69
75
61
68
56
68
73
66
62
76
C11H8N4S
(228)
C14H12N4OS
(284)
C13H10N4O2S
(286)
C15H14N4O2S
(314)
57.89
57.60
59.15
58.80
54.55
54.80
57.32
57.60
54.71
54.40
52.00
52.30
53.90
53.60
52.63
52.40
64.00
64.20
52.98
52.70
54.95
54.60
47.65
47.30
64.00
64.30
57.65
57.40
52.17
52.50
58.43
58.10
67.92
67.70
65.90
65.60
3.51
3.20
4.23
4.40
3.50
3.60
4.46
4.20
4.56
4.20
4.00
4.20
4.02
4.30
4.09
4.40
4.53
4.30
3.65
3.90
4.03
4.30
3.25
3.50
4.53
4.70
3.54
3.80
3.26
3.50
3.37
3.60
4.40
4.20
4.05
4.30
24.56
24.80
19.72
19.50
19.58
19.20
17.83
17.50
21.28
21.50
28.00
28.40
23.17
23.50
24.56
24.20
18.67
18.30
18.81
18.50
20.51
20.80
20.22
19.90
18.67
18.40
17.70
17.40
22.83
22.60
26.22
26.50
17.61
17.30
16.18
16.50
5
6
7
292–294
190–192
218–220
113–115
206–208
220–222
238–240
226–228
195–197
209–211
214–216
146–148
111–113
157–159
C
15H15N5O2S
(329)
8
C
13H12N6OS
(300)
9
C
19H17N7O3S
(423)
C15H14N6O2S
(342)
10
11
12
13
14
15
16
17
18
19
20
C
20H17N5OS
(375)
C23H19N7O4S2
(521)
C25H22N8O3S2
(546)
22H18N8O4S3
(554)
C20H17N5OS
(375)
19H14N5OSCl
(395.5)
16H12N6OS2
(368)
C13H9N5S
(267)
C18H14N4S
(318)
C
C
C
C
19H14N4OS
(346)
Antimicrobial Activity
The antimicrobial screening of the synthesized compounds was under-
taken using the diffusion agar technique.15 Table II lists the screening
results of the tested compounds against the Gram-positive bacte-
ria Staphylococcus aureus, Bacillus subtilis and the Gram-negative

1801

1802
Z. H. Ismail et al.
bacteria, Pseudomonas aeruginosa, Escherichia coli. In addition to
the pathogenic fungi Aspergillus fumigatus, Penicillium italicum,
Candida albicans, and Syncephalastrum racemosum. The reference
antibiotic chloramphenicol and fungicide Terbinafin were used as
a positive controles for comparison. The fungi cultures were main-
tained on Czapek’s Dox agar medium. The tested compounds were dis-
solved in N, N-dimethylformamide (DMF), which showed no inhibition
zones.
The results are illustrated in Table II. The antibacterial activity of
the synthesized compounds showed that the pyrazolopyrimidine having
hydrazide moiety 8 was found to be the most active compound against
Gram-positive bacteria (Staphylococcus aureus). Also, compound 8
showed a moderate activity against Bacillus subtilis, Aspergillus fu-
migatus, and Penicillium italicum. On the other hand compounds 8
and 17 exhibited a moderate activity against Gram-negative bacteria
Pseudomonas aeruginosa and Escherichia coli. In addition compound
12 having methoxazole moiety exhibited a modarate activity against
Gram positive bacteria Staphylococcus aureus.
These results indicated that the biologically active compound 8 was
almost as potent as the standard antibiotic chloramphenicol as positive
control.
EXPERIMENTAL
Apparatus and Methods
All m.p.s are uncorrected. Elemental analyses were carried out at the
microanalytical laboratories of the Faculty of Science, Cairo University.
The IR spectra (KBr) were measured on a Shimadzu IR 110 spectropho-
1
tometer, H-NMR spectra were obtained on a BRUKER proton NMR-
Avance 300 (300, MHz), in DMSO-d6 and CDCl3 as a solvent, using
tetramethylsilane (TMS) as internal standard. Mass spectra were run
on HP Model MS-5988.
Synthesis of 4-Mercapto-1-phenyl-1,5-dihydro-1 H -
pyrazolo[3,4-d]pyrimidine 3
Method A
A mixture of compound 1 (0.01 mmol), and P2S5 (5 g) in pyridine
(50 ml) was heated under reflux for 10 h. The solvent was removed
under reduced pressure and the obtained residue was washed with dil.
HCl, and recrystallized from dioxane to give 3 (Table I).

Synthesis of Some New Biologically Active Sulfur Compounds
1803
Method B
A mixture of compound 2 (0.01 mmol) and thiourea (0.015 mmol) in
ethanol was refluxed for 7 h. The obtained solid was recrystallized from
ethanol to give 2 (m.p. and m.m.p.).
Formation of 4-(Methylcarbonylmethylthio)-1-phenyl-
1 H -pyrazolo[3,4-d]pyrimidine 4 and 4-Thioacetic
Acid-1-phenyl-1 H -pyrazolo[3,4-d]pyrimidine 5 and
4-Ethoxycarbonylmethyl)thio-1-phenyl-1 H -pyrazolo-
[3,4-d]pyrimidine 6
To a solution of compound 3 (0.01 mmol) in dry acetone (50 ml), an-
hydrous K2CO3 (2 g) was added followed by either chloroacetone, 2-
chloroacetic acid, or ethyl bromoacetate (0.015 mmol). The reaction mix-
ture was heated under reflux for 24 h, filtered while hot, and the filtrate
was concentrated in vacuo to give 4-6 respectively (Table I).
Synthesis of N-(2-Hydroxyethyl)-4-[(1-phenyl-1 H -
pyrazolo[3,4-d]pyrimidin-4-yl)thio]acetamide 7
A solution of ester 6 (0.01 mmol) and 2-aminoethanol (0.02 mmol) in
ethanol (50 ml) was heated under reflux for 3 h. The precipitated solid
was filtered on hot, dried, and recrystallized from dioxane to give 7
(Table I).
Preparation of 4-[(1-Phenyl-1 H -pyrazolo
[3,4-d]pyrimidine-4-yl)thio]acetylhydrazine 8
A solution of the ester derivative 6 (0.01 mmol) and hydrazine hydrate
(85%, 10 ml) in ethanol (50 ml) was heated under reflux for 3 h. The
solvent was evaporated and the obtained residue was recrystallized
from ethanol to give 8 (Table I).
Formation of 1-Phenyl-1 H -4-[acetylthio-2-(5’-amino-4’-
carbethoxypyrazoline)-1-yl]pyrazolo[3,4-d]pyrimidine 9
A mixture of 8 (0.01 mmol) and ethyl-2-cyano-3-ethoxyacrylate
(0.012 mmol) in methanol containing few drops of acetic acid was re-
fluxed for 8 h. The obtained solid was recrystallized from ethanol to
give 9 (Table I).
Synthesis of 4-[(1-phenyl-1 H -pyrazolo[3,4-d]pyrimidin-4-
yl)-thio]acetoacetylhydrazine 10
To a solution of 8 (0.01 mmol) in acetic anhydride was refluxed for 1 h.
The obtained solid was recrystallized from ethanol to give 10 (Table I).

1804
Z. H. Ismail et al.
Synthesis of 4-[(Benzylaminocarbonylmethyl-4-
yl)thio]methyl-1-phenyl-pyrazolo[3,4-d]pyrimidine 11
A mixture of 3 (0.01 mmol) and 2ꢁ-chloro-benzylacetanilide (0.012 mmol)
in dimethylformamide (20 ml) was refluxed for 8 h. The obtained prod-
uct was recrystallized from dioxane to give 11 (Table I).
Formation of 4-(Substituted
Sulfamoylphenylaminocarbonylmethylthio)-1-phenyl-
pyrazolo[3,4-d]pyrimidine 12-14
A mixture of compound 3 (0.01 mmol) and substituted sulfamoyl-
phenylaminocarbonylmethyl chloride (0.012 mmol) in dimethylfor-
mamide (20 ml) was refluxed for 10 h. The obtained solid was recrys-
tallized from DMF-ethanol to give 12-14 respectively (Table I).
Synthesis of 4-[N-(Substitutedphenyl)-
carbamoylmethylthio]-1-phenyl-1 H -pyrazolo
[3,4-d]pyrimidine 15-17
A mixture of 3 (0.01 mmol) and 2ꢁ-chloro-4-substituted acetanilide
(0.012 mmol) in dimethylformamide (20 ml) was refluxed for 12 h. The
obtained solid was recrystallized from acetic acid to give 15-17 respec-
tively (Table I).
Synthesis of 4-Cyanomethylthio-1-phenyl-1 H -
pyrazolo[3,4-d]-pyrimidine 18 and
4-Phenylmethylthio-1-phenyl-1 H -pyrazolo-
[3,4-d]pyrimidine 19
To a solution of 3 (0.01 mmol) in dry acetone (50 ml), anhydrous potas-
sium carbonate (2 g) was added followed by either 2-chloroacetonitrile
or benzyl chloride (0.015 mmol). The reaction mixture was heated under
reflux for 20 h, filtered while hot, and the filterate was concentrated in
vacuo to give the crude product which was recrystallized from ethanol
to give 18 and 19 respectively (Table I).
Synthesis of 4-(Phenylcarbonylmethylthio)-1-phenyl-1 H -
pyrazolo[3,4-d]pyrimidine 20
A mixture of 3 (0.01 mmol), phenacylbromide (0.01 mmol), and anhy-
drous K2CO3 (2 g) in dry acetone (50 ml) was heated under reflux for
24 h. The reaction mixture was filtered while hot, and the filtrate was

Synthesis of Some New Biologically Active Sulfur Compounds
1805
concentrated under reduced pressure then cooled. The obtained solid
was filtered, dried, and recrystallized from ethanol to give 20 (Table I).
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