Eco-friendly synthesis and biological evaluation of substituted pyrano[2,3-c]pyrazoles

Article abstract of DOI:10.1016/j.bmcl.2012.06.055

An ecofriendly green approach for synthesis of substituted pyrano[2,3-c]pyrazoles has been developed via a multicomponent one pot approach in aqueous ethanol medium under totally non-catalytic conditions. The synthesized compounds were evaluated for their

Full text of DOI:10.1016/j.bmcl.2012.06.055

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5272–5278
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Eco-friendly synthesis and biological evaluation of substituted
pyrano[2,3-c]pyrazoles
Santhosh Reddy Mandha a, Sravanthi Siliveri b, Manjula Alla a, , Vittal Rao Bommena a,
⇑
Madhava Reddy Bommineni b, Sridhar Balasubramanian c
a Crop Protection Chemicals Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500607, India
b Department of Pharmaceutical Chemistry, G. Pulla Reddy College of Pharmacy, Mehdipatnam, Hyderabad 500028, India
c Laboratory of X-ray Crystallography, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An ecofriendly green approach for synthesis of substituted pyrano[2,3-c]pyrazoles has been developed
via a multicomponent one pot approach in aqueous ethanol medium under totally non-catalytic condi-
tions. The synthesized compounds were evaluated for their antibacterial, anti-inflammatory and
cytotoxic activities.
Received 22 February 2012
Revised 31 May 2012
Accepted 15 June 2012
Available online 29 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reactions
Non-catalytic conditions
Antibacterial activity
Anti-inflammatory activity
Cytotoxic activity
Substituted pyrano[2,3-c]pyrazoles are much sought after class
of heterocycles because of their potential applications in pharma-
ceutical field. They exhibit a wide range of biological activities like
antimicrobial,[1] anticancer,[2,3] anti-inflammatory,[4] inhibitors
of human Chk1 kinase[5] and also as biodegradable agrochemi-
ethanol or water as a solvent with a variety of catalysts.[11] The only
non-catalytic approach[12] reported for these compounds was low
yielding and thus limiting its scope. Even though there are many
non-catalytic methods available in literature for the construction
of pyranopyrazoles, construction of N1-phenylsubstituted pyrano-
pyrazoles are still carried out in a catalytic medium.[13] Herein,
we report a simple non-catalytic method for synthesis of both
pyranopyrazoles and N1-phenylsubstituted pyranopyrazoles by
using the mixture of water and ethanol (1:1) as a solvent media.
Further this protocol is amenable for constructing the spiroin-
doline and spirofluorene substituted pyranopyrazoles.
At the outset, synthesis of pyrano[2,3-c]pyrazoles via a multi-
component approach under non-catalytic conditions as shown in
Scheme 1, was envisaged. A one pot four component reaction
was carried out with ethylacetoacetate, hydrazine hydrate, malon-
onitrile and 4-hydroxybenzaldehyde in aqueous ethanol medium
(1:1) and heated to 100 °C. The reaction was completed in 2.5 h
precipitating the desired product 3d in 80% yield. The one pot four
component reactions were attempted with various aryl, heteroaryl
aldehydes and chloropyridinyloxy benzaldehydes.[14] Under the
optimized conditions, irrespective of the substituent present on
the aromatic ring containing aldehyde moiety, corresponding were
obtained in good yields. The substituent patterns are given in
Table 1.
cals.[6] Furthermore, they play
a significant role as crucial
synthetic intermediates.[7] Synthetic strategies of substituted
pyrano[2,3-c]pyrazoles have evolved a long way from the earlier
reported multistep protocols[8,9] to the present day multi-compo-
nent reactions (MCR’s). Conventional synthetic methodologies
reported, though have a broad scope but generate copious amount
of waste. As a result chemical industry is subjected to immense
pressure to get rid of such waste. In this aspect, multi-component
reactions have emerged as a valuable synthetic tool in the perspec-
tive of modern drug discovery because of their efficiency, intrinsic
atom economy and structural diversity of resulting products, when
compared to conventional multistep synthesis.
Literature survey reveals a variety of three and four component
MCR’s for the construction of different pyranopyrazoles. Among
them a three-component reaction between aromatic aldehyde, mal-
ononitrile, and substituted pyrazolin-5-ones in ethanol medium
was reported using triethylamine as catalyst.[10] Subsequently,
many synthetic methods have been developed involving either
However, when the one pot reaction was attempted by replac-
ing one of the substrates that is, hydrazine hydrate with phenyl
⇑
Corresponding author. Tel.: +91 040 27191441.
E-mail address: manjula@iict.res.in (M. Alla).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.06.055

S. R. Mandha et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5272–5278
5273
R
H3C
HN
CN
2a
N
O
NH2
3(a-j)
3f = R = 3-pyridinyl
3a = R = 3-OH-Ph
3b = R = 4-Br-Ph
3c = R = 4-CH3-Ph
3d = R = 4-OH-Ph
3e = R = C6F5
3g = R = thien-2-yl
EtOH/H2O
(1:1)
3-5 min, rt
3h = R = 4-C11H5Cl3NO
3i = R = 3-OC6H5-Ph
3j = R = 3-C11H5Cl3NO
CN
CN
CN
CN
100 °C
+
RCHO
R
CH
R
H3C
O
N
CN
2b
N
R1
H3C
N
N
O
NH2
2a & 2b
4(n-t)
Ph
4n = R = Ph
2a = R1 = H
4r = R = 3-OC6H5-Ph
4s = R = 3-pyridinyl
4t = R = 3-C11H5Cl3NO
4o = R = 4-OH-Ph
4p = R = 4-OCH3-Ph
4q = R = 4-NO2-Ph
2b = R1 = Ph
Scheme 1. Construction of various substituted pyrano[2,3-c]pyrazoles.
Table 1
Yields and melting point values of pyranopyrazole derivatives
Entry
R
R1
Product
Time (h)
Yielda (%)
Mpb (°C)
1
2
3
4
5
6
7
8
3-OH–C6H4
4-Br–C6H4
4-CH3–C6H4
4-OH–C6H4
C6F5
3-C5H4N
2-C4H3S
4-C11H5Cl3NO
3-OC6H5–C6H4
3-C11H5Cl3NO
—
—
—
C6H5
4-OH–C6H4
4-OCH3–C6H4
4-NO2–C6H4
3-OC6H5–C6H4
3-C5H4N
3-C11H5Cl3NO
—
H
H
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
—
2.2
2.5
3.0
2.5
2.5
3.0
3.0
3.0
2.5
2.5
2.5
3.0
3.0
2.5
2.5
3.0
1.5
2.0
2.5
3.0
2.0
2.5
75
80
84
80
64
88
80
87
87
88
89
86
88
88
86
85
80
86
93
89
80
81
248–249
178–179[15]
206–207[15]
225–227[15]
249–250
224–226
223–225
236–237
203–204
224–225
274–276[16]
244–247
3f
3g
3h
3i
3j
3k
3l
3m
4n
4o
4p
4q
4r
4s
4t
9
10
11
12
13
14
15
16
17
18
19
20
21
22
H
248–250
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
169–171[17]
210–212[18]
174–175[17]
195–197[17]
202–203
213–215[19]
137–139
219–221[16]
198–199
4u
4v
—
a
Isolated yields.
Literature references.
b
hydrazine, reaction was too sluggish. In order to improve the rate
of reaction, 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2b) was
isolated by performing an initial condensation reaction between
ethylacetoacetate and phenyl hydrazine through a known proce-
dure.[20] This was followed by the addition of carbonyl compound
and malononitrile to 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one
(2b) in aqueous ethanol medium to give the products 4n–v in
excellent yields. Likewise, the isolation of 3-methyl-1H-pyrazol-
5(4H)-one (2a) and reacting it with carbonyl compound and
malononitrile in aqueous ethanol medium resulted in better yields
for the synthesis of compounds 3a–m when compared to corre-
sponding one pot four component reaction. Another salient feature
of this protocol is that the reaction is facile with the ketones that is,
isatin and 9-fluorenone (Table 1, entry 11–12 and 21–22) and a
dialdehyde terephthalaldehyde (Table 1, entry 13) as shown in
Schemes 2 and 3.
from ethylacetoacetate and hydrazine hydrate) followed by an
intra-molecular cyclization to give polyfunctionalized pyrano
[2,3-c]pyrazoles. Knoevenagel condensation is known to occur in
non-catalytic conditions in protic solvents[22] and could well be
the driving force for the non-catalytic transformation. The struc-
tures of newly synthesized compounds were assigned on the basis
of their spectral data and those reported compounds by comparing
with earlier literature.
X-ray studies and molecular structure of pyranopyrazole (3e)
revealed that it exists in the crystal phase as a 2H, instead of 1H-
tautomer as shown in Figure 1(a), which is in congruence with
the literature reports on pyranopyrazoles.[23] In contrast to this,
N1-substituted pyranopyrazoles exist as ‘immobilized’ 1H-tautom-
ers.[24] X-ray structure of the compound 3e[25] was shown in
Figure 1(b).
Antibacterial studies: All the synthesized compounds were
screened for their antibacterial activity against two Gram positive
bacteria (Bacillus subtilis, Staphylococcus aureus), two Gram nega-
tive bacteria (Escherichia coli, Pseudomonas aeruginosa) with cipro-
floxacin as a standard. The study was carried out by Cup-plate
The mechanism of reaction is believed to involve the Knoevena-
gel condensation[21] with aromatic carbonyl compounds and mal-
ononitrile to form an alkene intermediate in situ. The intermediate
undergoes Michael addition with pyrazolin-5-one (formed in situ

5274
S. R. Mandha et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5272–5278
NH
NH
H3C
HN
O
2a
CN
NC
CN
N
N
O
NH2
3k
Isatin
100 °C
EtOH/H2O (1:1)
O
3-5 min, rt
N
H
H3C
N
O
2b
2a
2b
CN
O
O
4u
NH2
CN
CN
Ph
N
R1
H3C
N
2a & 2b
2a = R1= H
H3C
HN
2b = R1= Ph
CN
NC
N
CN
O
3l
NH2
9-Fluorenone
100 °C
EtOH/H2O (1:1)
3-5 min, rt
H3C
N
CN
N
O
4v
NH2
Ph
Scheme 2. Construction of spiroindoline and spirofluorene substituted pyrano[2,3-c]pyrazoles.
H2N
NC
O
C6F5
O
C6F5
O
N
H3C
N
H3C
HN
CN
NH
CN
CN
O
NC
CHO
CH3
N
N
EtOH/H2O
NH
NH2
NH2
CN
CN
H3C
H
(1:1)
N
2a
+
1H
100 °C, 3h
2H
3-5 min, rt
(a)
H3C
HN
CHO
CN
CN
CN
NH2
N
O
3m
Scheme 3. Construction of 4,40-(1,4-phenylene)bis(6-amino-3-methyl-1,4-dihy-
dropyrano[2,3-c]pyrazole-5-carbonitrile).
method[26] to determine the zone of inhibition (mm) against four
strains of bacteria. Antibacterial activity has been carried out at a
concentration of 100 lg/50 lL. Investigation of antibacterial data
revealed that compounds 3e, 3g, 3h, 3j, 4o, 4t and 4u showed good
activity against all the bacterial strains and 4r showed good activ-
ity against two strains Staphylococcus aureus and Escherichia coli as
shown in Table 2.
(b)
Screening of the compounds 3e, 3g, 3h, 3j, 4o, 4r, 4t and 4u for
their antibacterial activity were performed at different concentra-
tions that is, 0.39, 0.78, 1.56, 3.125, 6.25, 12.5, 25, 50 and 100 lg/
Figure 1. (a) 1H, 2H-tautomers of 3e. (b) The molecular structure of 3e, with the
atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability
level and H atoms are shown as small spheres of arbitrary radius.
mL by using Broth Microdilution MIC method. All the compounds
showed antibacterial activity against both gram positive and gram
negative standard strains and their MICs ranged between 1.56 and
tion 64.5, 72.0, 66.6, 70.9, 69.8, 68.8, 65.5, respectively) compara-
ble to that of standard Ibuprofen (% protection 72.3).
12.5
l
g/mL. The MICs of these compounds and ciprofloxacin were
By using mean paw edema values percentage protection against
edema formation calculated (Table 5) and also the percentage
protection of pyranopyrazole derivatives against edema formation
are represented in the form of graph as shown in Figure 2.
Cytotoxic activity evaluation (in vivo studies): Evaluation of cyto-
toxic activity of the synthesized compounds against MCF-7 (breast
cancer cell line) by MTT assay with Taxol as a standard reference[29]
has been carried out and the results are presented in Table 6.
determined by using the standard protocol of NCCLS Broth Micro-
dilution MIC method[27] and the results are tabulated in Table 3.
Anti-inflammatory studies: The inflammatory activities of some
of the synthesized compounds were evaluated using the Carra-
geenan induced paw edema bioassay in rats[28] shown in Table 4.
The results revealed that of all the tested compounds 3g–k, 4u
and 4v, exhibited significant anti-inflammatory activity (% protec-

S. R. Mandha et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5272–5278
5275
Table 2
Antibacterial data of pyrano[2,3-c]pyrazoles
Compound
Concentration (lg/50
l
L)
Zone of inhibition (mm)
B. subtilis E. coli
S. aureus
P. aeruginosa
Solvent (control)
Ciproflo-xacin
—
25
—
20
8
—
28
—
—
10
—
15
—
18
20
9
21
11
10
—
—
30
—
—
—
—
20
—
3a
3b
3c
3d
3e
3f
3g
3h
3i
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
—
—
10
13
18
—
15
15
7
16
13
10
—
6
15
5
8
15
—
15
15
15
—
14
14
11
15
10
17
—
9
15
6
8
—
15
14
—
20
22
9
23
12
10
—
14
16
10
15
18
—
3j
3k
3l
3m
4n
4o
4p
4q
4r
4s
4t
8
17
4
7
—
—
—
16
14
12
15
19
11
14
21
13
16
15
16
4u
4v
Table 3
Antibacterial activity of different compounds by Broth Microdilution MIC method
Concn (
l
g/mL)
Antibacterial activity against standard strains—compounds
3h 3j 4o 4r
3e
3g
4t
4u
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
0.39
0.78
1.56
3.125
6.25
12.5
25
+
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50
100
1, Bacillus subtilis; 2, Staphylococcus aureus; 3, Escherichia coli; 4, Pseudomonas aeruginosa; +, resistant; ꢀ, susceptible.
Ciprofloxacin is taken as a standard drug and its MIC is 1.56 lg/mL against all the four strains.
Table 4
Anti-inflammatory activity data of pyrano[2,3-c]pyrazoles
Treatment
Dose (mg/kg)
Mean paw edema volume in mL SEMa,b
30 min
1 h
2 h
3 h
4 h
Control
Standard (Ibuprofen)
3g
3h
3i
100
100
100
100
100
100
100
100
100
100
100
100
0.17 0.004
0.11 0.003
0.13 0.005
0.12 0.003
0.14 0.003
0.13 0.003
0.13 0.003
0.15 0.002
0.15 0.002
0.15 0.004
0.13 0.011
0.13 0.005
0.36 0.003
0.22 0.004
0.22 0.008
0.18 0.005
0.24 0.004
0.19 0.005
0.23 0.004
0.26 0.003
0.25 0.012
0.27 0.008
0.27 0.003
0.25 0.003
0.73 0.003
0.33 0.003
0.36 0.004
0.24 0.003
0.38 0.005
0.26 0.003
0.30 0.003
0.42 0.002
0.41 0.003
0.44 0.005
0.39 0.008
0.40 0.004
0.93 0.004
0.25 0.003
0.33 0.012
0.26 0.003
0.31 0.00
0.27 0.003
0.28 0.003
0.43 0.009
0.40 0.012
0.44 0.004
0.29 0.004
0.32 0.011
0.91 0.003
0.33 0.003
0.44 0.011
0.41 0.003
0.35 0.003
0.42 0.004
0.44 0.011
0.47 0.011
0.45 0.008
0.50 0.008
0.48 0.012
0.40 0.005
3j
3k
4n
4o
4p
4u
4v
a
SEM denotes Standard Error of Mean.
All data are significantly different from control (P < 0.001).
b
All tested compounds have shown significant cytotoxicity.
4q and 4u have shown cytotoxic activity with IC50 value falling
in the range of <20 g/mL. Compounds 3g and 3h have shown inhi-
bition in cell proliferation at an IC50 value of 4.463 g/mL and
Compounds 3e, 3f, 3j, 4n and 4o have shown cytotoxic activity
with IC50 value falling in the range of <50 g/mL and compounds
l
l
l

5276
S. R. Mandha et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5272–5278
Table 5
Percentage protection against edema formation
Treatment
Dose (mg/kg)
Percentage protection against edema formation
30 min
1 h
2 h
3 h
4 h
Standard (Ibuprofen)
100
100
100
100
100
100
100
100
100
100
100
38
41.6
38.8
50.0
33.3
47.2
36.1
27.7
30.5
25
52.7
50.8
67.1
47.9
64.3
54.7
42.4
43.8
39.7
46.5
45.2
72.3
64.5
72.0
66.6
70.9
69.8
53.7
56.9
52.6
68.8
65.5
64.4
51.6
54.9
61.5
53.8
51.6
48.3
50.5
45
3g
3h
3i
23.5
29.4
17.6
23.5
23.5
11.7
11.7
11.7
23.5
23.5
3j
3k
4n
4o
4p
4u
4v
25.0
30.5
47.2
56.6
4.443
l
g/mL, respectively whereas 3i has the most effective com-
g/mL. Compounds 3g, 3h and 3i are the
pound with IC50 = 1.630
l
effective cytotoxic compounds and their percentage inhibitions in
cell proliferation against MCF-7 breast cancer cell line were repre-
sented graphically as shown in Figure 3.
In summary, an efficient, economical and environmentally be-
nign multicomponent protocol for the construction of pyr-
ano[2,3-c]pyrazoles under non-catalytic conditions has been
achieved. Pyrano[2,3-c]pyrazoles have been evaluated for pharma-
cological activity profile. Synthesized compounds have shown
promising antibacterial and anti-inflammatory activities. In vivo
cytotoxic studies are carried out on MCF-7, Human breast tumor
cells. Of all the compounds tested, compound 3i with 3-phenoxy-
phenyl substitution emerged as the most potent compound. Com-
Figure 2. Graphical representation of anti-inflammatory activity.
Table 6
Cytotoxicity of synthesized compounds on MCF-7cell line
S. No.
Test compound
Treatment
concentration
Percentage inhibition
in cell proliferation
IC50 valuea
g/mL)
(l
(lg/mL)
1
3e
1
5
10
25
50
1.10
6.96
16.23
45.07
65.64
45.47
35.414
4.443
2
3
4
3f
1
5
10
25
50
0.41
10.10
16.33
25.16
74.95
3g
3h
1
2
3
4
5
0.28
19.08
22.03
41.77
61.74
0.5
5.34
17.44
31.88
42.47
65.22
68.64
4.463
1
2
4
6
8
5
6
3i
3j
0.1
0.25
0.5
1
2.5
5
8.26
13.96
20.25
43.47
68.64
83.72
1.630
1
5
10
25
0.41
16.33
34.56
42.38
42.829

S. R. Mandha et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5272–5278
5277
Table 6 (continued)
S. No. Test compound
Treatment
concentration
Percentage inhibition
in cell proliferation
IC50 valuea
g/mL)
(l
(lg/mL)
50
50.10
7
3k
3m
4n
4o
4p
4q
4u
1
5
10
25
50
ꢀ1.26
ꢀ3.16
0.51
—
—
ꢀ5.90
ꢀ4.93
8
1
5
10
25
50
11.45
23.35
24.37
24.78
26.68
9
1
5
10
25
50
1.67
22.41
26.86
55.49
84.08
25.77
47.464
—
10
11
12
13
1
5
10
25
50
2.10
5.96
22.88
30.82
50.23
1
5
10
25
50
0.76
4.19
8.99
11.57
29.98
1
5
10
25
50
2.04
12.51
30.82
85.45
96.42
15.146
16.766
1
5
10
25
50
19.26
26.58
40.26
64.62
86.54
a
Taxol as a standard reference IC50 = 15 nmol.
Figure 3. Acute toxicity IC50
(
lg/mL) of compounds 3g, 3h & 3i.

5278
S. R. Mandha et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5272–5278
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Acknowledgments
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