Conventional and microwave assisted synthesis of Some new N-[(4-oxo-2-substituted aryl -1, 3-thiazolidine)-acetamidyl]-5-nitroindazoles and its antimicrobial activity

Article abstract of DOI:10.1016/j.ejmech.2010.04.029

Several new N-[(4-oxo-2-substituted aryl-1, 3-thiazolidine)-acetamidyl]-5- nitroindazoles (4a-l) were synthesized from N-(arylidene amino acetamidyl)-5-nitroindazoles (3a-l). The reactions were carried out by both conventional as well as microwave method.

Full text of DOI:10.1016/j.ejmech.2010.04.029

European Journal of Medicinal Chemistry 45 (2010) 3541e3548
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Conventional and microwave assisted synthesis of Some new
N-[(4-oxo-2-substituted aryl ꢀ1, 3-thiazolidine)-acetamidyl]-5-nitroindazoles
and its antimicrobial activity
*
Apoorva Upadhyay , S.K. Srivastava, S.D. Srivastava
Synthetic Organic Chemistry Laboratory, Department of Chemistry, Dr. H.S. Gour University (A Central University), Sagar (M.P.) 470 003, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Several new N-[(4-oxo-2-substituted aryl-1, 3-thiazolidine)-acetamidyl]-5-nitroindazoles (4ael) were
synthesized from N-(arylidene amino acetamidyl)-5-nitroindazoles (3ael). The reactions were carried
out by both conventional as well as microwave method. The structures of these compounds were
confirmed by IR, 1H NMR, 13C NMR, FAB-mass spectra and also by microanalytical data. The newly
synthesized compounds were evaluated for their antimicrobial activity against variety of bacterial and
Received 21 September 2009
Received in revised form
24 April 2010
Accepted 25 April 2010
Available online 31 May 2010
fungal strains. The compounds 4g and 4h showed the maximum antibacterial activity (MIC 11 and 10
mL) against Escherichia coli and antifungal activity (MIC 9 and 8 g/mL) against Fusarium oxysporum.
Ó 2010 Elsevier Masson SAS. All rights reserved.
mg/
m
Keywords:
5-Nitroindazole
Thiazolidinone
Conventional and microwave irradiation
Antimicrobial agents
1. Introduction
2. Results and discussion
Microwave assisted heterocyclic synthesis is an efficient and
eco-friendly synthetic strategy and has now become a powerful
tool for green chemistry. Microwave irradiation has been applied to
organic reactions in the absence of solvent and/or in the presence of
a solid support, such as clays, alumina and silica, resulting in
shorter reaction times and better product yields than those
obtained by using conventional heating [1e7]. The indazole
nucleus is a pharmaceutically important and emerging heterocycle
with a broad spectrum of activities including anti-inflammatory [8],
antitumor [9], anti-HIV [10] and antimicrobial [11]. Particularly
5-nitroindazole and its derivatives have been found to possess wide
spectrum of activities like antiprotozoal [12], antimalarial [13] and
cytotoxic [14]. 4-Oxo-thiazolidine derivatives also exhibit antibac-
terial [15], antitubercular [16e18], antiviral [19e21] and anticancer
[22,23] properties. In the light of these observations this prompted
us to synthesize a new series of 5-nitroindazole derivatives by
incorporation the thiazolidine moiety. The structures of all
compounds have been confirmed by elemental analysis and spec-
tral analysis (IR, 1H NMR, 13C NMR and FAB Mass). All the
compounds have been screened for their antibacterial and anti-
fungal activity.
2.1. Chemistry
5-Nitroindazole on reaction with ethyl chloroacetate yielded
N-(ethyl ethanoate)-5-nitroindazole (1). The formation of
compound (1) was confirmed by the appearance of a signal at d 1.25
and
d 4.25 ppm due to CH3 and CH2 respectively in eCOOCH2CH3
(J ¼ 7 Hz) in the 1H NMR spectra and IR spectral band due to
1730 cmꢀ1 (pC]O of ester) also confirmed the formation of
compound (1). The compound (1) on amination with hydrazine
hydrate yielded N-(acetyl hydrazino)-5-nitroindazole (2). In the 1H
NMR spectra of (2) a peak at
CONH- and a peak at
d
8.20 ppm was observed due to
d
4.45 ppm was due to eNH2. Furthermore, in
the IR spectra, the bands at 1678 cmꢀ1 (pC]O of amide) and 3252,
3378 cmꢀ1 (eNHNH2) also confirmed the formation of compound
(2). The compound (2) on condensation with various aromatic
aldehydes yielded N-(arylidene amino acetamidyl)-5-nitro-
indazoles (3ael). The formation of (3ael) was supported by
the appearance of signals at
d 8.62e8.73 ppm due to eN]CH in
the 1H NMR spectra and IR spectra, the bands at 1635e1647 cmꢀ1
(N]CHe, acyclic) also confirmed the formation of (3a-l). The
compounds (3a-l) on reaction with thioglycolic acid underwent
dehydrative annulation afforded N-[(4-oxo-2-substituted aryl-1,
3-thiazolidine)-acetamidyl]-5-nitroindazoles (4ael). In the 1H
* Corresponding author. Tel.: þ91 9329176068.
E-mail address: upadhyay.apoorva@gmail.com (A. Upadhyay).
NMR spectra of (4ael) the peaks at d 3.33e3.47 ppm were observed
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.04.029

3542
A. Upadhyay et al. / European Journal of Medicinal Chemistry 45 (2010) 3541e3548
due to CH2 in the thiazolidine ring. In the IR spectra of (4ael) the
bands at 1710e1721 cmꢀ1 (pC]O, cyclic) also confirmed the
formation of thiazolidinones (Scheme 1).
All the reactions under microwave irradiation were completed
within 1e4 min whereas similar reactions under conventional
heating (steam bath) at reflux gave poor yields after much longer
reaction times. The impact of microwave irradiation and conven-
tional heating for the synthesis of compounds (3ael) and (4ael)
have been compared. The results are summarized in Table 1.
From the antimicrobial studies (Tables 2 and 3) we concluded
that (i) N-(acetyl hydrazino)-5-nitroindazole 2 showed higher
activity than the ester derivative 1. (ii) N-(arylidene amino acet-
amidyl)-5-nitroindazoles 3ael showed higher activity than acetyl
hydrazide derivatives 2. (iii) N-[(4-oxo-2-substituted aryl-1,3-
thiazolidine)-acetamidyl]-5-nitroindazoles 4ael showed higher
activity than the arylidene derivatives 3ael. (iv) Structure activity
relationship (SAR) study of the substitution pattern of the aryl
group toward antibacterial and antifungal activity have shown that
electron withdrawing and donating groups causes, respectively
more and less activity. The compounds 4g and 4h showed the
2.2. Antimicrobial activity
maximum antibacterial activity (MIC 11 and 10
mg/mL) against
The compounds 1, 2, 3ael and 4ael were screened for their
antibacterial activity against Escherichia coli, Bacillus subtilis and
E. coli and antifungal activity (MIC 9 and 8 g/mL) against F. oxy-
m
sporum. The compounds 4g and 4h in which a nitro group is present
at ortho and meta positions of the aryl ring, respectively possess
stronger antibacterial and antifungal activity than others. The
compounds 4c, 4d, 4e and 4f (halo substituents) having a less
electron withdrawing groups shows less antibacterial and anti-
fungal activity as compared to 4g and 4h. The hydroxy substituent
and unsubstituted benzene have shown less antibacterial and
antifungal activity as compared to nitro and halo substituents. The
compounds 4i, 4j, 4k and 4l shows very less antibacterial and
antifungal activity as compared to others because of the presence of
the electron donating groups such as methoxy, methyl and
dimethylamino.
Salmonella typhi at 50 and 100
activity against Aspergillus flavus, Penicillium citrinum and Fusarium
oxysporum at 50 and 100 g/mL concentrations by filter paper disk
mg/mL concentrations and antifungal
m
technique. The minimum inhibitory concentration (MIC) values of
the synthesized compounds were determined. Standard antibac-
terial Streptomycin and antifungal Griseofulvin were also tested
under the similar conditions for comparison. The results of the
antimicrobial activities are summarized in Tables 2e4. The results
of the antimicrobial screening data revealed that all the compounds
showed considerable and varied activity against the pathogenic
bacteria and fungi.
O2N
O2N
ClCH2COOCH2CH3
NH2NH2. H2O
N
N
Conventional (2 hr)
Microwave (2 min)
Conventional (8 hr)
Microwave (3.5 min)
CH2COOCH2CH3
N
N
H
(1)
O2N
O2N
ArCHO
N
N
N
Conventional (1-4 hr)
Microwave (1-3 min)
N
H
CH2CONHNH2
CH2CONHN = C
(2)
(3a-l)
Ar
O2N
SHCH2COOH/ZnCl2
N
Conventional (4-7 hr)
Microwave (2-4 min)
N
H
N
C
CH2CONH
Ar
(4a-l)
S
O
Compd. 3, 4
Ar
Compd. 3, 4
Ar
C6H5
2-NO2C6H4
3-NO2C6H4
2-CH3OC6H4
4-CH3OC6H4
4-CH3C6H4
a
b
c
d
e
f
g
h
i
2-OHC6H4
2-ClC6H4
4-ClC6H4
2-BrC6H4
3-BrC6H4
j
k
l
4-N(CH3)2 C6H4
Scheme 1..

A. Upadhyay et al. / European Journal of Medicinal Chemistry 45 (2010) 3541e3548
3543
Table 1
Comparison of conventional and microwave synthesis for 3ael and 4ael.
Table 3
Antifungal data of the compounds 1, 2, 3ael and 4ael.
Compound A.flavus P.citrinum
g/mL 50 g/mL 100
Comp.
Pa/watt
Conventional
Yield (%)
Microwave
Yield (%)
F.oxysporum
Time (hrs)
Time (min)
50
m
g/mL 100
m
m
m
g/mL 50
m
g/mL 100 mg/mL
3a
3b
3c
3d
3e
3f
3g
3h
3i
800
800
800
800
800
800
800
800
800
800
800
800
800
800
800
800
800
800
800
800
800
800
800
800
80
81
72
78
74
72
83
85
72
80
70
73
71
68
70
80
66
73
74
75
61
71
68
69
1
1
1.5
2
2
2
1
1
4
2
1
1
4
5
4
6
4
5
5
6
7
7
6
6
94
91
88
89
87
84
95
96
86
92
89
86
87
80
85
89
78
82
85
89
75
91
86
93
1
1
1
1.5
2
2
1
1
3
2
1
1
2
2
2
3
3.5
3.5
2
2.5
4
4
4
3.5
1
2
5.8
7
13.6
14.9
19
8
10
16.7
18
22
22.7
19.4
20.9
24
24.9
14
15.1
11
12.4
19
20.4
24
25
21.7
22.8
26.1
27
16.8
17.7
14
4
6
11.5
12
15.8
16.8
13.3
14.5
18
19
9.1
10
7.1
6
8.9
6.5
8.3
15
9
10.5
17.4
18.5
22
3a
3b
3c
3d
3e
3f
3g
3h
3i
15.5
16.8
20.5
21.4
18
16.2
20.1
20.8
17.8
18.8
22
22.9
12.6
13.9
10.8
11.4
17.1
18.5
22
22.9
19.8
20.8
24.2
25.1
15
20
22.9
19.8
20.7
24.2
25.4
15.2
16.2
12.6
13.8
20
21.4
25
25.8
22.6
23.7
27
16.4
17.8
21.4
22.5
11
12.2
8
9.5
19
22.7
23.8
12.8
14
3j
3k
3l
3j
3k
3l
4a
4b
4c
4d
4e
4f
4g
4h
4i
10
8.2
14.8
16
11.5
18.4
19.7
23.5
24.4
21
4a
4b
4c
4d
4e
4f
4g
4h
4i
16
17.3
21.3
22.3
18.8
20
23.6
24.7
13.9
14.8
11.1
12.6
27
19.4
20.2
17.2
18
21.4
22.3
12.5
13.6
10
22
25.6
26.5
16
4j
4k
4l
28.4
18
18.9
15.4
16.8
32
4j
17
16
4k
4l
13.2
14.5
28
12.9
13.9
28
a
Microwave irradiation power.
15.4
30
11.4
25
GFa
Zone of inhibition in mm.
a
A persual of Tables 2 and 3 shows that the antimicrobial activity
of pronounced at 100 g/mL. The antibacterial activity against
Griseofulvin.
m
E. coli, B. subtilis and S. typhi follow the following sequence:-
This shows that the substituent 3-NO2C6H4 on the compound 4
exhibit higher antibacterial activity against E. coli while the
compound 1 with substituent eCH2COOCH2CH3 replacing H from
NH is the least active compound against E. coli.
E. coli e 4h > 4g > 4d > 4c > 3h > 4f > 3g > 3d > 4e >
3c > 4b > 3f > 3e > 4a > 3b ¼ 4j > 4i > 3a > 4l > 3j > 4k > 3i
> 3l > 3k > 2 > 1.
Table 2
Antibacterial data of the compounds 1, 2, 3ael and 4ael.
Table 4
The minimal inhibitory concentrations (MIC) in
against bacterial and fungal strains.
mg/mL of synthesized compounds
Compond E. coli
B. subtilis
g/mL 50 g/mL 100
S. typhi
g/mL 50 g/mL 100 mg/mL
50
m
g/mL 100
m
m
m
m
Compound
E. coli B. subtilis S. typhi A. flavus P. citrinum F. oxysporum
1
2
5
7
8
10
3
5
5
7
4
6
7
8
1
35
32
22
20
16
17
18
18
15
15
27
25
31
30
18
16
13
13
17
15
11
10
20
20
25
22
8
45
43
30
25
20
18
22
21
17
16
38
38
42
41
23
21
17
16
20
18
15
15
30
25
40
36
12
e
38
36
22
20
17
17
18
18
15
15
30
25
34
32
18
17
15
15
17
17
13
12
22
20
30
25
10
e
34
32
20
19
17
17
19
18
14
13
23
22
30
27
19
18
14
13
17
17
11
11
20
19
23
22
e
40
38
30
28
22
20
28
25
20
18
35
32
38
36
25
22
17
17
20
20
15
14
28
28
32
30
e
30
28
17
15
13
13
15
15
11
11
20
18
25
23
15
15
11
11
13
13
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
14
16.4
18
21
21.9
19.4
20.1
22.8
23.5
14
11.5
12.8
16
16.8
14
15.1
18
18.7
9
14.8
16
12.7
13.8
16.9
18
15
15.9
19
20
9.8
11
16
17.5
21
21.7
19
20
22.8
23.6
13.5
14.8
10
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
15.4
18.2
19
16.8
17.4
20
20.9
11.5
12.6
9
10.6
17.2
18.4
21.4
22.3
19.2
20.2
23.5
24.6
14.8
16
19.4
20.1
17.4
18.3
21
21.9
12.8
13.9
9
3j
3k
3l
15
11
10
6
7
12.5
19.1
20.5
24.5
25.6
21.8
23
26.9
28
17.2
18
7.5
13.5
14.7
18
18.8
16
16.9
20
21
11.5
12.4
9
10.4
23
11
8.6
14.6
16
19.2
20
17.2
18
21.2
22
12
4a
4b
4c
4d
4e
4f
4g
4h
4i
17.4
18.9
22.6
23.7
20.5
21.4
25.5
26.1
15
18.4
19.9
23
23.9
21
21.9
25
25.8
16.1
17
13
8
4j
16
13.8
10.1
11.5
25
17
15
20
18
e
4k
4l
12
13.5
26
14.8
16
30
12.2
13.8
27
13.3
14.9
28
SMa
4l
Streptomycin
Griseofulvin
Zone of Inhibition in mm.
e
9
11
6
a
Streptomycin.

3544
A. Upadhyay et al. / European Journal of Medicinal Chemistry 45 (2010) 3541e3548
B. subtilis e 4h > 4g > 4d > 4c > 3h > 4f > 3g > 4e >
reaction time and energetically profitable. The solvent free condi-
tion contributes to saving in cost and diminishes the waste disposal
problem. Some of the synthesized compounds showed significant
antibacterial and antifungal activity.
3d > 3c > 4b > 3f > 3e ¼ 4a > 4j ¼ 3b > 4i > 3a > 3j > 4l > 3i >
4k > 3l > 3k > 2 > 1.
It clearly indicates that the antibacterial activity against B. sub-
tilis is also the same as that against E. coli. Here the occurrence of
3-NO2C6H4 has the highest antibacterial activity; while the
compound 1 has the least antibacterial activity against B. subtilis.
4. Experimental section
All the melting points were taken in open capillary tubes.
Formation of the compounds was routinely checked by TLC using
silica gel ‘G’ and the spots were exposed to iodine vapours for
visualization. IR spectra were recorded on Shimadzu 8201 PC
spectrophotometer. The 1H NMR spectra were recorded at 400 MHz
and 13C NMR spectra were recorded at 100 MHz on Bruker DRX-300
S.typhi e 4h > 4g > 4d > 3h > 4c > 3g > 4f > 3d > 3c ¼ 4e >
3f > 4b > 3e > 4a > 3b > 4j > 4i > 3a > 4l > 3j > 3i > 4k > 3l >
3k > 2 > 1.
Once again the compound with 3-NO2C6H4 substituent in
compound 4 has the highest antibacterial activity while the
compound 1 is the least active compound in case of S. typhi.
At this stage it is interesting to mention that all the newly
synthesized compounds exhibit the following antibacterial
sequence against the three bacteria used:-
in CDCl3 using TMS as an internal standard on d scale. The FAB-mass
spectra were recorded on a Jeol SX 102 mass spectrometer.
Microwave assisted reactions were carried out in Microwave oven
(Bajaj 2100 ETC, 800W, 2450 MHz). All the compounds gave satis-
factory C, H and N percentage within the experimental limits.
4.1. Synthesis of N-(ethyl ethanoate)-5-nitroindazole (1)
E. coli > S. typhi > B. subtilis
4.1.1. Conventional method
Furthermore, the antibacterial activities against these bacteria
are slightly smaller than Streptomycin.
Equimolar solution of 5-nitroindazole (30 g, 0.18 mol) and ethyl
chloroacetate (22.55 g, 0.18 mol) in acetone (100 ml) was stirred for
about 2 h. The solvent was removed in vacuo and the residue thus
obtained was purified over the column of silica gel and recrystal-
lized from acetone to furnish compound 1. Yield 78%; m.p.
Similar type of results are obtained in case of antifungal activity
of the newly synthesized compounds. Here also the substituent
3-NO2C6H4 exhibit pronounced antifungal behavior. Also, that the
newly synthesized compounds have less antifungal potential than
Griseofulvin, used as a standard. The following antifungal sequence
against the three fungi used:-
264e266 ꢁC; IR [ , cmꢀ1, KBr]: 3046 (CeH, AreH), 1730 (pC]O,
n
ester), 1601 (N¼CHe, cyclic), 1530,1338 (ArNO2), 1430 (NeCH2); 1H
NMR [400 MHz, CDCl3]:
d
7.90 (s, 1H, N¼CH-, cyclic), 7.26e7.60 (m,
3H, AreH), 4.25 (q, 2H, J ¼ 7 Hz, COOCH2CH3), 2.51 (s, 2H, NeCH2),
1.25 (t, 3H, J ¼ 7 Hz, COOCH2CH3); 13C NMR [100 MHz, CDCl3]:
F.oxysporum > A.flavus > P.citrinum
d
168.9 (COeO), 142.0 (CeNO2, aromatic), 135.0 (N¼CHe, cyclic),
110.9e122.2 (C of aromatic ring), 61.1 (CH2 CH3), 33.3 (N-CH2), 14.5
(CH2 CH3); Mass (m/z): 249 [M]þ, 204, 203, 176, 162, 134, 88; Anal.
(%) for C11H11N3O4, Calcd. C, 53.01; H, 4.42; N, 16.87. Found: C,
52.98; H, 4.39; N, 16.83.
2.3. Cytotoxic activity
According to their behavior against the bacterial and fungal
strains, we have selected five different 5-nitroindazoles, which are
the most active. Then, these compounds were tested against three
tumour cell lines, human colon adenocarcinoma (HT-29), Human
mammary adenocarcinoma (MCF-7) and human kidney carcinoma
4.1.2. Microwave method
A mixture of 5-nitroindazole (30 g, 0.18 mol) and ethyl chlor-
oacetate (22.55 g, 0.18 mol) was taken in 250 ml beaker, mixed
well and irradiated in microwave oven 800W for 2 min. The
completion of the reaction was monitored by TLC. After comple-
tion of the reaction the beaker was removed from the oven. The
mixture was cooled and the product was recrystallized from
acetone to furnish compound 1. Yield 90%; m.p. 264e266 ꢁC.
Spectral and analytical data were found to similar as reported for
conventional method.
(TK-10) at 100
mM concentration and cell survival percentages
(% SP) are gathered in Table 5. The cytotoxicity test was carried out
according to a known procedure [24]. The results of cytotoxic
activity indicate that the compound (4h) showed the maximum
cytotoxicity against the tested cell lines.
3. Conclusion
In conclusion, we have developed a simple and efficient method
for the synthesis of 4-oxo-thiazolidines having a 5-nitroindazole
nucleus. We have used microwave irradiation technique. This is
a solvent free reaction that leads to considerable saving in the
4.2. Synthesis of N-(acetyl hydrazino)-5-nitroindazole (2)
4.2.1. Conventional method
Equimolar solution of the compound 1 (27 g, 0.11 mol) and
hydrazine hydrate (5.43 g, 0.11 mol) in dioxane (90 ml) was stirred
for about 8 h. The solvent was removed in vacuo and the residue
thus obtained was purified over the column of silica gel and
recrystallized from acetone to furnish compound 2. Yield 80%; m.
Table 5
Cytotoxicity to MCF-7, TK-10 and HT-29 cell lines.
p. 210e211 ꢁC; IR [ , cmꢀ1, KBr]: 3252, 3378 (eNHNH2), 3045
n
Compound
% SP
(CeH, AreH), 1678 (pC]O, amide), 1600 (N]CHe,cyclic),
MCF-7
TK-10
HT-29
1527,1333 (ArNO2), 1427 (NeCH2); 1H NMR [400 MHz, CDCl3]:
3h
4c
4d
4g
4h
50
45
41
35
29
54
48
45
39
33
59
52
48
43
36
d
8.20 (s, 1H, CONH), 7.89 (s, 1H, N]CHe, cyclic), 7.25e7.61 (m,
3H, AreH), 4.45 (s, 2H, NH2), 2.49 (s, 2H, NeCH2); 13C NMR
[100 MHz, CDCl3]: 168.0 (CONH), 142.2 (CeNO2, aromatic), 135.2
d
(N]CHe, cyclic), 111.9e122.0 (C of aromatic ring), 33.5 (NeCH2);
% SP ¼ cell survival percentages at 100
m
M concentration.
Mass (m/z): 235[M]þ, 204, 189, 176, 162, 134, 88; Anal. (%) for

A. Upadhyay et al. / European Journal of Medicinal Chemistry 45 (2010) 3541e3548
3545
C9H9N5O3, Calcd. C, 45.96; H, 3.83; N, 29.79. Found: C, 45.90;
H, 3.79; N, 29.76.
4.5. N-(2-chlorobenzylidene amino acetamidyl)-5-nitroindazole
(3c)
4.2.2. Microwave method
m.p. 152e155 ꢁC; IR [
n
, cmꢀ1, KBr]: 3042 (CeH, AreH), 1669
A mixture of compound 1 (27 g, 0.11 mol) and hydrazine hydrate
(5.43 g, 0.11 mol) was taken in 250 ml beaker, mixed well and
irradiated in microwave oven 800W for 3.5 min. The completion
of the reaction was monitored by TLC. After completion of the
reaction the beaker was removed from the oven. The mixture
was cooled and the product was recrystallized from acetone to
furnish compound 2. Yield 91%; m.p. 210e211 ꢁC. Spectral and
analytical data were found to similar as reported for conventional
method.
(pC]O, amide), 1639 (N]CHe, acyclic), 1605 (N]CHe, cyclic),
1523,1327 (ArNO2), 1432 (NeCH2), 754 (AreCl); 1H NMR [400 MHz,
CDCl3]:
1H, N]CHe, cyclic), 7.20e7.55 (m, 7H, AreH), 2.54 (s, 2H, NeCH2);
13C NMR [100 MHZ, CDCl3]:
167.7 (CONH), 143.0 (N]CHe,
d 8.73 (s, 1H, N]CHe, acyclic), 8.18 (s, 1H, CONH), 7.87 (s,
d
acyclic), 142.7 (CeNO2, aromatic), 135.8 (N]CHe, cyclic), 134.3
(CeCl, aromatic), 112.8e122.3 (C of aromatic ring), 33.8 (NeCH2);
Mass (m/z): 357.5 [M]þ, 311, 219, 204, 195, 181, 176, 162, 153, 138,
134, 88; Anal. (%) for C16H12N5O3Cl, Calcd. C, 53.71; H, 3.36; N,19.58.
Found: C, 53.67; H, 3.31; N, 19.52.
4.3. Synthesis of N-(benzylidene amino acetamidyl)-5-
4.6. N-(4-chlorobenzylidene amino acetamidyl)-5-nitroindazole
nitroindazole (3a)
(3d)
4.3.1. Conventional method
m.p. 156e158 ꢁC; IR [ , cmꢀ1, KBr]: 3041 (CeH, AreH), 1671
n
Equimolar solution of the compound 2 (1.8 g, 0.008 mol) and
benzaldehyde (0.81 g, 0.008 mol) in dioxane (30 ml) was stirred
for about 1 h. The solvent was removed in vacuo and the residue
thus obtained was purified over the column of silica gel and
recrystallized from chloroform to furnish compound 3a. Yield
(pC]O, amide), 1636 (N]CHe, acyclic), 1603 (N]CHe, cyclic),
1528,1325 (ArNO2), 1434 (NeCH2), 757 (AreCl); 1H NMR [400 MHz,
CDCl3]:
1H, N]CHe, cyclic), 7.21e7.57 (m, 7H, AreH), 2.55 (s, 2H, NeCH2);
13C NMR [100 MHz, CDCl3]:
167.5 (CONH), 143.3 (N]CHe,
d 8.72 (s, 1H, eN]CHe, acyclic), 8.16 (s, 1H, CONH), 7.85 (s,
d
80%; m.p. 200e202 ꢁC; IR [
n
, cmꢀ1, KBr]: 3043 (CeH, AreH), 1674
acyclic), 142.5 (CeNO2, aromatic), 135.3 (N]CHe, cyclic), 134.0
(CeCl, aromatic), 112.0e122.1 (C of aromatic ring), 33.7 (NeCH2);
Mass (m/z): 357.5 [M]þ, 311, 219, 204, 195, 181, 176, 162, 153, 138,
134, 88; Anal. (%) For C16H12N5O3Cl, Calcd. C, 53.71; H, 3.36; N,19.58
Found: C, 53.68; H, 3.34; N, 19.54.
(pC]O, amide), 1635 (N]CHe, acyclic), 1604 (N]CHe, cyclic),
1524,1329 (ArNO2), 1428 (NeCH2). 1H NMR [400 MHz, CDCl3]:
d
8.21 (s, 1H, CONH), 8.70 (s, 1H, N]CHe, acyclic), 7.86 (s, 1H, N]
CHecyclic), 7.27e7.63 (m, 8H, AreH), 2.52 (s, 2H, NeCH2); 13C
NMR [100 MHz, CDCl3]: 168.1 (CONH), 143.2 (N]CH, acyclic),
d
142.3 (CeNO2, aromatic), 135.6 (N]CHe, cyclic), 112.1e122.2 (C
of aromatic ring), 33.4 (NeCH2); Mass (m/z): 323 [M]þ, 277, 219,
204, 176, 162, 161, 147, 134, 119, 104, 88; Anal. (%) for C16H13N5O3,
Calcd. C, 59.44; H, 4.02; N, 21.67. Found: C, 59.40; H, 3.98;
N, 21.63.
4.7. N-(2-bromobenzylidene amino acetamidyl)-5-nitroindazole
(3e)
m.p. 190e192 ꢁC; IR [ , cmꢀ1, KBr]: 3040 (CeH, AreH), 1666
n
(pC]O, amide), 1638 (N]CHe, acyclic), 1607 (N]CHe, cyclic),
1526,1323 (ArNO2), 1436 (NeCH2), 618 (AreBr); 1H NMR [400 MHz,
4.3.2. Microwave method
CDCl3]:
1H, N]CHe, cyclic), 7.22e7.58 (m, 7H, AreH), 2.53 (s, 2H, NeCH2);
13C NMR [100 MHz, CDCl3]:
167.8 (CONH), 143.6 (N]CHe,
acyclic), 141.9 (CeNO2, aromatic), 135.1 (N]CHe, cyclic), 118.2
(CeBr, aromatic), 111.7e122.4 (C of aromatic ring), 33.9 (NeCH2);
Mass (m/z): 401.9 [M]þ, 356, 240, 226, 219, 208, 198, 183, 176, 162,
134, 88; Anal. (%) For C16H12N5O3Br, Calcd. C, 47.76; H, 2.98; N, 17.41.
Found: C, 47.71; H, 2.93; N, 17.37.
d 8.69 (s, 1H, eN]CHe, acyclic), 8.14 (s, 1H, CONH), 7.88 (s,
A mixture of the compound 2 (1.8 g, 0.008 mol) and benzalde-
hyde (0.81 g, 0.008 mol) was taken in 250 ml beaker, mixed well
and irradiated in microwave oven 800W for 1 min. The completion
of the reaction was monitored by TLC. After completion of the
reaction the beaker was removed from the oven. The mixture was
cooled and the product was recrystallized from chloroform to
furnish compound 3a. Yield 94%; m.p. 200e202 ꢁC. Spectral and
analytical data were found to similar as reported for conventional
method.
d
4.8. N-(3-bromobenzylidene amino acetamidyl)-5-nitroindazole
Other compounds 3bel were prepared similarly by treating 2
with various aromatic aldehydes.
(3f)
m.p. 188e190 ꢁC; IR [ , cmꢀ1, KBr]: 3044 (CeH, AreH), 1661
n
(pC]O, amide), 1640 (N]CHe, acyclic), 1606 (N]CHe, cyclic),
4.4. N-(2-hydroxybenzylidene amino acetamidyl)-5-nitroindazole
1522,1326 (ArNO2), 1433 (NeCH2), 620 (AreBr). 1H NMR [400 MHz,
(3b)
CDCl3]:
1H, N]CHe, cyclic), 7.24e7.56 (m, 7H, AreH), 2.56 (s, 2H, NeCH2);
13C NMR [100 MHz, CDCl3]:
168.2 (CONH), 143.4 (N]CHe,
d 8.65 (s, 1H, eN]CHe, acyclic), 8.11 (s, 1H, CONH), 7.91 (s,
m.p. 260e261 ꢁC; IR [
n
, cmꢀ1, KBr]: 3246 (AreOH), 3047 (CeH,
d
AreH), 1672 (pC]O, amide), 1637 (N¼CHe, acyclic), 1602
acyclic), 141.7 (CeNO2, aromatic), 135.5 (N]CHe, cyclic), 118.4
(CeBr, aromatic), 111.5e122.8 (C of aromatic ring), 34.0 (NeCH2);
Mass (m/z): 401.9 [M]þ, 356, 240, 226, 219, 208, 198, 183, 176, 162,
134, 88; Anal. (%) For C16H12N5O3Br, Calcd. C, 47.76; H, 2.98; N, 17.41.
Found: C, 47.73; H, 2.94; N, 17.38.
(N¼CHe, cyclic), 1520, 1324 (ArNO2), 1431 (NeCH2); 1H NMR
[400 MHz, CDCl3]:
acyclic), 8.22 (s, 1H, CONH), 7.84 (s, 1H, N¼CHe, cyclic), 7.23e7.59
d
11.95 (s, 1H, AreOH), 8.71 (s, 1H, eN¼CHe,
(m, 7H, AreH), 2.50 (s, 2H, NeCH2); 13C NMR [100 MHz, CDCl3]:
d
167.9 (CONH), 165.1 (CeOH, aromatic), 143.1 (N]CHe, acyclic),
142.4 (CeNO2, aromatic), 135.4 (N]CHe, cyclic), 112.3e122.6 (C
of aromatic ring), 33.6 (NeCH2); Mass (m/z): 339 [M]þ, 293, 219,
204, 177, 176, 163, 162, 135, 134, 120, 88; Anal. (%) for C16H13N5O4,
Calcd. C, 56.64; H, 3.83; N, 20.65. Found: C, 56.59; H, 3.79;
N, 20.61.
4.9. N-(2-nitrobenzylidene amino acetamidyl)-5-nitroindazole (3g)
m.p. 210e212 ꢁC; IR [ , cmꢀ1, KBr]: 3048 (CeH, AreH),1662
n
(pC]O, amide), 1642 (N]CHe, acyclic), 1609 (N]CHe, cyclic),
1525,1328 (ArNO2), 1429 (NeCH2); 1H NMR [400 MHz, CDCl3]:

3546
A. Upadhyay et al. / European Journal of Medicinal Chemistry 45 (2010) 3541e3548
d
8.68 (s, 1H, eN]CHe, acyclic), 8.13 (s, 1H, CONH), 7.93 (s, 1H, N]
(%) For C17H15N5O3 Calcd. C, 60.53; H, 4.45; N, 20.77. Found:
C, 60.51; H, 4.41; N, 20.72.
CH-cyclic), 7.28e7.62 (m, 7H, AreH), 2.60 (s, 2H, NeCH2); 13C NMR
[100 MHz, CDCl3]:
d 168.5 (CONH), 143.5 (N]CHe, acyclic), 141.6
(CeNO2, aromatic), 135.7 (N]CHe, cyclic), 111.2e122.5 (C of
aromatic ring), 34.1 (NeCH2); Mass (m/z): 368 [M]þ, 322, 219, 206,
204, 192, 176, 164, 149, 134, 88; Anal. (%) For C16H12N6O5 Calcd. C,
52.17; H, 3.26; N, 22.82. Found: C, 52.13; H, 3.21; N, 22.80.
4.14. N-(4-dimethylaminobenzylidene amino acetamidyl)-5-
nitroindazole (3l)
m.p. 205e206 ꢁC; IR [ , cmꢀ1, KBr]: 3054 (CeH, AreH), 2910,
n
2852 (NeCH3), 1668 (pC]O, amide), 1647 (N]CHe, acyclic),1612
(N]CHe, cyclic), 1536,1336 (ArNO2), 1438 (NeCH2); 1H NMR
[400 MHz, CDCl3]: 8.63 (s, 1H, eN]CHe, acyclic), 8.23 (s, 1H,
CONH), 7.98 (s, 1H, N]CHe, cyclic), 7.34e7.64 (m, 7H, AreH), 3.12
(s, 6H, 2 ꢂ CH3), 2.63 (s, 2H, NeCH2); 13C NMR [100 MHz, CDCl3]:
4.10. N-(3-nitrobenzylidene amino acetamidyl)-5-nitroindazole
(3h)
m.p. 214e215 ꢁC; IR [ , cmꢀ1, KBr]: 3050 (CeH, AreH), 1664
n
d
168.7 (CONH), 144.1 (N]CHe, acyclic), 143.0 (CeNO2, aromatic),
(pC]O, amide), 1641 (N]CHe, acyclic), 1608 (N]CHe, cyclic),
1529,1332 (ArNO2), 1435 (NeCH2), 1H NMR [400 MHz, CDCl3]:
136.4 (N]CHe, cyclic), 110.3e123.1 (C of aromatic ring), 34.7
(NeCH2), 23.7 (NCH3); Mass (m/z): 366 [M]þ, 320, 219, 204, 190,
176, 162, 147, 134, 88; Anal. (%) For C18H18N6O3 Calcd. C, 59.02; H,
4.92; N, 22.95. Found: C, 58.97; H, 4.88; N, 22.90.
d
8.66 (s, 1H, -N¼CH-acyclic), 8.12 (s, 1H, CONH), 7.92 (s, 1H, N]CH-
cyclic), 7.31e7.65 (m, 7H, AreH), 2.59 (s, 2H, NeCH2); 13C NMR
[100 MHz, CDCl3]: 168.3 (CONH), 143.7 (N]CHe, acyclic), 141.8
d
(C-NO2, aromatic), 135.9 (N]CHe, cyclic), 111.3e122.7 (C of
aromatic ring), 34.3 (NeCH2); Mass (m/z): 368 [M]þ, 322, 219, 206,
204, 192, 176, 164, 149, 134, 88; Anal. (%) For C16H12N6O5 Calcd. C,
52.17; H, 3.26; N, 22.82. Found: C, 52.14; H, 3.23; N, 22.83.
4.15. Synthesis of N-[(4-oxo-2-phenyl ꢀ1,3-thiazolidine)-
acetamidyl]-5-nitroindazole (4a)
4.15.1. Conventional method
Equimolar solution of the compound 3a (1.5 g, 0.005 mol) and
thioglycolic acid (0.43 g, 0.005 mol) with a pinch of anhydrous
ZnCl2 in acetone (25 ml) was stirred for about 4 h. The solvent was
removed in vacuo and the residue thus obtained was purified over
the column of silica gel and recrystallized from chloroform to
4.11. N-(2-methoxybenzylidene amino acetamidyl)-5-nitroindazole
(3i)
m.p. 220e222 ꢁC; IR [ , cmꢀ1, KBr]: 3049 (CeH, AreH),2825
n
(AreOCH3),1663 (pC]O, amide),1644 (N]CHe, acyclic),1610 (N]
furnish compound 4a. Yield 71%; m.p. 194e195 ꢁC; IR [ , cmꢀ1, KBr]:
n
CH-cyclic), 1533,1331 (ArNO2), 1437 (NeCH2), 1H NMR [400 MHz,
3052 (CeH, AreH), 2980 (NeCHeS), 1712 (pC]O, cyclic), 1670
(pC]O, amide), 1614 (N]CHe, cyclic), 1538,1339 (ArNO2), 1441
CDCl3]:
1H, N]CHe, cyclic), 7.30e7.67 (m, 7H, AreH), 3.96 (s, 3H, OCH3),
2.58 (s, 2H, NeCH2); 13C NMR [100 MHz, CDCl3]:
168.4 (CONH),
d 8.67 (s, 1H, eN]CHe, acyclic), 8.15 (s, 1H, CONH), 7.94 (s,
(NeCH2), 690 (CeSeC); 1H NMR [400 MHz, CDCl3]:
d
8.25 (s, 1H,
CONH), 7.99 (s, 1H, N]CHe, cyclic), 7.36e7.70 (m, 8H, AreH), 4.10
(s, 1H, eNeCHe), 3.40 (s, 2H, CH2, cyclic), 2.62 (s, 2H, NeCH2); 13
NMR [100 MHz, CDCl3]: 171.0 (CO,cyclic), 168.9 (CONH), 141.3
d
144.0 (N]CHe, acyclic), 142.6 (CeNO2, aromatic), 136.1 (N]CHe,
cyclic),110.5e122.9 (C of aromatic ring), 55.8 (OCH3), 34.5 (NeCH2);
Mass (m/z): 353 [M]þ, 219, 204, 191, 177, 176, 162, 149, 134, 88; Anal.
(%) For C17H15N5O4 Calcd. C, 57.79; H, 4.25; N,19.83. Found: C, 57.73;
H, 4.21; N, 19.79.
C
d
(CeNO2, aromatic), 136.6 (N]CHe, cyclic), 110.1e123.4 (C of
aromatic ring), 44.2 (CH2 of thiazolidinone ring) 40.3 (NCHS), 34.9
(NeCH2); Mass (m/z): 397 [M]þ, 369, 351, 323, 235, 221, 219, 207,
204, 193, 178, 176, 165, 162, 150, 136, 134, 88; Anal. (%) for
C18H15N5O4S, Calcd. C, 54.41; H, 3.78; N, 17.63. Found: C, 54.37;
H, 3.73; N, 17.58.
4.12. N-(4-methoxybenzylidene amino acetamidyl)-5-nitroindazole
(3j)
m.p. 224e225 ꢁC; IR [ , cmꢀ1, KBr]: 3053 (CeH, AreH), 2828
n
4.15.2. Microwave method
(AreOCH3),1665 (pC]O, amide),1643 (N]CHe, acyclic),1613 (N]
A mixture of the compound 3a (1.5g, 0.005 mol) and thioglycolic
acid (0.43 g, 0.005 mol) with a pinch of anhydrous ZnCl2 was taken
in 250 ml beaker, mixed well and irradiated in microwave oven
800W for 2 min. The completion of the reaction was monitored by
TLC. After completion of the reaction the beaker was removed from
the oven. The mixture was cooled and the product was recrystal-
lized from chloroform to furnish compound 4a. Yield 87%; m.p.
194e195 ꢁC. Spectral and analytical data were found to similar as
reported for conventional method.
CHe, cyclic), 1532,1335 (ArNO2), 1439 (NeCH2); 1H NMR [400 MHz,
CDCl3]:
1H, N]CHe, cyclic), 7.29e7.66 (m, 7H, AreH), 3.95 (s, 3H, OCH3),
2.57 (s, 2H, NeCH2); 13C NMR [100 MHz, CDCl3]:
168.6 (CONH),
d 8.64 (s, 1H, eN]CHe, acyclic), 8.17 (s, 1H, CONH), 7.95 (s,
d
143.8 (N]CHe, acyclic), 143.1 (CeNO2, aromatic), 136.3 (N]CH,
cyclic),110.4e123.0 (C of aromatic ring), 55.5 (OCH3), 34.2 (NeCH2);
Mass (m/z): 353 [M]þ, 219, 204, 191, 177, 176, 162, 149, 134, 88; Anal.
(%) For C17H15N5O4 Calcd. C, 57.79; H, 4.25; N,19.83. Found: C, 57.76;
H, 4.22; N, 19.78.
Other compounds 4bel were prepared similarly by using 3bel
respectively.
4.13. N-(4-methylbenzylidene amino acetamidyl)-5-nitroindazole
(3k)
4.16. N-[{4-oxo-2-(2-hydroxyphenyl)-1, 3-thiazolidine}-
acetamidyl]-5-nitroindazole (4b)
m.p. 200e201 ꢁC; IR [ , cmꢀ1, KBr]: 3051 (CeH, AreH), 2920
n
(AreCH3), 1667 (pC]O,amide),1645 (N]CHe, acyclic),1611 (N]
m.p. 252e253 ꢁC; IR [ , cmꢀ1, KBr]: 3243 (AreOH), 3056 (CeH,
n
CHe, cyclic), 1534,1337 (ArNO2), 1440 (NeCH2); 1H NMR [400 MHz,
AreH), 2981 (NeCHeS), 1714 (pC]O, cyclic), 1673 (pC]O, amide),
1616 (N]CHe, cyclic), 1535,1342 (ArNO2), 1443 (NeCH2), 691
CDCl3]:
1H, N]CHe, cyclic), 7.32e7.68 (m, 7H, AreH), 2.61 (s, 2H, NeCH2),
2.37 (s, 3H, AreCH3); 13C NMR [100 MHz, CDCl3]:
168.8 (CONH),
d 8.62 (s, 1H, eN]CHe, acyclic), 8.19 (s, 1H, CONH), 7.96 (s,
(CeSeC); 1H NMR [400 MHz, CDCl3].
d 11.97 (s, 1H, AreOH), 8.26 (s,
d
1H, CONH), 7.97 (s, 1H, N]CHe, cyclic), 7.33e7.72 (m, 7H, AreH),
4.12 (s, 1H, eNeCHe), 3.41 (s, 2H, CH2, cyclic), 2.64 (s, 2H, NeCH2);
143.9 (N]CHe, acyclic), 142.8 (CeNO2, aromatic), 136.0 (N]CHe,
cyclic), 110.0e123.2 (C of aromatic ring), 34.4 (NeCH2), 22.5 (CH3);
Mass (m/z): 337 [M]þ, 291, 219, 204, 190, 176, 162, 147, 134, 88; Anal.
13C NMR [100 MHz, CDCl3]:
d
171.2 (CO,cyclic), 169.0 (CONH), 164.9
(CeOH, aromatic), 141.0 (CeNO2, aromatic), 136.2 (N]CHe, cyclic),

A. Upadhyay et al. / European Journal of Medicinal Chemistry 45 (2010) 3541e3548
3547
110.2e123.6 (C of aromatic ring), 44.4 (CH2 of thiazolidinone ring),
40.6 (NCHS), 34.8 (NeCH2); Mass (m/z): 413 [M]þ, 385, 367, 339,
251, 237, 223, 219, 209, 204, 194, 181, 176, 166, 162, 152, 134, 88;
Anal. (%) for C18H15N5O5S, Calcd. C, 52.30; H, 3.63; N, 16.95. Found:
C, 52.25; H, 3.58; N, 16.91.
eNeCHe), 3.39 (s, 2H, CH2, cyclic), 2.67 (s, 2H, NeCH2); 13C NMR
[100 MHz, CDCl3]: 171.4 (CO,cyclic), 169.5 (CONH), 143.9 (CeNO2,
d
aromatic), 137.1 (N]CHe, cyclic), 118.8 (CeBr, aromatic),
111.1e124.0 (C of aromatic ring), 44.6 (CH2 of thiazolidinone ring),
41.1 (NCHS), 35.1 (NeCH2); Mass (m/z): 475.9 [M]þ, 448, 430, 402,
314, 300, 286, 272, 257, 244, 229, 219, 215, 204, 176, 162, 134, 88;
Anal. (%) for C18H14N5O4SBr, Calcd. C, 45.38; H, 2.94; N, 14.70.
Found: C, 45.34; H, 2.91; N, 14.67.
4.17. N-[{4-oxo-2-(2-chlorophenyl)-1,3-thiazolidine}-acetamidyl]-
5-nitroindazole (4c)
m.p. 148e150 ꢁC; IR [
n
, cmꢀ1, KBr]: 3060 (C-H, AreH), 2982
4.21. N-[{4-oxo-2-(2-nitrophenyl)-1,3-thiazolidine}-acetamidyl]-5-
(NeCHeS), 1710 (pC]O, cyclic), 1675 (pC]O, amide), 1618 (N]
CHe, cyclic), 1537,1341 (ArNO2), 1445 (NeCH2), 727 (AreCl), 692
nitroindazole (4g)
(CeSeC); 1H NMR [400 MHz, CDCl3]:
d
8.24 (s, 1H, CONH), 8.01 (s,
m.p. 202e203 ꢁC; IR [ , cmꢀ1, KBr]: 3064 (C-H, Ar-H), 2976
n
1H, N]CHe, cyclic), 7.38e7.69 (m, 7H, AreH), 4.11 (s, 1H, NeCHe),
(NeCHeS), 1715 (pC]O, cyclic), 1679 (pC]O, amide), 1620 (N]
3.42 (s, 2H, CH2, cyclic), 2.65 (s, 2H, NeCH2); 13C NMR [100 MHz,
CHe, cyclic), 1544,1347 (AreNO2),1448 (NeCH2), 693 (CeSeC); 1H
CDCl3]:
d
171.1 (CO,cyclic), 169.1 (CONH), 141.2 (CeNO2, aromatic),
NMR [400 MHz, CDCl3]:
cyclic), 7.42e7.73 (m, 7H, AreH), 4.14 (s, 1H, eNeCH), 3.37 (s, 2H,
CH2, cyclic), 2.70 (s, 2H, NeCH2); 13C NMR [100 MHz, CDCl3]:
171.6
(CO,cyclic), 169.4 (CONH), 140.0 (CeNO2, aromatic), 136.9 (N]CHe,
cyclic), 111.6e123.9 (C of aromatic ring), 45.0 (CH2 of thiazolidinone
ring), 41.3 (NCHS), 35.3 (NeCH2); Mass (m/z): 442 [M]þ, 414, 396,
368, 280, 266, 252, 238, 223, 219, 210, 204, 195, 181, 176, 162, 134,
88; Anal. (%) for C18H14N6O6S, Calcd. C, 48.87; H, 3.17; N, 19.00.
Found: C, 48.83; H, 3.12; N, 18.97.
d 8.30 (s, 1H, CONH), 8.03 (s, 1H, N]CHe,
136.5 (N]CHe, cyclic), 134.5 (CeCl, aromatic), 110.6e123.3 (C of
aromatic ring), 44.1 (CH2 of thiazolidinone ring), 41.0 (NCHS), 34.6
(NeCH2); Mass (m/z): 431.5 [M]þ, 403, 385, 357, 269, 255, 241, 227,
219, 212, 204, 199, 184, 176, 170, 162, 134, 88; Anal. (%) for
C18H14N5O4SCl, Calcd. C, 50.06; H, 3.24; N, 16.22. Found: C, 50.01;
H, 3.21; N, 16.20.
d
4.18. N-[{4-oxo-2-(4-chlorophenyl)-1,3-thiazolidine}-acetamidyl]-
5-nitroindazole (4d)
4.22. N-[{4-oxo-2-(3-nitrophenyl)-1,3-thiazolidine}-acetamidyl]-
5-nitroindazole (4h)
m.p. 153e154 ꢁC; IR [
n
, cmꢀ1, KBr]: 3059 (CeH, AreH), 2985
(NeCHeS), 1711 (pC]O, cyclic), 1677 (pC]O, amide), 1615 (N]
CHe, cyclic), 1540,1340 (ArNO2), 1442 (NeCH2), 725 (AreCl), 695
m.p. 206e207 ꢁC; IR [ , cmꢀ1, KBr]: 3063 (CeH, AreH), 2977
n
(CeSeC); 1H NMR [400 MHz, CDCl3]:
d
8.27 (s, 1H, CONH), 8.04 (s,
(NeCHeS), 1717 (pC]O, cyclic), 1681 (pC]O, amide), 1617 (N]
1H, N]CHe, cyclic), 7.37e7.71 (m,7H, AreH), 4.15 (s, 1H, NeCH),
CHe, cyclic), 1545,1346 (AreNO2), 1447 (NeCH2), 696 (CeSeC); 1H
3.47 (s, 2H, CH2, cyclic), 2.69 (s, 2H, NeCH2); 13C NMR [100 MHz,
NMR [400 MHz, CDCl3]:
cyclic),7.40e7.77 (m, 7H, AreH), 4.18 (s, 1H, eNeCH), 3.35 (s, 2H,
CH2, cyclic), 2.68 (s, 2H, NeCH2); 13C NMR [100 MHz, CDCl3]:
171.9
d 8.32 (s, 1H, CONH), 8.06 (s, 1H, N]CHe,
CDCl3]:
d 171.3 (CO,cyclic), 169.3(CONH), 141.1 (CeNO2, aromatic),
136.7 (N]CHe, cyclic), 134.6 (CeCl, aromatic), 110.8e123.5 (C of
aromatic ring), 44.3 (CH2 of thiazolidinone ring), 41.2 (NCHS), 35.0
(NeCH2); Mass (m/z): 431.5 [M]þ, 403, 385, 357, 269, 255, 241, 227,
219, 212, 204, 199, 184, 176, 170, 162, 134, 88; Anal. (%) for
C18H14N5O4SCl, Calcd. C, 50.06; H, 3.24; N, 16.22. Found: C, 50.02;
H, 3.20; N, 16.21.
d
(CO,cyclic), 169.6 (CONH), 146.3 (N]CH), 140.8 (CeNO2, aromatic),
137.2 (N]CHe, cyclic), 111.4e124.4 (C of aromatic ring), 44.8 (CH2
of thiazolidinone ring), 41.5 (NCHS), 35.5 (NeCH2); Mass (m/z): 442
[M]þ, 414, 396, 368, 280, 266, 252, 238, 223, 219, 210, 204, 195, 181,
176, 162, 134, 88; Anal. (%) for C18H14N6O6S, Calcd. C, 48.87; H, 3.17;
N, 19.00. Found: C, 48.84; H, 3.14; N, 18.98.
4.19. N-[{4-oxo-2-(2-bromophenyl)-1,3-thiazolidine}-acetamidyl]-
5-nitroindazole (4e)
4.23. N-[{4-oxo-2-(2-methoxyphenyl)-1,3-thiazolidine}-
acetamidyl]-5-nitroindazole (4i)
m.p. 180e181 ꢁC; IR [ , cmꢀ1, KBr]: 3062 (CeH, AreH), 2983
n
(NeCHeS), 1713 (pC]O, cyclic), 1676 (pC]O, amide), 1619 (N]
CHe, cyclic), 1542,1344 (ArNO2), 1444 (NeCH2), 694 (CeSeC), 621
m.p. 207e208 ꢁC; IR [ , cmꢀ1, KBr]: 3058 (CeH, AreH), 2975
n
(NeCHeS), 2826 (AreOCH3), 1720 (pC]O, cyclic), 1685 (pC]O,
amide), 1621 (N]CHe, cyclic), 1548,1349 (AreNO2), 1450 (NeCH2),
(AreBr); 1H NMR [400 MHz, CDCl3]:
d 8.29 (s, 1H, CONH), 8.02 (s,
1H, N]CHe, cyclic), 7.35e7.74 (m, 7H, AreH), 4.13 (s, 1H,
eNeCHe), 3.71 (s, 2H, NeCH2), 3.43 (s, 2H, CH2, cyclic), 2.66 (s, 2H,
698 (CeSeC); 1H NMR [400 MHz, CDCl3]:
d 8.31 (s, 1H, CONH), 8.08
(s, 1H, N]CH-cyclic), 7.43e7.75 (m, 7H, AreH), 3.38 (s, 2H, CH2,
cyclic) 4.19 (s, 1H, eNeCHe), 3.92 (s, 3H, OeCH3), 2.72 (s, 2H,
NeCH2); 13C NMR [100 MHz, CDCl3]:
d 171.5 (CO,cyclic), 169.2
(CONH),141.4 (CeNO2, aromatic),136.8 (N]CH, cyclic),118.5 (CeBr,
aromatic),111.0e123.7 (C of aromatic ring), 44.5 (CH2 of thiazoli-
dinone ring), 41.4 (NCHS), 35.2 (NeCH2); Mass (m/z): 475.9 [M]þ,
448, 430, 402, 314, 300, 286, 272, 257, 244, 229, 219, 215, 204, 176,
162, 134, 88; Anal. (%) for C18H14N5O4SBr, Calcd. C, 45.38; H, 2.94;
N, 14.70. Found: C, 45.33; H, 2.92; N, 14.65.
NeCH2); 13C NMR [100 MHz, CDCl3]:
d 171.7 (CO,cyclic), 169.8
(CONH), 141.5 (CeNO2, aromatic), 137.0 (N]CHe, cyclic),
111.8e124.2 (C of aromatic ring), 55.6 (OCH3), 44.7 (CH2 of thia-
zolidinone ring), 41.8 (NCHS), 35.4 (NeCH2); Mass (m/z): 427 [M]þ,
399, 381, 353, 265, 251, 237, 223, 219, 208, 204, 195, 180, 176, 166,
162, 134, 88; Anal. (%) for C19H17N5O5S, Calcd. C, 53.39; H, 3.98;
N, 16.39. Found: C, 53.33; H, 3.95; N, 16.33.
4.20. N-[{4-oxo-2-(3-bromophenyl)-1,3-thiazolidine}-acetamidyl]-
5-nitroindazole (4f)
4.24. N-[{4-oxo-2-(4-methoxyphenyl)-1,3-thiazolidine}-
acetamidyl]-5-nitroindazole (4j)
m.p. 184e185 ꢁC; IR [ , cmꢀ1, KBr] 3065 (CeH, AreH),: 2979
n
(NeCHeS), 1716 (pC]O, cyclic), 1680 (pC]O, amide), 1622 (N]
CHe, cyclic), 1541,1343 (ArNO2), 1446 (NeCH2), 689 (CeSeC), 622
m.p. 202e203 ꢁC; IR [ , cmꢀ1, KBr]: 3057 (CeH, AreH), 2978
n
(NeCHeS), 2827 (AreOCH3), 1718 (pC]O, cyclic), 1682 (pC]O,
amide), 1623 (N]CHe, cyclic), 1546,1352 (AreNO2), 1449
(AreBr); 1H NMR [400 MHz, CDCl3]:
d
8.28 (s, 1H, CONH), 8.05 (s,
1H, N]CHe, cyclic), 7.39e7.76 (m, 7H, AreH), 4.17 (s, 1H,
(NeCH2), 697 (CeSeC); 1H NMR [400 MHz, CDCl3]:
d 8.33 (s,

3548
A. Upadhyay et al. / European Journal of Medicinal Chemistry 45 (2010) 3541e3548
1H, CONH),8.07 (s, 1H, N]CHe, cyclic), 7.41e7.79 (m, 7H,
AreH), 4.21 (s, 1H, eNeCHe), 3.93 (s, 3H, OCH3), 3.36 (s, 2H,
CH2, cyclic), 2.74 (s, 2H, NeCH2); 13C NMR [100 MHz, CDCl3]:
Acknowledgement
The authors are thankful to SAIF, CDRI Lucknow (India) for
providing the spectral and analytical data of the compounds.
Authors are also thankful to the Head, Department of Chemistry for
providing the laboratory facility and Head, Department of Botany
and Ms. Supriya Gupta for biological screening. One of the author
(A.upadhyay) is also grateful to UGC, New Delhi (India) for the
award of UGC Meritorious Research Fellowship.
d
172.0 (CO,cyclic), 169.9 (CONH), 142.1 (CeNO2, aromatic),
137.4 (N]CHe, cyclic), 112.2e124.6 (C of aromatic ring), 55.4
(OCH3), 44.9 (CH2 of thiazolidinone ring), 41.6 (NCHS), 35.6
(NeCH2); Mass (m/z): 427 [M]þ, 399, 381, 353, 265, 251, 237,
223, 219, 208, 204, 195, 180, 176, 166, 162, 134, 88; Anal. (%) for
C19H17N5O5S, Calcd. C, 53.39; H, 3.98; N, 16.39. Found: C, 53.34;
H, 3.96; N, 16.36.
References
4.25. N-[{4-oxo-2-(4-methylphenyl)-1,3-thiazolidine}-acetamidyl]-
5-nitroindazole (4k)
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m.p. 190e191 ꢁC; IR [ , cmꢀ1, KBr]: 3061 (CeH, AreH), 2984
n
(NeCHeS), 2922 (AreCH3), 1721 (pC]O, cyclic), 1684 (pC]O,
amide), 1625 (N]CHe, cyclic), 1550,1350 (AreNO2), 1451
(NeCH2), 699 (CeSeC); 1H NMR [400 MHz, CDCl3]:
d 8.35 (s,
1H, CONH), 8.09 (s, 1H, N]CH-cyclic), 7.45e7.78 (m, 7H, AreH),
4.20 (s, 1H, eNeCHe), 3.33 (s, 2H, CH2, cyclic), 2.71 (s, 2H,
NeCH2), 2.35 (s, 3H, AreCH3); 13C NMR [100 MHz, CDCl3]:
d
171.8 (CO,cyclic), 169.7 (CONH), 143.5 (CeNO2, aromatic),
137.5 (N]CHe, cyclic), 112.4e124.3 (C of aromatic ring), 45.1
(CH2 of thiazolidinone ring), 41.9 (NCHS), 35.8 (NeCH2), 22.8
(CH3); Mass (m/z): 411 [M]þ, 385, 365, 337, 249, 235, 221, 219,
207, 204, 192, 179, 176, 164, 162, 150, 134, 88; Anal. (%) for
C19H17N5O4S, Calcd. C, 55.47; H, 4.14; N, 17.03. Found: C, 55.42;
H, 4.10; N, 17.00.
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4.26. N-[{4-oxo-2-(4-dimethylaminophenyl)-1,3-thiazolidine}-
acetamidyl]-5-nitroindazole (4l)
m.p. 192e194 ꢁC; IR [ , cmꢀ1, KBr]: 3066 (CeH, AreH), 2986
n
(NeCHeS), 2912, 2850 (NeCH3), 1719 (pC]O, cyclic), 1683 (pC]
O, amide), 1626 (N]CHe, cyclic), 1549,1351 (AreNO2), 1452
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(NeCH2), 700 (CeSeC); 1H NMR [400 MHz, CDCl3]:
d 8.34 (s, 1H,
CONH), 8.11 (s, 1H, N]CHe, cyclic), 7.44e7.80 (m, 7H, AreH), 3.34
(s, 2H, CH2, cyclic) 4.16 (s, 1H, eNeCHe), 3.14 (s, 6H, 2 ꢂ CH3),
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d 172.1 (CO,
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cyclic), 170.0 (CONH), 145.5 (N]CH), 143.8 (CeNO2, aromatic),
137.3 (N]CHe, cyclic), 112.5e124.1 (C of aromatic ring), 45.3 (CH2
of thiazolidinone ring), 41.7 (NCHS), 35.7 (NeCH2), 23.9 (NCH3);
Mass (m/z): 440 [M]þ, 412, 394, 366, 278, 264, 250, 236, 221, 219,
208, 204, 193, 179, 176, 162, 134, 88; Anal. (%) for C20H20N6O4S,
Calcd. C, 54.54; H, 4.54; N, 19.09. Found: C, 54.49; H, 4.50; N,
19.03.