Design, synthesis, and characterization of some novel pyrazolo [1,5-a] pyrimidines as potent antimicrobial agents

Article abstract of DOI:10.1002/jhet.413

(Chemical Equation Presented) A novel series of pyrazolo [1,5-a] pyrimidines were synthesized by the condensation of substituted chalcones with 5-amino pyrazole in presence of dimethyl formamide. All the synthesized products were characterized by the spec

Full text of DOI:10.1002/jhet.413

1250
Design, Synthesis, and Characterization of Some Novel Pyrazolo
[1,5-a] Pyrimidines as Potent Antimicrobial Agents
Vol 47
Bhaskar S. Dawane,* Shankaraiah G. Konda, and Sainath B. Zangade
Organic Research Laboratory, Department of Chemistry, Yeshwant Mahavidyalaya,
Nanded-431602, Maharashtra, India
*E-mail: bhaskardawane@rediffmail.com
Received October 27, 2009
DOI 10.1002/jhet.413
Published online 13 July 2010 in Wiley Online Library (wileyonlinelibrary.com).
A novel series of pyrazolo [1,5-a] pyrimidines were synthesized by the condensation of substituted
chalcones with 5-amino pyrazole in presence of dimethyl formamide. All the synthesized products were
characterized by the spectral analysis. Further, all newly synthesized compounds were screened for their
antimicrobial activity. Most of the compounds showed potent activity.
J. Heterocyclic Chem., 47, 1250 (2010).
INTRODUCTION
The starting 5-amino pyrazole was prepared in two
steps from the corresponding amine by the diazotization
and then treatment with malononitrile followed by reac-
tion with hydrazine hydrate [16] (Scheme 1), while the
novel a,b-unsaturated carbonyl compounds 2(a–h) were
prepared in the presence of base by conventional
Claisen–Schmidt condensation of substituted acetophe-
nones and 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-
carbaldehyde (Scheme 2). Finally, the synthesis of pyra-
zolo [1,5-a] pyrimidines 3(a–h) were attempted by the
reacting 5-amino pyrazole with a,b-unsaturated carbonyl
compounds (chalcones) using NaOH in presence of
DMF as reaction solvent (Scheme 3).
Pyrazole nucleus has wide applications in medicinal
chemistry. The ring system plays an important role in
many biological processes, and many therapeutic agents
contain pyrazole moiety. Several pyrazoles with antimi-
crobial, antiviral, and anticancer properties have been
reported [1]. Certain alkyl pyrazoles have shown signi-
ficant antiallergic, anti-inflammatory, and antiarthritic
properties [2,3]. Many pyrazole-fused heterocyclic com-
pounds have been to exhibit biological activity and
widely used studied in pesticide and medicine [4–6].
Pyrazolopyrimidines are of considerable chemical and
pharmacological importance as purine analogues [7,8],
and have antitumor, antileukemic activities. Pyrazolo
[1,5-a] pyrimidines useful properties, as antimetabolites
in purine biochemical reactions [9–11]. These interesting
biological activities reported for pyrazolopyrimidines
have stimulated chemists to develop new class of these
compounds.
The formation of products were assumed to proceed
through the Micheal-type addition of the ring nitrogen
in 5-amino pyrazole (which is more active) to the acti-
vated double bond followed by intramolecular cycliza-
tion [17,18] with the elimination of water and dehydro-
genation. The structures of compounds were appropri-
ately established by the spectroscopic and analytical
methods.
The results of the antimicrobial screening data are
given in Table 1. In comparison with reference drugs,
compounds 3a, 3b, and 3c showed effective activity
against all the tested microbes. Compounds 3a and 3b
showed near to par activity against Bacillus subtilis.
Only the compound 3a was showed potent activity
against Escherichia coli than standard penicillin drug.
RESULTS AND DISCUSSION
In continuation of our work on the synthesis of some
new bioactive heterocyclic compounds [12–15], herein
we report a new series of pyrazolo [1,5-a] pyrimidines
by the condensation of chalcones with the 5-amino pyr-
azole in dimethyl formamide (DMF).
C
V
2010 HeteroCorporation

September 2010
Design, Synthesis, and Characterization of Some Novel Pyrazolo
[1,5-a] pyrimidines as Potent Antimicrobial Agents
1251
Scheme 1. Synthesis of 5-amino pyrazole.
Scheme 2. Synthesis of chalcones.
Scheme 3. Synthesis of pyrazolo [1,5-a] pyrimidines.
Compound 3b showed stronger activity against Aspergil-
lus flavus than reference Nystatin drug. On the other
hand, compounds 3(d–h) displayed moderate antimicro-
bial activity.
As far as the antimicrobial results are concerned only
the three compounds displayed very good activity. Pyra-
zolo [1,5-a] pyrimidines carrying p-chloro phenyl, p-
hydroxy phenyl, and p-methoxy phenyl at C5-position
emerged as active in both antibacterial and antifungal
screening. The substitution of o-hydroxy phenyl may
increase the antimicrobial activity against various patho-
gens. When we compared the activity of substituted
compounds with a nonsubstituted compound (3g), the
substituted compounds showed higher activity.
Table 1
Antimicrobial activity of synthesized compounds 3(a–h).
Product
A
B
C
D
3a
3b
3c
3d
3e
3f
3g
25
22
22
18
20
18
14
16
24
NA
27
26
27
15
18
21
16
20
28
NA
17
16
16
14
11
12
10
12
NA
18
15
18
15
12
10
11
8
15
NA
16
CONCLUSIONS
In summary, we have designed and synthesized some
novel pyrazolo [1,5-a] pyrimidines by the condensation
of substituted chalcones with 5-amino pyrazole in pres-
ence of a base (solid sodium hydroxide) in dimethylfor-
mamide. The preliminary in vitro antimicrobial screen-
ing of this series revealed that compounds 3a, 3b, and
3c showed potent activity when compared with standard
drug. Therefore, the present study is useful drugs in
3h
Reference1
Reference2
Zone of inhibitions are expressed in mm.
A ¼ Escherichia coli, B ¼ Bacillus subtilis, C ¼ Fusarium monilifor-
mae, D ¼ Aspergillus flavus, Reference 1 ¼ Penicillin, Reference 2 ¼
Nystatin, NA ¼ Not Applicable.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1252
B. S. Dawane, S. G. Konda, and S. B. Zangade
Vol 47
Table 2
Yields and physical data of synthesized products 3(a–h).
medicinal investigation against bacterial and fungal
diseases.
Time
(h)
Yield
(%)
M.P.
(ꢁC)
Entry
Product
R1
R2
EXPERIMENTAL
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
H
H
H
Cl
OH
OCH3
F
4
4
4
5
5
4
5
5
72
68
70
68
65
60
65
66
173–175
210–212
188–190
166–168
225–227
194–196
152–154
178–180
Melting points were uncorrected and determined in an open
capillary tube. IR spectra were recorded on FTIR Shimadzu
1
spectrometer. H NMR spectra were recorded in DMSO-d6 on
Avance 300 MHz spectrometer using TMS as an internal
standard. The mass spectra were recorded on EI-Shimadzu-
GC-MS spectrometer. Elemental analyses were performed on a
Carlo Erba 106 Perkin-Elmer model 240 analyzer.
H
H
H
NO2
Br
3g
3h
H
OH
H
H
General procedure for the synthesis of chalcone deriva-
tives 2(a–h). A mixture of substituted acetophenone 1 (1
mmol),
5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbalde-
2.36 (s, 3H, CH3), d 7.10–8.29 (m, 11H, Ar-H þ CH¼¼CH)
ppm; M.S. (m/z): 400 (Mþ), 402 (Mþ2), 404 (Mþ4); Anal.
Calcd for C19H14N2OClBr: C, 56.81; H, 3.51; N, 6.97%.
Found: C, 56.72; H, 3.62; N, 6.91%.
1-(phenyl)-3-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4yl)-
propenone (2g). Color, Pale yellow; Yield, 76%; IR (KBr):
1650 (>C¼¼O), 1595 (AC¼¼N); 1H NMR (DMSO-d6): d 2.32
(s, 3H, CH3), d 7.06–8.28 (m, 12H, Ar-H þ CH¼¼CH) ppm;
M.S. (m/z): 322 (Mþ), 324 (Mþ2); Anal. Calcd for
C19H15N2OCl: C, 70.72; H, 4.68; N, 8.68%. Found: C, 70.84;
H, 4.56; N, 8.75%.
hyde (1 mmol) and NaOH (2 mmol) were dissolved in ethanol
(20 mL) solution. The reaction mixture was heated for 2 h. The
progress of the reaction was monitored by TLC. After comple-
tion of the reaction, the contents were poured in ice cold water
and then acidified by dil. HCl. The solid obtained was filtered
and washed with cold water. Then crude product was crystal-
lized from acetic acid to give the corresponding product 2.
1-(4-chloro-phenyl)-3-(5-chloro-3-methyl-1-phenyl-1H-pyr-
azol-4yl)-propenone (2a). Color, Dark yellow; Yield, 81%; IR
1
(KBr): 1648 (>C¼¼O), 1598 (AC¼¼N); H NMR (DMSO-d6): d
2.36 (s, 3H, CH3), d 7.05–8.22 (m, 11H, Ar-H þ CH¼¼CH)
ppm; M.S. (m/z): 357 (Mþ), 359 (Mþ2), 361 (Mþ4); Anal.
Calcd for C19H14N2OCl2: C, 63.88; H, 3.95; N, 7.84%. Found:
C, 63.96; H, 3.83; N, 7.98%.
1-(2-hydroxy-phenyl)-3-(5-chloro-3-methyl-1-phenyl-1H-pyr-
azol-4yl)-propenone (2h). Color, Yellow; Yield, 78%; IR
1
(KBr): 1652 (>C¼¼O), 1606 (AC¼¼N); H NMR (DMSO-d6): d
2.36 (s, 3H, CH3), d 7.05–8.22 (m, 11H, Ar-H þ CH¼¼CH), d
10.82 (s, 1H, OH) ppm; M.S. (m/z): 338 (Mþ), 340 (Mþ2);
Anal. Calcd for C19H15N2O2Cl: C, 67.36; H, 4.46; N, 8.27%.
Found: C, 67.48; H, 4.52; N, 8.18%.
1-(4-hydroxy-phenyl)-3-(5-chloro-3-methyl-1-phenyl-1H-pyr-
azol-4yl)-propenone (2b). Color, Yellow; Yield, 78%; IR
1
(KBr): 1652 (>C¼¼O), 1608 (AC¼¼N); H NMR (DMSO-d6): d
2.31 (s, 3H, CH3), d 5.58 (s, 1H, OH), d 7.11–8.29 (m, 11H,
Ar-H þ CH¼¼CH) ppm; M.S. (m/z): 338 (Mþ), 340 (Mþ2);
Anal. Calcd for C19H15N2O2Cl: C, 67.36; H, 4.46; N, 8.27%.
Found: C, 67.48; H, 4.35; N, 8.36%.
Typical procedure for the synthesis of pyrazolo [1,5-a]
pyrimidines 3(a–h). A mixture of 2a (1 mmol), 5-amino pyr-
azole (1 mmol), and 1–2 pallets of NaOH were dissolved in
DMF (15 mL). The reaction mixture was refluxed for the pe-
riod as shown in Table 2. The progress of the reaction was
monitored by TLC. After completion, the reaction mixture was
extracted with diethyl ether (2 ꢀ 20 mL). The combined or-
ganic layers were dried over anhydrous Na2SO4, and the sol-
vent was evaporated under reduced pressure. The crude prod-
uct was recrystallized from aqueous acetic acid to give the
product 3a. Similarly, other analogues of this were synthesized
by using the same procedure.
1-(4-methoxy-phenyl)-3-(5-chloro-3-methyl-1-phenyl-1H-pyr-
azol-4yl)-propenone (2c). Color, Yellow; Yield, 80%; IR
1
(KBr): 1651 (>C¼¼O), 1602 (AC¼¼N); H NMR (DMSO-d6): d
2.34 (s, 3H, CH3), d 3.32 (s, 3H, OCH3), d 7.08–8.21 (m,
11H, Ar-H þ CH¼¼CH) ppm; M.S. (m/z): 352 (Mþ), 354
(Mþ2); Anal. Calcd for C20H17N2O2Cl: C, 68.09; H, 4.86; N,
7.94%. Found: C, 68.02; H, 4.97; N, 7.82%.
1-(4-fluoro-phenyl)-3-(5-chloro-3-methyl-1-phenyl-1H-pyra-
zol-4yl)-propenone (2d). Color, Yellow; Yield, 76%; IR
2-Amino-3-(4-chloro-phenylazo)-5-(4-chloro-phenyl)-7-(5-
chloro-3-methyl-1-phenyl-1H-pyrazol-4yl)-pyrazolo [1,5-a]
pyrimidine (3a). Color, Brown; IR (KBr): 3256 (ANH2),
1
(KBr): 1648 (>C¼¼O), 1615 (AC¼¼N); H NMR (DMSO-d6): d
2.36 (s, 3H, CH3), d 7.12–8.26 (m, 11H, Ar-H þ CH¼¼CH)
ppm; M.S. (m/z): 340 (Mþ), 342 (Mþ2); Anal. Calcd for
C19H14N2OFCl: C, 69.97; H, 4.14; N, 8.22%. Found: C, 66.91;
H, 4.27; N, 8.35%.
1
1616 (AC¼¼N); H NMR (DMSO-d6): d 2.26 (s, 3H, CH3), d
5.21 (bs, 2H, NH2), d 7.12–8.28 (m, 13H, Ar-H), d 8.34 (s,
1H, 6H-of pyrimidine) ppm; 13C NMR (DMSO-d6): d 10, 101,
112, 118 (2 ꢀ C), 120, 121 (2 ꢀ C), 124, 126, 127 (2 ꢀ C),
128 (2 ꢀ C), 129 (2 ꢀ C), 130 (2 ꢀ C), 131, 132, 133, 135,
136, 138, 151, 158, 163, 166 ppm; M.S. (m/z): 573 (Mþ), 575
(Mþ2), 577 (Mþ4), 579 (Mþ6); Anal. Calcd for
C28H19N8Cl3: C, 58.60; H, 3.34; N, 19.53%. Found: C, 58.56;
H, 3.42; N, 19.64%.
1-(4-nitro-phenyl)-3-(5-chloro-3-methyl-1-phenyl-1H-pyra-
zol-4yl)-propenone (2e). Color, Reddish yellow; Yield, 75%;
IR (KBr): 1646 (>C¼¼O), 1599 (AC¼¼N); 1H NMR (DMSO-
d6): d 2.31 (s, 3H, CH3), d 7.06–8.21 (m, 11H, Ar-H þ
CH¼¼CH) ppm; M.S. (m/z): 368 (Mþ), 370 (Mþ2); Anal.
Calcd for C19H14N3O3Cl: C, 61.71; H, 4.38; N, 11.63%.
Found: C, 61.84; H, 4.31; N, 11.72%.
1-(4-bromo-phenyl)-3-(5-chloro-3-methyl-1-phenyl-1H-pyr-
azol-4yl)-propenone (2f). Color, Yellow; Yield, 78%; IR
(KBr): 1652 (>C¼¼O), 1605 (AC¼¼N); H NMR (DMSO-d6): d
2-Amino-3-(4-chloro-phenylazo)-5-(4-hydroxy-phenyl)-7-(5-
chloro-3-methyl-1-phenyl-1H-pyrazol-4yl)-pyrazolo
[1,5-a]
pyrimidine (3b). Color, Brown; IR (KBr): 3251 (ANH2), 1618
1
(AC¼¼N); 1H NMR (DMSO-d6): d 2.29 (s, 3H, CH3), d 5.25
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Design, Synthesis, and Characterization of Some Novel Pyrazolo
[1,5-a] pyrimidines as Potent Antimicrobial Agents
1253
(bs, 2H, NH2), d 5.68 (s, 1H, OH), d 7.08–8.21 (m, 13H, Ar-
H), d 8.32 (s, 1H, 6H-of pyrimidine) ppm; M.S. (m/z): 555
(Mþ), 557 (Mþ2), 559 (Mþ4); Anal. Calcd for
C28H20N8OCl2: C, 60.55; H, 3.63; N, 20.17%. Found: C,
60.42; H, 3.71; N, 20.11%.
and Bacillus subtilis (MTCC 1789). The antifungal activity
was evaluated against Fusarium moniliformae (MTCC 156)
and Aspergillus flavus (MTCC 2501) were procured from Insti-
tute of Microbial technology (IMTech), Chandigarh, India. The
antibiotic penicillin (25 lg/mL) and nystatin (25 lg/mL) was
used as reference drug for antibacterial and antifungal activity,
respectively. Dimethyl sulphoxide (1%, DMSO) was used a
control with out compound.
The culture strains of bacteria were maintained on nutrient
agar slant at 37 6 0.5ꢁC for 24 h. The antibacterial activity
was evaluated using nutrient agar plate seeded with 0.1 mL of
respective bacterial culture strain suspension prepared in sterile
saline (0.85%) of 105 CFU/mL dilutions. The wells of 6 mm
diameter were filled with 0.1 mL of compound solution at
fixed concentration 25 lg/mL separately for each bacterial
strain. All the plates were incubated at 37 6 0.5ꢁC for 24 h.
Zone of inhibition of compounds in mm were noted.
For antifungal activity, all the culture strains of fungi
maintained on potato dextrose agar (PDA) slant at 27 6 0.2ꢁC
for 24–48 h, until sporulation. Spore of strains were transferred
into 5 mL of sterile distilled water containing 1% Tween-80 (to
suspend the spore properly). The spores were counted
by haemocytometer (106 CFU/mL). Sterile PDA plate was
prepared containing 2% agar; 0.1 mL of each fungal spore
suspension was spread on each plate and incubated at 27 6
0.2ꢁC for 12 h. After incubation well prepared using sterile cork
borer and each agar well was filled with 0.1 mL of compound
solution at fixed concentration 25 lg/mL. The plates were kept
in refrigerator for 20 min for diffusion and then incubated at 27
6 0.2ꢁC for 24–28 h. After incubation, zone of inhibition of
compounds were measured in mm along with standard.
2-Amino-3-(4-chloro-phenylazo)-5-(4-methoxy-phenyl)-7-(5-
chloro-3-methyl-1-phenyl-1H-pyrazol-4yl)-pyrazolo [1,5-a] py-
rimidine (3c). Color, Dark brown; IR (KBr): 3322 (ANH2),
1
1616 (AC¼¼N); H NMR (DMSO-d6): d 2.26 (s, 3H, CH3), d
5.28 (bs, 2H, NH2), d 3.38 (s, 1H, OH), d 7.05–8.25 (m, 13H,
Ar-H), d 8.38 (s, 1H, 6H-of pyrimidine) ppm; M.S. (m/z): 569
(Mþ), 571 (Mþ2), 573 (Mþ4); Anal. Calcd for
C29H22N8OCl2: C, 61.17; H, 3.89; N, 19.68%. Found: C,
61.31; H, 3.76; N, 19.76%.
2-Amino-3-(4-chloro-phenylazo)-5-(4-fluoro-phenyl)-7-(5-
chloro-3-methyl-1-phenyl-1H-pyrazol-4yl)-pyrazolo [1,5-a]
pyrimidine (3d). Color, Brown; IR (KBr): 3286 (ANH2),
1618 (AC¼¼N); 1H NMR (DMSO-d6): d 2.21 (s, 3H, CH3),
d 5.32 (bs, 2H, NH2), d 7.11–8.28 (m, 13H, Ar-H), d 8.32
(s, 1H, 6H-of pyrimidine) ppm; M.S. (m/z): 557 (Mþ),
559 (Mþ2), 561 (Mþ4); Anal. Calcd for C28H19N8FCl2: C,
60.33; H, 3.44; N, 20.10%. Found: C, 60.42; H, 3.38; N,
20.24%.
2-Amino-3-(4-chloro-phenylazo)-5-(4-nitro-phenyl)-7-(5-
chloro-3-methyl-1-phenyl-1H-pyrazol-4yl)-pyrazolo [1,5-a] py-
rimidine (3e). Color, Brown; IR (KBr): 3318 (ANH2), 1617
(AC¼¼N); 1H NMR (DMSO-d6): d 2.26 (s, 3H, CH3), d 5.25
(bs, 2H, NH2), d 7.15–8.31 (m, 13H, Ar-H), d 8.41 (s, 1H,
6H-of pyrimidine) ppm; M.S. (m/z): 584 (Mþ), 586 (Mþ2),
588 (Mþ4); Anal. Calcd for C28H19N9O2Cl2: C, 56.16; H,
3.25; N, 21.57%. Found: C, 56.28; H, 3.18; N, 21.66%.
2-Amino-3-(4-chloro-phenylazo)-5-(4-bromo-phenyl)-7-(5-
chloro-3-methyl-1-phenyl-1H-pyrazol-4yl)-pyrazolo [1,5-a] py-
rimidine (3f). Color, Reddish brown; IR (KBr): 3338 (ANH2),
Acknowledgments. The authors gratefully acknowledge UGC-
New Delhi for the Postdoctoral Research Award (No. F.30-1/
2009, SAII). The authors are also thankful to Principal, Yeshwant
Mahavidyalaya, Nanded, for providing laboratory facilities and
Director, IICT, Hyderabad, for providing necessary instrumental
facilities.
1
1615 (AC¼¼N); H NMR (DMSO-d6): d 2.24 (s, 3H, CH3), d
5.18 (bs, 2H, NH2), d 7.11–8.26 (m, 13H, Ar-H), d 8.35 (s,
1H, 6H-of pyrimidine) ppm; M.S. (m/z): 618 (Mþ), 620
(Mþ2), 622 (Mþ4), 624 (Mþ6); Anal. Calcd for
C28H19N8Cl2Br: C, 54.39; H, 3.10; N, 18.12%. Found: C,
54.32; H, 3.21; N, 18.23%.
2-Amino-3-(4-chloro-phenylazo)-5-(phenyl)-7-(5-chloro-3-
methyl-1-phenyl-1H-pyrazol-4yl)-pyrazolo [1,5-a] pyrimi-
dine (3g). Color, Brown; IR (KBr): 3352 (ANH2), 1618
(AC¼¼N); 1H NMR (DMSO-d6): d 2.28 (s, 3H, CH3), d 5.28
(bs, 2H, NH2), d 7.05–8.21 (m, 14H, Ar-H), d 8.31 (s, 1H,
6H-of pyrimidine) ppm; M.S. (m/z): 539 (Mþ), 541 (Mþ2),
543 (Mþ4); Anal. Calcd for C28H20N8Cl2: C, 62.35; H, 3.74;
N, 20.77%. Found: C, 62.46; H, 3.68; N, 20.66%.
2-Amino-3-(4-chloro-phenylazo)-5-(4-hydroxy-phenyl)-7-(5-
chloro-3-methyl-1-phenyl-1H-pyrazol-4yl)-pyrazolo [1,5-a] py-
rimidine (3h). Color, Brown; IR (KBr): 3238 (ANH2), 1616
(AC¼¼N); 1H NMR (DMSO-d6): d 2.21 (s, 3H, CH3), d 5.22
(bs, 2H, NH2), d 7.11–8.28 (m, 13H, Ar-H), d 8.38 (s, 1H,
6H-of pyrimidine), d 11.56 (s, 1H, OH) ppm; M.S. (m/z): 555
(Mþ), 557 (Mþ2), 559 (Mþ4); Anal. Calcd for
C28H20N8OCl2: C, 60.55; H, 3.63; N, 20.17%. Found: C,
60.62; H, 3.68; N, 20.24%.
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Vol 47
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet