Synthesis of 4-thiazolidine derivatives of 6-nitroindazole: Pharmaceutical importance

Article abstract of DOI:10.4067/s0717-97072012000100018

New series of N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(substituted phenyl)-4-oxo-5-(substituted benzylidene)-1,3-thiazolidine-carboxamide, compounds 5(a-j) have been synthesized from 6-nitroindazole. Structures of all the synthesized compounds were confir

Full text of DOI:10.4067/s0717-97072012000100018

J. Chil. Chem. Soc., 57, Nº 1 (2012)
SYNTHESIS OF 4-THIAZOLIDINE DERIVATIVES OF 6-NITROINDAZOLE: PHARMACEUTICAL
IMPORTANCE
PUSHKAL SAMADHIYA*, RITU SHARMA, SANTOSH K. SRIVASTAVA, SAVITRI D. SRIVASTAVA
Department of Chemistry, Dr. H.S. Gour University (A Central University), Sagar-470003, India
(Received: August 2, 2011 - Accepted: December 26, 2011)
ABSTRACT
New series of N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(substituted phenyl)-4-oxo-5-(substituted benzylidene)-1,3-thiazolidine-carboxamide, compounds
5(a-j) have been synthesized from 6-nitroindazole. Structures of all the synthesized compounds were confirmed by chemical and spectral analyses such as IR, 1H
NMR, 13C NMR and FAB-Mass. All the synthesized compounds were screened for their antibacterial, antifungal, antitubercular and antiinflammatory activities.
Keyword: 6-nitroindazole, thiazolidinone, antimicrobial, antitubercular, antiinflammatory.
INTRODUCTION
EXPERIMENTAL
Several azoles scaffold have been described in literature including indazole.
Indazole derivatives are important nitrogen containing nine membered bicyclic
heterocyclic compounds with applications as several biological activities
and agrochemicals besides possessing important pharmacological activities
such as antimicrobial, protein kinase inhibitors, antiproliferative, nitric
oxide synthesis, anesthesia and antiprotozoal activity1-6. The indazole ring
system is also present in many other compounds such as herbicides, dyes or
sweeteners like guanidine-1H-indazole. Despite the many useful applications
of indazole derivatives, indazole chemistry remains less studied compared to
other heteroaromatic compounds such as indole or benzimidazole. Indazole
is a ten-π electron aromatic heterocyclic system. Like the pyrazole molecule,
indazole resembles both pyridine and pyrrole and its reactivity reflects this dual
behaviour.
Melting points were taken in open capillaries and are uncorrected.
Progress of reaction was monitored by silica gel-G coated TLC plates in
MeOH: CHCl3 system (1:9). The spot was visualized by exposing dry plate
in iodine vapours. IR spectra were recorded in KBr disc on a Schimadzu 8201
PC, FTIR spectrophotometer (nmax in cm-1) and 1H and 13C NMR spectra were
measured on a Brucker DRX-300 spectrometer in CDCl3 at 300 and 75 MHz
respectively using TMS as an internal standard. All chemical shifts were
reported on d scales. The FAB-Mass spectra were recorded on a Jeol SX–102
mass spectrometer. Elemental analyses were performed on a Carlo Erba–1108
analyzer. The analytical data of all the compounds were highly satisfactory.
For column chromatographic purification of the products, Merck silica Gel 60
(230-400 Mesh) was used. Inflammatory (in vivo) study has been approved by
institutional ethical committee, Dr. H.S. Gour University, Sagar. The reagent
grade chemicals were purchased from the commercial sources and further
purified before use.
Thiazolidine ring system derives special important from the fact that it
plays important role in medicinal chemistry. Substituted thiazolidine derivatives
represent important key intermediates for synthesis of pharmacologically
active drug thiazolidinone has wide range of biological activities such as
antifungal, antiproliferative, antiinflammatory, antimalarial, herbicidal and
Method for the synthesis of the compound 1:
6-Nitroindazole (0.308 mole) and 1-bromo-3-chloropropane (0.308 mole)
in ethanol (100 ml) were stirred on a magnetic stirrer for about 6.30 hours
at room temperature. The completion of the reaction was monitored by silica
gel-G coated TLC plates. After the completion of the reaction the product was
filtered and purified over a silica gel packed column chromatography using
CHCl3 : CH OH (8 : 2 v/v) system as eluant (150 ml). The purified product was
dried under 3vacuo and recrystallized from acetone at room temperature to yield
compound 1 (Figure 1).
antiviral property7-12
.
As part of a continuing effort to develop novel heterocyclic compounds
with potential therapeutic biological activities, several chemists are currently
involved in the synthesis of numbers of indazole derivatives. In the present
study, we have decided to synthesize new series of compounds showed in
Scheme 1.
Figure 1: Structure of compound 1.
N1-(3-chloropropyl)-6-nitroindazole 1:
Yield: 65%; m.p. 163-165 ºC; IR (cm-1): 768 (C-Cl), 899 (C-N), 1326 (N-
1
CH2), 1532 (NO2), 1572 (C=C), 1448, 2842, 2889, (CH2), 3020 (CH-Ar); H
NMR (CDCl3, 300 MHz) δ: 2.20-2.26 (m, 2H, H-9), 3.41 (t, 2H, J = 7.45 H-10),
4.26 (t, 2H, J = 7.45 Hz, H-8), 7.86-8.35 (m, 4H, Ar-H); 13C NMR (CDCl , 75
MHz) δ: 34.4 (C-9), 42.8 (C-10), 47.1 (C-8), 118.7 (C-4), 120.4 (C-7), 1322.2
(C-5), 126.1 (C-3a), 136.2 (C-6), 137.0 (C-3), 135.7 (C-7a),; FAB-Mass (m/z):
239 [M+]; Anal. Calcd. for C10H10N3O2Cl: C 50.20, H 4.20, N 17.11; found C
50.17, H 4.13, N, 17.08.
Method for the synthesis of the compound 2:
Compound 1 (0.208 mole) and urea (0.208 mole) in ethanol (100 ml) were
stirred on a magnetic stirrer for about 4.30 hours at room temperature. The
completion of the reaction was monitored by silica gel-G coated TLC plates.
After the completion of the reaction the product was filtered and purified over
a silica gel packed column chromatography using CHCl3 : CH3OH (8 : 2 v/v)
Scheme 1: Synthesis of compounds 1, 2, 3(a-j), 4(a-j) and 5(a-j).
e-mail: pushkalsamadhiya@rediffmail.com
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J. Chil. Chem. Soc., 57, Nº 1 (2012)
system as eluant (120 ml). The purified product was dried under vacuo and
recrystallized from ethanol at room temperature to yield compound 2 (Figure
2).
1H, H-1’) 7.89 (s, 1H, H-11), 7.71-8.16 (m, 8H, Ar-H); 13C NMR (CDCl , 75
MHz) δ: 28.6 (C-9), 38.7 (C-10), 46.6 (C-8), 118.5 (C-4), 121.4 (C-7), 1322.4
(C-5), 124.7 (C-3a), 123.9 (C-13 and C-17), 124.2 (C-14 and C-16), 127.4 (C-
15), 129.5 (C-12), 132.1 (C-6), 133.5 (C-3), 141.9 (C-7a), 150.6 (C-11), 161.8
(C-2’); FAB-Mass (m/z): 385 [M+]; Anal. Calcd. for C18H16N5O3Cl: C 56.03, H
4.18, N 18.15; found C 55.97, H 4.15, N 18.12.
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-N’-[(3-chlorophenyl)-
methylidene]-urea (3c):
Yield: 65%; m.p. 162-163 ºC; IR (cm-1): 751 (C-Cl), 875 (C-N), 1337 (N-
CH2), 1532 (NO2), 1543 (C=C), 1556 (N=CH), 1657 (C=O), 1431, 2848, 2890
1
(CH2), 3032 (CH-Ar), 3362 (NH); H NMR (CDCl3, 300 MHz) δ: 2.21-2.27
(m, 2H, H-9), 3.40-3.45 (m, 2H, H-10), 4.20 (t, 2H, J = 7.45 Hz, H-8), 5.62 (s,
1H, H-1’), 7.90 (s, 1H, H-11), 7.75-8.20 (m, 8H, Ar-H); 13C NMR (CDCl , 75
MHz) δ: 31.4 (C-9), 42.5 (C-10), 48.9 (C-8), 118.9 (C-4), 120.2 (C-7), 1322.7
(C-5), 123.1 (C-3a), 123.5 (C-13), 123.9 (C-17), 125.6 (C-14), 126.3 (C-16),
129.6 (C-15), 131.4 (C-12), 133.9 (C-6), 134.4 (C-3), 141.7 (C-7a), 152.5 (C-
11), 162.7 (C-2’); FAB-Mass (m/z): 385 [M+]; Anal. Calcd. for C18H16N5O3Cl:
C 56.03, H 4.18, N 18.15; found C 55.99, H 4.17, N,18.11.
Figure 2: Structure of compound 2.
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-N’-[(2-chlorophenyl)-
methylidene]-urea (3d):
N1-{3-(aminocarbamyl)-propyl}-6-nitroindazole 2:
Yield: 74%; m.p. 145-147 ºC; IR (cm-1): 752 (C-Cl), 872 (C-N), 1328 (N-
CH2), 1523 (NO2), 1556 (C=C), 1648 (CO), 1435, 2839, 2910 (CH2), 3027
Yield: 62%; m.p. 164-165 ºC; IR (cm-1): 746 (C-Cl), 878 (C-N), 1344 (N-
CH2), 1529 (NO2), 1537 (C=C), 1566 (N=CH), 1661 (C=O), 1453, 2852, 2892
1
(CH-Ar), 3342 (NH), 3456 (NH2); H NMR (CDCl , 300 MHz) δ: 2.18-2.22
1
(m, 2H, H-9), 3.30-3.34 (m, 2H, H-10), 4.18 (t, 2H3, J = 7.45 Hz, H-8), 5.72
(s, 1H, H-1’), 5.92 (s, 2, H-3’), 7.34-7.96 (m, 4H, Ar-H);13C NMR (CDCl , 75
MHz) δ: 33.1 (C-9), 42.4 (C-10), 46.7 (C-8), 117.6 (C-4), 119.3 (C-7), 1321.4
(C-5), 125.8 (C-3a), 134.5 (C-6), 136.7 (C-3), 139.2 (C-7a), 161.7 (C-2’);
FAB-Mass (m/z): 263 [M+]; Anal. Calcd for C11H13N5O3: C 50.18, H 4.97, N
26.60; found C 50.10, H 4.92, N 26.54.
(CH2), 3034 (CH-Ar), 3360 (NH); H NMR (CDCl3, 300 MHz) δ: 2.31-2.35
(m, 2H, H-9), 3.40-3.47 (m, 2H, H-10), 4.21 (t, 2H, J = 7.40 Hz, H-8), 5.64 (s,
1H, H-1’), 7.92 (s, 1H, H-11), 7.69-8.30 (m, 8H, Ar-H); 13C NMR (CDCl , 75
MHz) δ: 31.7 (C-9), 42.8 (C-10), 48.4 (C-8), 117.8 (C-4), 119.7 (C-7), 1323.3
(C-5), 123.6 (C-3a), 123.9 (C-13), 124.0 (C-17), 124.6 (C-14), 124.8 (C-16),
126.6 (C-15), 130.2 (C-12), 133.8 (C-6), 134.5 (C-3), 140.1 (C-7a), 152.7 (C-
11), 160.7 (C-2’); Mass(FAB): 385 [M+]; Anal. Calcd. for C18H16N5O3Cl: C
56.03, H 4.18, N 18.15; found C 55.97, H 4.15, N 18.14.
General methods for the synthesis of compounds 3(a-j)
The compound 2 (0.026 mole) and benzaldehyde (0.026 mole) in ethanol
(100 ml) in the presence of 2-4 drops of glacial acetic acid were first stirred
on a magnetic stirrer for about 2.00 hours followed by reflux on a steam
bath for about 2.30 hours. The completion of the reaction was monitored by
silica gel-G coated TLC plates. The product was filtered and cooled at room
temperature. The filtered product was purified over a silica gel packed column
chromatography using CH3OH : CHCl3 (7 : 3 v/v) as eluant (80 ml). The
purified product was dried under vacuo and recrystallized from acetone at room
temperature to furnish compound 3a (Figure 3).
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-N’-[(4-bromophenyl)-
methylidene]-urea (3e):
Yield: 64%; m.p. 159-161 ºC; IR (cm-1): 749 (C-Cl), 881 (C-N), 1340 (N-
CH2), 1526 (NO2), 1538 (C=C), 1565 (N=CH), 1656 (C=O), 1454, 2847, 2900
1
(CH2), 3035 (CH-Ar), 3367 (NH); H NMR (CDCl3, 300 MHz) δ: 2.30-2.36
(m, 2H, H-9), 3.41-3.50 (m, 2H, H-10), 4.33 (t, 2H, J = 7.50 Hz, H-8), 5.65 (s,
1H, H-1’), 7.93 (s, 1H, H-11), 7.74-8.26 (m, 8H, Ar-H); 13C NMR (CDCl , 75
MHz) δ: 29.2 (C-9), 40.3 (C-10), 47.5 (C-8), 116.7 (C-4), 121.4 (C-7), 1321.8
(C-57), 122.5 (C-13 and C-17), 122.9 (C-3a), 123.7 (C-14 and C-16), 127.3 (C-
15), 129.1 (C-12), 131.6 (C-6), 132.9 (C-3), 142.4 (C-7a), 153.7 (C-11), 160.0
(C-2’); FAB-Mass (m/z): 430 [M+]; Anal. Calcd. for C18H16N5O3Br: C 50.24, H
3.74, N 16.27; found C 50.21, H 3.71, N 16.22.
Compounds 3 (b-j) have also been synthesized by using similar method
as above.
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-N’-[(3-bromophenyl)-
methylidene]-urea (3f):
Yield: 68%; m.p. 157-158 ºC; IR (cm-1): 755 (C-Cl), 874 (C-N), 1334 (N-
CH2), 1532 (NO2), 1541 (C=C), 1570 (N=CH), 1662 (C=O), 1445, 2846, 2891
1
(CH2), 3042 (CH-Ar), 3365 (NH); H NMR (CDCl3, 300 MHz) δ: 2.21-2.29
(m, 2H, H-9), 3.42-3.50 (m, 2H, H-10), 4.28 (t, 2H, J = 7.45 Hz, H-8), 5.59 (s,
1H, H-1’), 7.94 (s, 1H, H-11), 7.79-8.29 (m, 8H, Ar-H);13C NMR (CDCl , 75
MHz) δ: 29.5 (C-9), 32.7 (C-10), 46.3 (C-8), 117.9 (C-4), 120.4 (C-7), 1321.5
(C-5), 123.1 (C-3a), 124.3 (C-13), 124.8 (C-17), 125.4 (C-14), 126.3 (C-16),
129.6 (C-15), 130.7 (C-12), 131.8 (C-6), 132.9 (C-3), 141.2 (C-7a), 154.6 (C-
11), 162.3 (C-2’); FAB-Mass (m/z): 430 [M+]; Anal. Calcd. for C18H16N5O3Br:
C 50.24, H 3.74, N 16.27; found C 50.18, H 3.72, N 16.23.
Figure 3: Structure of compound 3(a-j).
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-N’-[(2-bromophenyl)-
methylidene]-urea (3g):
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-N’-[(phenyl)-methylidene]-
urea (3a):
Yield: 69%; m.p. 159-160 ºC; IR (cm-1): 752 (C-Cl), 876 (C-N), 1335 (N-
CH2), 1531 (NO2), 1544 (C=C), 1567 (N=CH), 1654 (C=O), 1446, 2853, 2893
Yield: 62%; m.p. 147-148 ºC; IR (cm-1): 742 (C-Cl), 871 (C-N), 1328 (N-
CH2), 1523 (NO2), 1534 (C=C), 1555 (N=CH), 1650 (C=O), 1442, 2839, 2897
1
(CH2), 3037 (CH-Ar), 3370 (NH); H NMR (CDCl3, 300 MHz) δ: 2.21-2.28
1
(CH2), 3027 (CH-Ar), 3356 (NH); H NMR (CDCl3, 300 MHz) δ: 2.22-2.27
(m, 2H, H-9), 3.50-3.55 (m, 2H, H-10), 4.29 (t, 2H, J = 7.50 Hz, H-8), 5.60 (s,
1H, H-1’), 7.97 (s, 1H, H-11), 7.81-8.25 (m, 8H, Ar-H); 13C NMR (CDCl , 75
MHz) δ: 29.9 (C-9), 32.1 (C-10), 45.8 (C-8), 117.3 (C-4), 120.4 (C-7), 1322.6
(C-5), 124.1 (C-3a), 124.5 (C-13), 124.9 (C-17), 125.6 (C-14), 126.1 (C-16),
129.9 (C-15), 131.4 (C-12), 134.3 (C-6), 135.4 (C-3), 142.6 (C-7a), 153.7 (C-
11), 159.5 (C-2’); FAB-Mass (m/z): 430 [M+]; Anal. Calcd. for C18H16N5O3Br:
C 50.24, H 3.74, N 16.27; found C 50.18, H 3.70, N 16.21.
(m, 2H, H-9), 3.24-3.27 (m, 2H, H-10), 4.14 (t, 2H, J = 7.45 Hz, H-8), 5.89 (s,
1H, H-1’), 7.98 (s, 1H, H-11), 7.22-7.97 (m, 9H, Ar-H); 13C NMR (CDCl , 75
MHz) δ: 28.1 (C-9), 38.4 (C-10), 45.3 (C-8), 115.7 (C-4), 119.4 (C-7), 1320.5
(C-5), 121.5 (C-3a), 121.8 (C-13 and C-17), 122.4 (C-14 and C-16), 126.5 (C-
15), 128.4 (C-12), 131.3 (C-6), 132.5 (C-3), 139.2 (C-7a), 150.6 (C-11), 159.9
(C-2’); FAB-Mass (m/z): 351 [M+]; Anal. Calcd. for C18H17N5O3: C 61.53, H
4.87, N 19.93; found C 61.51, H 4.80, N 19.85.
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-N’-[(4-nitrophenyl)-
methylidene]-urea (3h):
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-N’-[(4-chlorophenyl)-
methylidene]-urea (3b):
Yield: 62%; m.p. 162-163 ºC; IR (cm-1): 750 (C-Cl), 877 (C-N), 1339 (N-
CH2), 1527 (NO2), 1536 (C=C), 1560 (N=CH), 1663 (C=O), 1455, 2845, 2898
Yield: 66%; m.p. 165-167 ºC; IR (cm-1): 746 (C-Cl), 905 (C-N), 1351 (N-
CH2), 1534 (NO2), 1572 (C=C), 1580 (N=CH), 1633 (C=O), 1447, 2845, 2917
1
(CH2), 3038 (CH-Ar), 3357 (NH); H NMR (CDCl3, 300 MHz) δ: 2.24-2.30
1
(CH2), 3014 (CH-Ar), 3344 (NH); H NMR (CDCl3, 300 MHz) δ: 2.23-2.28
(m, 2H, H-9), 3.46-3.53 (m, 2H, H-10), 4.36 (t, 2H, J = 7.40 Hz, H-8), 5.61 (s,
1H, H-1’), 7.98 (s, 1H, H-11), 7.84-8.22 (m, 8H, Ar-H); 13C NMR (CDCl3, 75
(m, 2H, H-9), 3.40-3.45 (m, 2H, H-10), 4.26 (t, 2H, J = 7.45 Hz, H-8), 5.66 (s,
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J. Chil. Chem. Soc., 57, Nº 1 (2012)
MHz) δ: 30.3 (C-9), 44.4 (C-10), 46.0 (C-8), 115.5 (C-4), 122.9 (C-7), 123.4
(C-5), 123.8 (C-3a), 124.3 (C-13 and C-17), 124.6 (C-14 and C-16), 128.4 (C-
15), 130.4 (C-12), 132.7 (C-6), 133.7 (C-3), 141.5 (C-7a), 154.6 (C-11), 161.9
(C-2’); FAB-Mass (m/z): 396 [M+]; Anal. Calcd. for C18H16N6O5: C 54.54, H
4.06, N 21.20; found C 54.51, H 4.02, N 21.17.
thiazolidine-carboxamide (4b):
Yield: 67; m.p. 189-190 ºC; IR (cm-1): 667 (C-S-C), 882 (C-N), 1345 (N-
CH2), 1532 (NO2), 1550 (C=C), 1662 (C=O), 1742 (CO cyclic), 1458, 2851,
2899 (CH2), 2962 (S-CH2), 3040 (CH-Ar), 3366 (NH); 1H NMR (CDCl3, 300
MHz) δ: 2.20-2.24 (m, 2H, H-9), 3.32 (s, 2H, H-5”), 3.35-3.39 (m, 2H, H-10),
4.28 (t, 2H, J = 7.45 Hz, H-8), 5.23 (s, 1H, H-2”), 5.72 (s, 1H, H-1’), 7.23-7.74
(m, 8H, Ar-H); 13C NMR (CDCl3, 75 MHz) δ: 33.8 (C-9), 39.2 (C-5”), 46.6
(C-10), 50.9 (C-8), 62.4 (C-2”), 120.4 (C-4), 124.8 (C-7), 127.6 (C-5), 131.5
(C-3a), 132.3 (C-12 and C-16), 133.8 (C-14), 134.4 (C-13 and C-15), 136.7
(C-6), 139.7 (C-11), 140.9 (C-3), 144.9 (C-7a), 163.0 (C-2’), 171.7 (C-4”);
FAB-Mass (m/z): 460 [M+]; Anal. Calcd. for C H18N5O4SCl: C, 52.23, H, 3.94,
N, 15.22 %; found C, 52.19, H, 3.89, N, 15.1820%.
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-N’-[(3-nitrophenyl)-
methylidene]-urea (3i):
Yield: 64%; m.p. 166-167 ºC; IR (cm-1): 748 (C-Cl), 882 (C-N), 1336 (N-
CH2), 1535 (NO2), 1540 (C=C), 1563 (N=CH), 1658 (C=O), 1456, 2850, 2896
1
(CH2), 3040 (CH-Ar), 3358 (NH); H NMR (CDCl3, 300 MHz) δ: 2.30-2.36
(m, 2H, H-9), 3.50-3.54 (m, 2H, H-10), 4.37 (t, 2H, J = 7.40 Hz, H-8), 5.63 (s,
1H, H-1’), 7.95 (s, 1H, H-11), 7.73-8.27 (m, 8H, Ar-H); 13C NMR (CDCl , 75
MHz) δ: 30.6 (C-9), 41.5 (C-10), 47.8 (C-8), 116.4 (C-4), 120.9 (C-7), 1321.9
(C-5), 122.5 (C-3a), 123.4 (C-13), 123.7 (C-17), 124.8 (C-14), 125.7 (C-16),
128.1 (C-15), 131.5 (C-12), 133.9 (C-6), 135.6 (C-3), 140.6 (C-7a), 154.3 (C-
11), 161.9 (C-2’); FAB-Mass (m/z): 396 [M+]; Anal. Calcd. for C18H16N6O5: C
54.54, H 4.06, N 21.20; found C 54.49, H 4.03, N 21.16.
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(3-chlorophenyl)-4-oxo-1,3-
thiazolidine-carboxamide (4c):
Yield: 68%; m.p. 185-186 ºC; IR (cm-1): 671 (C-S-C), 884 (C-N), 1341 (N-
CH2), 1536 (NO2), 1552 (C=C), 1665 (C=O), 1745 (CO cyclic), 1462, 2853,
2903 (CH2), 2958 (S-CH2), 3035 (CH-Ar), 3365 (NH); 1H NMR (CDCl3, 300
MHz) δ: 2.24-2.29 (m, 2H, H-9), 3.40 (s, 2H, H-5”), 3.43-3.48 (m, 2H, H-10),
4.22 (t, 2H, J = 7.50 Hz, H-8), 5.24 (s, 1H, H-2”), 5.73 (s, 1H, H-1’), 7.30-7.80
(m, 8H, Ar-H); 13C NMR (CDCl3, 75 MHz) δ: 31.1 (C-9), 34.5 (C-5”), 43.8
(C-10), 50.9 (C-8), 60.1 (C-2”), 120.3 (C-4), 125.4 (C-7), 126.6 (C-5), 130.7
(C-3a), 131.2 (C-12), 131.9 (C-16), 133.4 (C-14), 134.6 (C-13), 135.2 (C-15),
137.3 (C-6), 137.9 (C-3),139.4 (C-11), 142.7 (C-7a),161.9 (C-2’), 172.5 (C-
4”); FAB-Mass (m/z): 460 [M+]; Anal. Calcd. for C20H N5O4SCl: C, 52.23, H,
3.94, N, 15.22 %; found C, 52.17, H, 3.91, N, 15.19 %1.8
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-N’-[(2-nitrophenyl)-
methylidene]-urea (3j):
Yield: 66%; m.p. 160-161 ºC; IR (cm-1): 753 (C-Cl), 879 (C-N), 1338 (N-
CH2), 1526 (NO2), 1542 (C=C), 1557 (N=CH), 1660 (C=O), 1447, 2851, 2901
1
(CH2), 3036 (CH-Ar), 3369 (NH); H NMR (CDCl3, 300 MHz) δ: 2.25-2.31
(m, 2H, H-9), 3.42-3.49 (m, 2H, H-10), 4.25 (t, 2H, J = 7.50 Hz, H-8), 5.58 (s,
1H, H-1’), 7.93 (s, 1H, H-11), 7.76-8.28 (m, 8H, Ar-H); 13C NMR (CDCl , 75
MHz) δ: 30.8 (C-9), 40.9 (C-10), 47.2 (C-8), 116.6 (C-4), 120.6 (C-7), 1321.9
(C-5), 122.1 (C-13), 122.5 (C-3a), 122.9 (C-17), 123.5 (C-14), 123.9 (C-16),
127.2 (C-15), 128.6 (C-12), 131.6 (C-6), 132.9 (C-3), 139.7 (C-7a), 154.1 (C-
11), 162.2 (C-2’); FAB-Mass (m/z): 396 [M+]; Anal. Calcd. for C18H16N6O5: C
54.54, H 4.06, N 21.20; found C 54.47, H 4.04, N 21.12.
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(2-chloro phenyl)-4-oxo-1,3-
thiazolidine-carboxamide (4d):
Yield: 64%; m.p. 180-181 ºC; IR (cm-1): 672 (C-S-C), 885 (C-N), 1342 (N-
CH2), 1540 (NO2), 1547 (C=C), 1670 (C=O), 1749 (CO cyclic), 1453, 2849,
2904 (CH2), 2963 (S-CH2), 3036 (CH-Ar), 3372 (NH); 1H NMR (CDCl3, 300
MHz) δ: 2.23-2.28 (m, 2H, H-9), 3.38 (s, 2H, H-5”), 3.41-3.46 (m, 2H, H-10),
4.29 (t, 2H, J = 7.45 Hz, H-8), 5.21 (s, 1H, H-2”), 5.74 (s, 1H, H-1’), 7.36-7.86
(m, 8H, Ar-H); 13C NMR (CDCl3, 75 MHz) δ: 31.6 (C-9), 34.5 (C-5”), 42.7
(C-10), 50.4 (C-8), 60.9 (C-2”), 119.9 (C-4), 124.6 (C-7), 125.6 (C-5), 130.2
(C-3a), 130.7 (C-12), 131.1 (C-16), 132.6 (C-14), 133.8 (C-13), 134.6 (C-15),
135.5 (C-6), 136.4 (C-3), 138.1 (C-11), 139.9 (C-7a), 164.6 (C-2’), 172.7 (C-
4”); FAB-Mass (m/z): 460 [M+]; Anal. Calcd. for C20H N5O4SCl: C, 52.23, H,
3.94, N, 15.22 %; found C, 52.22, H, 3.90, N, 15.20%.18
General methods for the synthesis of compounds 4(a-j):
The compound 3a (0.011 mole) and thioglycolic acid (0.011 mole)
in ethanol (50 ml) in the presence of ZnCl were allowed to react at room
temperature. The reaction mixture was first2stirred on a magnetic stirrer for
about 2.30 hours followed by reflux on a steam bath for about 5.00 hours. The
completion of the reaction was monitored by silica gel-G coated TLC plates.
The product was filtered and cooled at room temperature. The filtered product
was purified over a silica gel packed column chromatography using CH3OH :
CHCl3 (7 : 3 v/v) as eluant (70 ml). The purified product was dried under vacuo
and recrystallized from acetone at room temperature to furnish compound
4a(Figure 4).
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(4-bromo phenyl)-4-oxo-1,3-
thiazolidine-carboxamide (4e):
Compounds 4(b-j) have also been synthesized by using similar method
as above.
Yield: 65%; m.p. 174-175 ºC; IR (cm-1): 670 (C-S-C), 886 (C-N), 1340 (N-
CH2), 1542 (NO2), 1555 (C=C), 1671 (C=O), 1750 (CO cyclic), 1454, 2855,
2905 (CH2), 2964 (S-CH2), 3038 (CH-Ar), 3371 (NH); 1H NMR (CDCl3, 300
MHz) δ: 2.27-2.34 (m, 2H, H-9), 3.40 (s, 2H, H-5”), 3.42-3.47 (m, 2H, H-10),
4.31 (t, 2H, J = 7.45 Hz, H-8), 5.22 (s, 1H, H-2”), 5.79 (s, 1H, H-1’), 7.38-7.83
(m, 8H, Ar-H);13C NMR (CDCl , 75 MHz) δ: 30.7 (C-9), 35.4 (C-5”), 42.3 (C-
10), 49.1 (C-8), 59.6 (C-2”), 1173 .5 (C-4), 122.8 (C-7), 123.5 (C-5), 129.7 (C-
3a), 130.5 (C-12 and C-16), 132.3 (C-14), 133.7 (C-13 and C-15), 135.2 (C-6),
136.8 (C-3), 138.5 (C-11), 141.3 (C-7a),162.6 (C-2’), 175.7 (C-4”); FAB-Mass
(m/z): 504 [M+]; Anal. Calcd. for C H18N5O4SBr: C, 47.62, H, 3.52, N, 13.88
%; found C, 47.57, H, 3.45, N, 13.8320 %.
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(3-bromo phenyl)-4-oxo-1,3-
thiazolidine-carboxamide (4f):
Yield: 67%; m.p. 178-179 ºC; IR (cm-1): 665 (C-S-C), 888 (C-N), 1346 (N-
CH2), 1534 (NO2), 1556 (C=C), 1664 (C=O), 1738 (CO cyclic), 1455, 2860,
2906 (CH2), 2960 (S-CH2), 3034 (CH-Ar), 3365 (NH); 1H NMR (CDCl3, 300
MHz) δ: 2.20-2.25 (m, 2H, H-9), 3.28 (s, 2H, H-5”), 3.31-3.36 (m, 2H, H-10),
4.30 (t, 2H, J = 7.50 Hz, H-8), 5.20 (s, 1H, H-2”), 5.80 (s, 1H, H-1’), 7.25-7.79
(m, 8H, Ar-H); 13C NMR (CDCl3, 75 MHz) δ: 32.8 (C-9), 35.7 (C-5”), 40.4
(C-10), 47.7 (C-8), 58.5 (C-2”), 117.8 (C-4), 123.4 (C-7), 124.3 (C-5), 129.8
(C-3a), 128.6 (C-12), 129.3 (C-16), 130.4 (C-14), 131.5 (C-13), 133.2 (C-6),
134.9 (C-3), 133.4 (C-15), 136.5 (C-11), 142.4 (C-7a), 165.3 (C-2’), 173.6 (C-
4”); FAB-Mass (m/z): 504 [M+]; Anal. Calcd. for C H N5O4SBr: C, 47.62, H,
3.52, N, 13.88 %; found C, 47.61, H, 3.45 N, 13.812%0 .18
Figure 4: Structure of compound 4(a-j).
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(phenyl)-4-oxo-1,3-
thiazolidine-carboxamide (4a):
Yield: 65%; m.p. 160-161 ºC; IR (cm-1): 663 (C-S-C), 880 (C-N), 1339 (N-
CH2), 1531 (NO2), 1545 (C=C), 1661 (C=O), 1737 (CO cyclic), 1452, 2848,
2896 (CH2), 2958 (S-CH2), 3033, (CH-Ar), 3362 (NH); 1H NMR (CDCl3, 300
MHz) δ: 2.26-2.32 (m, 2H, H-9), 3.28-3.33 (m, 2H, H-10), 3.40 (s, 2H, H-5”),
4.21 (t, 2H, J = 7.45 Hz, H-8), 5.21 (s, 1H, H-2”), 5.62 (s, 1H, H-1’), 7.12-8.01
(m, 9H, Ar-H); 13C NMR (CDCl3, 75 MHz) δ: 30.2 (C-9), 33.5 (C-5”), 39.4
(C-10), 47.5 (C-8), 56.1 (C-2”), 117.3 (C-4), 122.5 (C-7), 123.3 (C-5), 128.6
(C-3a), 127.3 (C-12 and C-16), 129.7 (C-14), 130.1 (C-12 and C-15), 133.6
(C-6), 134.5 (C-3), 136.2 (C-11), 142.1 (C-7a), 161.6 (C-2’), 169.8 (C-4”);
FAB-Mass (m/z): 425 [M+]; Anal. Calcd. for C20H19N5O4S: C, 56.46, H, 4.50,
N, 16.46 %; found C, 56.41, H, 4.43, N, 16.39 %.
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(2-bromo phenyl)-4-oxo-1,3-
thiazolidine-carboxamide (4g):
Yield: 68%; m.p. 172-173 ºC; IR (cm-1): 668 (C-S-C), 890 (C-N), 1348 (N-
CH2), 1537 (NO2), 1553 (C=C), 1663 (C=O), 1740 (CO cyclic), 1461, 2855,
2910 (CH2), 2963 (S-CH2), 3041 (CH-Ar), 3366 (NH); 1H NMR (CDCl3, 300
MHz) δ: 2.22-2.26 (m, 2H, H-9), 3.35 (s, 2H, H-5”), 3.42-3.46 (m, 2H, H-10),
4.25 (t, 2H, J = 7.40 Hz, H-8), 5.19 (s, 1H, H-2”), 5.77 (s, 1H, H-1’), 7.26-7.77
(m, 8H, Ar-H); 13C NMR (CDCl3, 75 MHz) δ: 34.4 (C-9), 36.8 (C-5”), 39.9
(C-10), 48.4 (C-8), 59.5 (C-2”), 118.6 (C-4), 125.5 (C-7), 126.6 (C-5), 129.7
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(4-chlorophenyl)-4-oxo-1,3-
1038

J. Chil. Chem. Soc., 57, Nº 1 (2012)
(C-12), 130.2 (C-16), 130.5 (C-3a), 131.6 (C-14), 132.7 (C-13), 133.1 (C-15),
134.8 (C-6), 135.7 (C-3), 137.5 (C-11), 140.7 (C-7a),165.8 (C-2’), 173.3 (C-
4”); FAB-Mass (m/z): 504 [M+]; Anal. Calcd. for C20H N5O4SBr: C, 47.62, H,
3.52, N, 13.88 %; found C, 47.59, H, 3.48, N, 13.79 %1.8
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(4-nitrophenyl)-4-oxo-1,3-
thiazolidine-carboxamide (4h):
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(phenyl)-4-oxo-5-
(benzylidene)-1,3-thiazolidine-carboxamide (5a):
Yield: 62%; m.p. 162-163 ºC; IR (cm-1): 670 (C-S-C), 885 (C-N), 1343
(N-CH2), 1536 (NO2), 1666 (C=O), 1741 (CO cyclic), 1457, 2854, 2902 (CH2),
2941 (C=CH), 3038 (CH-Ar), 3366 (NH); 1H NMR (CDCl3, 300 MHz) δ: 2.12-
2.16 (m, 2H, H-9), 3.43-3.49 (m, 2H, H-10), 4.16 (t, 2H, J = 7.40 Hz, H-8),
5.10 (s, 1H, H-2”), 5.69 (s, 1H, H-1’), 6.52 (s, 1H, H-17), 7.77-8.31 (m, 14H,
Ar-H);13C NMR (CDCl3, 75 MHz) δ: 32.8 (C-9), 40.1 (C-10), 54.3 (C-8), 60.5
(C-2”), 117.6 (C-4), 123.2 (C-7), 125.4 (C-5), 127.3 (C-19 and C-23), 128.1
(C-12 and C-16), 129.2 (C-3a), 129.7 (C-20 and C-22), 130.5 (C-14), 131.4 (C-
13 and C-15), 132.1 (C-18), 134.8 (C-6), 135.7 (C-3), 137.6 (C-11), 138.2 (C-
17), 140.7 (C-5”), 142.3 (C-7a), 162.0 (C-2’), 170.7 (C-4”); FAB-Mass (m/z):
513 [M+]; Anal. Calcd. for C27H23N5O4S: C, 63.14, H, 4.51, N, 13.63 %; found
C, 63.12, H, 4.49, N, 13.57 %.
Yield: 66%; m.p. 177-179 ºC; IR (cm-1): 673 (C-S-C), 893 (C-N), 1349 (N-
CH2), 1538 (NO2), 1549 (C=C), 1666 (C=O), 1746 (CO cyclic), 1459, 2854,
2897 (CH2), 2955 (S-CH2), 3036 (CH-Ar), 3368 (NH); 1H NMR (CDCl3, 300
MHz) δ: 2.20-2.25 (m, 2H, H-9), 3.39 (s, 2H, H-5”), 3.43-3.49 (m, 2H, H-10),
4.21 (t, 2H, J = 7.45 Hz, H-8), 5.36 (s, 1H, H-2”), 5.70 (s, 1H, H-1’), 7.26-7.84
(m, 8H, Ar-H);13C NMR (CDCl , 75 MHz) δ: 32.2 (C-9), 36.9 (C-5”), 40.3 (C-
10), 51.8 (C-8), 57.2 (C-2”), 1183.6 (C-4), 123.4 (C-5), 124.7 (C-7), 127.6 (C-12
and C-16), 128.8 (C-3a), 129.9 (C-14), 130.4 (C-13 and C-15), 135.7 (C-11),
132.6 (C-6), 133.7 (C-3), 143.1 (C-7a), 162.4 (C-2’), 174.3 (C-4”); FAB-Mass
(m/z): 470 [M+]; Anal. Calcd. for C20H18N6O6S: C, 51.06, H, 3.85, N, 17.86 %;
found C, 51.00, H, 3.78, N, 17.79 %.
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(4-chlorophenyl)-4-oxo-5-(4-
chloro benzylidene)-1,3-thiazolidine-carboxamide (5b):
Yield: 64%; m.p. 179-180 ºC; IR (cm-1): 672 (C-S-C), 744 (C-Cl), 887 (C-
N), 1345 (N-CH2), 1544 (NO2), 1566 (C=CH), 1672 (C=O), 1742 (CO cyclic),
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(3-nitrophenyl)-4-oxo-1,3-
thiazolidine-carboxamide (4i):
1
1462, 2861, 2906 (CH2), 2947 (C=CH), 3040 (CH-Ar), 3370 (NH); H NMR
Yield: 64%; m.p. 180-181 ºC; IR (cm-1): 666 (C-S-C), 887 (C-N), 1350 (N-
CH2), 1539 (NO2), 1546 (C=C), 1669 (C=O), 1747 (CO cyclic), 1456, 2850,
2905 (CH2), 2957 (S-CH2), 3037 (CH-Ar), 3369 (NH); 1H NMR (CDCl3, 300
MHz) δ: 2.19-2.24 (m, 2H, H-9), 3.28-3.33 (m, 2H, H-10), 3.37 (s, 2H, H-5”),
4.20 (t, 2H, J = 7.40 Hz, H-8), 5.41 (s, 1H, H-2”), 5.69 (s, 1H, H-1’), 7.29-7.81
(m, 8H, Ar-H); 13C NMR (CDCl3, 75 MHz) δ: 33.4 (C-9), 37.4 (C-5”), 41.6
(C-10), 49.7 (C-8), 58.1 (C-2”), 119.6 (C-4), 124.8 (C-7), 125.6 (C-5), 128.4
(C-12), 129.5 (C-3a), 129.7 (C-16), 130.7 (C-14), 131.6 (C-13), 133.5 (C-6),
133.7 (C-15), 134.2 (C-3), 136.8 (C-11), 142.7 (C-7a), 163.4 (C-2’), 174.5 (C-
4”); FAB-Mass (m/z): 470 [M+]; Anal. Calcd. for C20H18N6O6S : C, 51.06, H,
3.85, N, 17.86 %; found C, 51.04, H, 3.80, N, 17.81%.
(CDCl , 300 MHz) δ: 2.15-2.20 (m, 2H, H-9), 3.45-3.51 (m, 2H, H-10), 4.20
(t, 2H,3J = 7.40 Hz, H-8), 5.16 (s, 1H, H-2”), 5.75 (s, 1H, H-1’), 6.57 (s, 1H,
H-17), 7.79-8.37 (m, 12H, Ar-H);13C NMR (CDCl3, 75 MHz) δ: 32 (C-9), 40.6
(C-10), 54.9 (C-8), 60.7 (C-2”), 118.2 (C-4), 123.5 (C-7), 126.5 (C-5), 127.7
(C-19 and C-23), 128.4 (C-12 and C-16), 129.4 (C-3a), 129.8 (C-20 and C-22),
131.3 (C-14), 131.9 (C-13 and C-15), 132.6 (C-18), 136.4 (C-3), 134.4 (C-6),
137.6 (C-11), 141.2 (C-17), 142.3 (C-5”), 142.9 (C-7a), 162.5 (C-2’), 171.1
(C-4”); FAB-Mass (m/z): 582 [M+]; Anal. Calcd. for C27H21N5O4SCl2: C, 55.67,
H, 3.63, N, 12.02 %; found C, 55.57, H, 3.55, N, 11.95 %.
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(3-chloro phenyl)-4-oxo-5-(3-
chloro benzylidene)-1,3-thiazolidine-carboxamide (5c):
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(2-nitrophenyl)-4-oxo-1,3-
thiazolidine-carboxamide (4j):
Yield: 62%; m.p. 175-176 ºC; IR (cm-1): 670 (C-S-C), 749 (C-Cl), 888 (C-
N), 1346 (N-CH2), 1530 (NO2), 1578 (C=CH) 1647 (C=O), 1743 (CO cyclic),
1
Yield: 68%; m.p. 178-179 ºC; IR (cm-1): 675 (C-S-C), 889 (C-N), 1347 (N-
CH2), 1541 (NO2), 1548 (C=C), 1668 (C=O), 1748 (CO cyclic), 1460, 2852,
2902 (CH2), 2965 (S-CH2), 3040 (CH-Ar), 3370 (NH); 1H NMR (CDCl3, 300
MHz) δ: 2.24-2.29 (m, 2H, H-9), 3.29 (s, 2H, H-5”), 3.34-3.39 (m, 2H, H-10),
4.26 (t, 2H, J = 7.50 Hz, H-8), 5.22 (s, 1H, H-2”), 5.72 (s, 1H, H-1’), 7.34-7.92
(m, 8H, Ar-H); 13C NMR (CDCl3, 75 MHz) δ: 34.7 (C-9), 37.1 (C-5”), 41.5
(C-10), 48.6 (C-8), 60.4 (C-2”), 119.7 (C-4), 126.2 (C-7), 127.3 (C-5), 129.6
(C-12), 130.4 (C-3a), 130.7 (C-16), 131.3 (C-14), 132.8 (C-13), 134.1 (C-15),
135.3 (C-3), 136.9 (C-6), 137.3 (C-11), 142.8 (C-7a), 163.1 (C-2’), 175.7 (C-
4”); FAB-Mass (m/z): 470 [M+]; Anal. Calcd. for C20H18N6O6S: C, 51.06, H,
3.85, N, 17.86 %; found C, 51.01, H, 3.82, N, 17.85 %.
1450, 2839, 2923 (CH2), 2946 (C=CH), 3047 (CH-Ar), 3362 (NH); H NMR
(CDCl , 300 MHz) δ: 2.19-2.24 (m, 2H, H-9), 3.46-3.50 (m, 2H, H-10), 4.15
(t, 2H,3J = 7.50 Hz, H-8), 5.22 (s, 1H, H-2”), 5.74 (s, 1H, H-1’), 6.65 (s, 1H,
H-17), 7.85-8.39 (m, 12H, Ar-H); 13C NMR (CDCl , 75 MHz) δ: 35.8 (C-9),
44.1 (C-10), 49.3 (C-8), 60.9 (C-2”), 122.6 (C-4), 3124.2 (C-7), 128.4 (C-5),
128.7 (C-19), 128.9 (C-23), 129.1 (C-12), 129.8 (C-16), 130.2 (C-3a), 130.7
(C-20), 131.2 (C-22), 131.8 (C-14), 132.2 (C-13), 132.7 (C-15), 133.1 (C-18),
135.3 (C-6), 136.6 (C-3), 138.6 (C-11), 140.6 (C-17), 141.3 (C-7a), 143.7
(C-5”), 166.0 (C-2’), 173.4 (C-4”); Mass (FAB) 582 [M+]; Anal. Calcd. for
C27H21N O4SCl2: C, 55.67, H, 3.63, N, 12.02 %; found C, 55.59, H, 3.60, N,
11.98 %5.
General methods for the synthesis of compounds 5(a-j):
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(2-chloro phenyl)-4-oxo-5-(2-
chloro benzylidene)-1,3-thiazolidine-carboxamide (5d):
The compound 4a (0.007 mole) and benzaldehyde (0.007 mole) in
ethanol (50 ml) in the presence of CH3CH2ONa were allowed to react at room
temperature. The reaction mixture was first stirred on a magnetic stirrer for
about 2.00 hours followed by reflux on a steam bath for about 4.30 hours. The
completion of the reaction was monitored by silica gel-G coated TLC plates.
The product was filtered and cooled at room temperature. The filtered product
was purified over a silica gel packed column chromatography using CH OH :
CHCl (7 : 3 v/v) as eluant as eluant (50 ml). The purified product was3dried
under3vacuo and recrystallized from acetone at room temperature to furnish
compound 5a (Figure 5).
Yield: 68%; m.p. 172-173 ºC; IR (cm-1): 676 (C-S-C), 741 (C-Cl), 890 (C-
N), 1347 (N-CH2), 1541 (NO2), 1568 (C=CH), 1667 (C=O), 1744 (CO cyclic),
1
1464, 2856, 2903 (CH2), 2949 (C=CH), 3042 (CH-Ar), 3372 (NH); H NMR
(CDCl , 300 MHz) δ: 2.22-2.27 (m, 2H, H-9), 3.54-3.59 (m, 2H, H-10), 4.22
(t, 2H,3J = 7.50 Hz, H-8), 5.18 (s, 1H, H-2”), 5.77 (s, 1H, H-1’), 6.67 (s, 1H,
H-17), 7.83-8.40 (m, 12H, Ar-H); 13C NMR (CDCl , 75 MHz) δ: 36.5 (C-9),
43.4 (C-10), 50.0 (C-8), 57.3 (C-2”), 119.6 (C-4), 3125.5 (C-7), 126.4 (C-5),
128.3 (C-19), 128.7 (C-23), 129.4 (C-12), 129.7 (C-16), 130.2 (C-3a), 130.9
(C-20), 131.1 (C-22), 131.7 (C-14), 132.4 (C-13), 132.8 (C-15), 133.6 (C-18),
135.8 (C-6), 137.7 (C-3), 139.6 (C-11), 141.5 (C-17), 141.7 (C-7a), 143.8 (C-
5”), 163.7 (C-2’), 171.8 (C-4”); FAB-Mass (m/z): 582 [M+]; Anal. Calcd. for
C27H21N O4SCl2: C, 55.67, H, 3.63, N, 12.02 %; found C, 55.64, H, 3.57, N,
12.00 %5.
Compounds 5 (b-j) have also been synthesized by using similar method
as above.
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(4-bromo phenyl)-4-oxo-5-(4-
bromo benzylidene)-1,3-thiazolidine-carboxamide (5e):
Yield: 64%; m.p. 169-171 ºC; IR (cm-1): 679 (C-S-C), 891 (C-N), 1352
(N-CH2), 1542 (NO2), 1572 (C=CH), 1670 (C=O), 1746 (CO cyclic), 1465,
2859, 2904 (CH2), 2945 (C=CH), 3044 (CH-Ar), 3375 (NH); 1H NMR (CDCl3,
300 MHz) δ: 2.23-2.28 (m, 2H, H-9), 3.49-3.55 (m, 2H, H-10), 4.27 (t, 2H, J =
7.40 Hz, H-8), 5.15 (s, 1H, H-2”), 5.78 (s, 1H, H-1’), 6.68 (s, 1H, H-17), 7.81-
8.32 (m, 12H, Ar-H); 13C NMR (CDCl3, 75 MHz) δ: 33.7 (C-9), 41.6 (C-10),
51.3 (C-8), 61.7 (C-2”), 121.6 (C-4), 123.6 (C-7), 125.5 (C-5), 129.3 (C-19
and C-23), 130.3 (C-12 and C-16), 130.9 (C-3a), 131.7 (C-20 and C-22), 132.5
(C-14), 133.6 (C-13 and C-15), 134.5 (C-18), 136.6 (C-6), 138.7 (C-3), 139.7
(C-17), 140.4 (C-11), 141.6 (C-7a), 143.5 (C-5”), 163.8 (C-2’), 171.5 (C-4”);
Mass (FAB) 671 [M+]; Anal. Calcd. for C H21N5O4SBr2: C, 48.30, H, 3.15, N,
10.43 %; found C, 48.21, H, 3.14, N, 10.3297 %.
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(3-bromophenyl)-4-oxo-5-(3-
Figure 5: Structure of compound 5(a-j).
1039

J. Chil. Chem. Soc., 57, Nº 1 (2012)
bromo benzylidene)-1,3-thiazolidine-carboxamide (5f):
the filter paper disc diffusion method and the concentrations have been used in
μg/mL. All the synthesized compounds have been screened in vitro for their
antibacterial activity against B. subtilis, E. coli and S. aureus and antifungal
activity against A. niger, A. flavus and C. albicans Standards for antibacterial
and antifungal activities Streptomycin and Griseofulvin respectively were
used. The antitubercular activity screened against the M. tuberculosis. For
the antitubercular activity isoniazid and rifampicin were used as standard.
Standards also screened under the similar conditions for comparison. Results
are given in Table 1.
Yield: 61%; m.p. 173-174 ºC; IR (cm-1): 680 (C-S-C), 892 (C-N), 1348 (N-
CH2), 1538 (NO2), 1573 (C=CH), 1671 (C=O), 1748 (CO cyclic), 1466, 2860,
2905 (CH ), 2944 (C=CH), 3046 (CH-Ar), 3367 (NH); 1H NMR (CDCl3, 300
MHz) δ: 22.22-2.29 (m, 2H, H-9), 3.47-3.52 (m, 2H, H-10), 4.24 (t, 2H, J = 7.45
Hz, H-8), 5.23 (s, 1H, H-2”), 5.78 (s, 1H, H-1’), 6.58 (s, 1H, H-17), 7.89-8.36
(m, 12H, Ar-H); 13C NMR (CDCl3, 75 MHz) δ: 35.6 (C-9), 41.4 (C-10), 48.8
(C-8), 61.5 (C-2”), 119.4 (C-4), 125.5 (C-7), 127.4 (C-5), 129.8 (C-19), 130.0
(C-23), 130.3 (C-12), 130.7 (C-16), 131.4 (C-3a), 131.7 (C-20), 132.0 (C-22),
132.5 (C-14), 133.4 (C-13), 133.8 (C-15), 134.7 (C-18), 136.6 (C-6), 137.2 (C-
3), 138.3 (C-11), 140.6 (C-17), 141.6 (C-7a), 142.7 (C-5”), 164.6 (C-2’), 174.7
(C-4”); FAB-Mass (m/z): 671 [M+]; Anal. Calcd. for C27H21N5O4SBr2: C, 48.30,
H, 3.15, N, 10.43 %; found C, 48.27, H, 3.10, N, 10.40 %.
Antiinflammatory activities
Carageenan induced rat paw oedema method was employed for evaluating
the antiinflammatory activity of compounds at a dose 50 mg/ kg bw in albino
rats (weighing 80-110 gm, each group contain 5 animal) using phenylbutazone
as a standard drug for comparison at a dose 30 mg/ kg bw. The rate paw
oedema was produced by the method of winter et al. The percentage inhibition
of inflammation was calculated by applying Newbould formula. In vivo study
has been approved institutional ethical committee, Dr. H.S. Gour University,
Sagar. Results of compounds 1, 2, 3(a-j), 4(a-j) and 5(a-j) were given in Table
2.
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(2-bromophenyl)-4-oxo-5-(2-
bromo benzylidene)-1,3-thiazolidine-carboxamide (5g):
Yield: 63%; m.p. 165-166 ºC; IR (cm-1): 674 (C-S-C), 885 (C-N), 1343 (N-
CH2), 1536 (NO2), 1565 (C=CH) 1666 (C=O), 1741 (CO cyclic), 1457, 2854,
2902 (CH ), 2941 (C=CH), 3038 (CH-Ar), 3366 (NH); 1H NMR (CDCl3, 300
MHz) δ: 22.21-2.28 (m, 2H, H-9), 3.50-3.55 (m, 2H, H-10), 4.25 (t, 2H, J = 7.45
Hz, H-8), 5.27 (s, 1H, H-2”), 5.81 (s, 1H, H-1’), 6.62 (s, 1H, H-17), 7.84-8.42
(m, 12H, Ar-H); 13C NMR (CDCl3, 75 MHz) δ: 34.4 (C-9), 42.4 (C-10), 49.9
(C-8), 59.4 (C-2”), 121.2 (C-4), 124.8 (C-7), 126.3 (C-5), 130.6 (C-19), 130.8
(C-23), 131.1 (C-12), 131.7 (C-16), 132.5 (C-3a), 132.8 (C-20), 133.4 (C-22),
133.8 (C-14), 134.4 (C-13), 134.8 (C-15), 135.5 (C-18), 137.7 (C-6), 138.9 (C-
3), 139.4 (C-11), 140.5 (C-17), 141.3 (C-7a), 142.8 (C-5”), 165.6 (C-2’), 174.6
(C-4”); FAB-Mass (m/z): 671 [M+]; Anal. Calcd. for C27H21N5O4SBr2: C, 48.30,
H, 3.15, N, 10.43 %; found C, 48.23, H, 3.13, N, 10.42 %.
RESULTS AND DISCUSSION
The reaction of 1-bromo-3-chloropropane with 6-nitroindazole was
carried out in the methanol to afford compound 1. The spectroscopic analyses
of compound 1 showed absorption peaks for N-CH and C-Cl at 13268 cm-1
and 768 cm-1 respectively in the IR spectrum. This fact also supported by the
disappearance of NH absorption of the 6-nitroindazole. The compound 1 on
the reaction with urea yielded compound 2. In the spectroscopic analyses of
compound 2 we found three absorption peaks in IR spectrum for NH, NH2 and
CO at 3342, 3456 and 1648 cm-1 respectively while absorption of C-Cl has been
disappeared in the IR spectrum of compound 1. This fact was also supported
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(4-nitrophenyl)-4-oxo-5-(4-
nitro benzylidene)-1,3-thiazolidine-carboxamide (5h):
Yield: 66%; m.p. 170-171 ºC; IR (cm-1): 673 (C-S-C), 895 (C-N), 1351
(N-CH2), 1544 (NO2), 1567 (C=CH), 1675 (C=O), 1747 (CO cyclic), 1461,
1
1
by H and 13C NMR spectra because two signals appeared in the H NMR
spectrum for NH and NH at δ 5.72 and δ 5.92 ppm respectively. The formation
of the compound 2 was2fully supported by a CO group gives a signal at δ
161.7 ppm in the 13C NMR spectrum of the compound 2. All the facts together
are strong evidence for the synthesis of compound 2. Compound 2 give the
condensation reaction with substituted benzaldehydes to yield compounds 3(a-
1
1
2855, 2911 (CH2), 2952 (C=CH), 3043 (CH-Ar), 3370 (NH); H NMR: H
NMR (CDCl3, 300 MHz) δ: 2.21-2.25 (m, 2H, H-9), 3.50-3.54 (m, 2H, H-10),
4.31 (t, 2H, J = 7.50 Hz, H-8), 5.23 (s, 1H, H-2”), 5.82 (s, 1H, H-1’), 6.64 (s,
1H, H-17), 7.86-8.46 (m, 12H, Ar-H); 13C NMR (CDCl , 75 MHz) δ: 36.3 (C-
9), 44.3 (C-10), 50.5 (C-8), 59.5 (C-2”), 120.2 (C-4), 1236.7 (C-7), 128.4 (C-5),
130.1 (C-19 and C-23), 131.6 (C-12 and C-16), 132.2 (C-3a), 132.7 (C-20 and
C-22), 133.5 (C-14), 134.5 (C-13 and C-15), 135.3 (C-18), 137.4 (C-6), 139.3
(C-3), 139.8 (C-11), 141.5 (C-17), 142.4 (C-7a), 144.7 (C-5”), 164.2 (C-2’),
174.4 (C-4”); FAB-Mass (m/z): 603 [M+]; Anal. Calcd. for C27H21N7O8S: C,
53.72, H, 3.50, N, 16.24 %; found C, 53.69, H, 3.49, N, 16.20 %.
j). Structure confirmed by IR, H NMR and 13C NMR spectra of compounds
1
3(a-j). In the IR spectra an absorption found in the range of 1555-1580 cm-1
while a strong signal appeared in the range of δ 7.89-7.98 and δ 150.6-154.6
1
ppm in the H NMR and 13C NMR spectra of compounds 3(a-j) respectively.
1
The facts also supported by the disappearance of the signal of NH2 in the H
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(3-nitro phenyl)-4-oxo-5-(3-
nitro benzylidene)-1,3-thiazolidine-carboxamide (5i):
NMR spectra. The compounds 3(a-j) on reaction with thioglycolic acid in
the presence of ZnCl2 gives the cycloaddition reaction and produced a five
membered cyclic ring known as thiazolidinone ring, compounds 4(a-j). The
compounds 4(a-j) showed a characteristic absorption of the cyclic carbonyl
group in the range of 1737-1750 cm-1 in the IR spectra. The 1H NMR spectra
aroused our attention and clearly indicate the presence of the active methylene
group in the thiazolidine ring in the range of δ 3.28-3.40 ppm. The 13C NMR
spectra of compounds 4(a-j) also supported the fact that cyclic carbonyl group
present and a signal appeared in the range of δ 169.8-175.7 ppm. These all
fact also supported by the two evidences that are (a) disappearance of N=CH
proton and (b) appearance of N-CH proton in the range of δ 5.19-5.41 ppm in
Yield: 65%; m.p. 173-175 ºC; IR (cm-1): 675 (C-S-C), 896 (C-N), 1349 (N-
CH2), 1546 (NO2), 1571 (C=CH), 1676 (C=O), 1745 (CO cyclic), 1460, 2856,
2912 (CH ), 2943 (C=CH), 3045 (CH-Ar), 3369 (NH); 1H NMR (CDCl3, 300
MHz) δ: 22.26-2.30 (m, 2H, H-9), 3.54-3.59 (m, 2H, H-10), 4.28 (t, 2H, J = 7.40
Hz, H-8), 5.26 (s, 1H, H-2”), 5.75 (s, 1H, H-1’), 6.71 (s, 1H, H-17), 7.82-8.45
(m, 12H, Ar-H); 13C NMR (CDCl3, 75 MHz) δ: 34.4 (C-9), 43.5 (C-10), 52.6
(C-8), 58.2 (C-2”), 122.4 (C-4), 124.9 (C-7), 126.7 (C-5), 131.6 (C-19), 131.9
(C-23), 132.2 (C-12), 132.9 (C-16), 133.4 (C-20), 133.7 (C-3a), 133.9 (C-22),
134.1 (C-14), 135.0 (C-13), 135.7 (C-15), 136.9 (C-18), 138.8 (C-6), 139.5 (C-
3), 140.2 (C-11), 141.4 (C-17), 141.3 (C-7a), 143.5 (C-5”), 165.7 (C-2’), 172.1
(C-4”); FAB-Mass (m/z): 603 [M+]; Anal. Calcd. for C27H21N7O8S: C, 53.72, H,
3.50, N, 16.24 %; found C, 53.67, H, 3.47, N, 16.22 %.
1
the H NMR spectra of compounds 4(a-j). The compounds 4(a-j) underwent
the Knoevenagel condensation reaction with substituted benzaldehydes in the
presence of C2H5ONa to afford the compounds 5(a-j). In the 1H NMR spectra
of the compounds 5(a-j), we found the disappearance of two methylene protons
of compounds 4(a-j) and an appearance of a new signal for C=CH in the range
of δ 6.52-6.71 ppm in the 1H NMR and two new signals for C=CH and C=CH
appeared in the range of δ 138.2-141.5 and δ 140.7-144.7 ppm in the 13C NMR
spectra of the compounds 5(a-j). These all above facts clearly confirmed the
synthesis of all final products.
The results of the all described activities (antibacterial, antifungal,
antitubercular and antiinflammatory) were summarized in Tables 1 and 2.
The result of the antimicrobial screening data revealed that all the synthesized
compounds showed considerable and varied activities against the selected
microorganisms. Antimicrobial, antitubercular and anti-inflammatory activities
data (as shown in Table 1 and 2) revealed that all the synthesized compounds
have a structure activity relationship (SAR) because an activity of compounds
varies with substitution. Nitro group containing compounds showed higher
activity than chloro and bromo group containing compounds. Chloro and
bromo derivatives also have higher activity than other rested compounds.
On the basis of SAR, concluded that the activity of compounds depends on
electron withdrawing nature of the substituted groups. The sequence of the
activity is following
N-[3-(1H-6-nitroindazol-1-yl)-propyl]-2-(2-nitro phenyl)-4-oxo-5-(2-
nitro benzylidene)-1,3-thiazolidine-carboxamide (5j):
Yield: 64%; m.p. 172-173 ºC; IR (cm-1): 681 (C-S-C), 897 (C-N), 1352 (N-
CH2), 1543 (NO2), 1569 (C=CH), 1677 (C=O), 1749 (CO cyclic), 1458, 2858,
2914 (CH ), 2950 (C=CH), 3048 (CH-Ar), 3374 (NH); 1H NMR (CDCl3, 300
MHz) δ: 22.33-2.37 (m, 2H, H-9), 3.51-3.56 (m, 2H, H-10), 4.23 (t, 2H, J = 7.40
Hz, H-8), 5.21 (s, 1H, H-2”), 5.72 (s, 1H, H-1’), 6.59 (s, 1H, H-17), 7.78-8.41
(m, 12H, Ar-H); 13C NMR (CDCl3, 75 MHz) δ: 35.4 (C-9), 42.5 (C-10), 52.6
(C-8), 58.6 (C-2”), 120.6 (C-4), 125.8 (C-7), 127.4 (C-5), 131.1 (C-19), 131.6
(C-23), 132.6 (C-12), 132.9 (C-16), 133.2 (C-3a), 133.7 (C-20), 133.9 (C-22),
134.6 (C-14), 135.4 (C-13), 135.8 (C-15), 136.4 (C-18), 138.5 (C-6), 140.2 (C-
3), 141.7 (C-11), 140.3 (C-17), 141.8 (C-7a), 144.7 (C-5”), 163.3 (C-2’), 173.5
(C-4”); FAB-Mass (m/z): 603 [M+]; Anal. Calcd. for C27H21N7O8S: C, 53.72, H,
3.50, N, 16.24 %; found C, 53.70, H, 3.42, N, 16.18 %.
Biological study
Antibacterial, antifungal and antitubercular activities
Series of newly synthesized compounds were active against selected
microorganisms. The minimal inhibition concentrations were determined using
1040

J. Chil. Chem. Soc., 57, Nº 1 (2012)
Table 1: Antibacterial, antifungal and antitubercular activities of compounds 1, 2, 3(a-j), 4(a-j) and 5(a-j).
Antitubercular
activity
Antibacterial activity
Antifungal activity
Comp.
B. subtilis
E. coli
S. aureus
A. niger
A. flavus
C. albicans
M. tuberculosis
1
12.25
10.25
9.25
7.50
7.25
7.75
7.50
8.25
7.75
6.25
6.25
6.75
8.25
6.50
6.25
5.50
6.50
7.25
6.25
5.25
5.25
3.75
9.25
3.75
3.25
3.50
3.25
3.50
4.00
3.25
3.25
3.25
3.25
-
17.25
14.25
12.25
6.75
6.50
7.25
7.25
7.50
8.00
5.75
5.25
4.75
6.25
5.25
5.00
4.75
5.25
5.75
5.00
4.75
3.25
5.50
7.25
6.25
2.00
2.25
2.00
2.25
6.25
1.75
2.00
1.75
1.75
-
16.50
13.25
11.25
6.25
6.50
6.75
7.75
7.25
7.50
6.25
5.50
6.25
9.25
5.25
5.50
5.50
5.75
6.25
5.50
6.25
6.50
5.25
6.50
6.25
3.25
2.25
2.50
2.50
3.75
2.25
2.50
2.25
2.25
-
14.5
12.5
10.50
10.25
8.50
12.5
9.25
8.50
15.25
12.50
8.25
9.25
12.50
10.75
12.50
7.50
10.25
8.50
9.75
8.50
7.50
7.75
15.5
8.5
18.5
15.25
10.75
8.25
10.5
8.75
10.50
13.50
8.75
10.25
10.50
8.25
10.75
12.25
10.75
8.75
9.50
12.50
12.75
7.25
8.50
6.25
15.5
9.25
7.75
8.25
6.75
7.75
10.5
7.50
7.25
7.25
-
22.50
21.75
21.75
18.25
18.75
17.50
18.50
17.25
18.75
16.50
12.75
13.75
19.75
15.25
14.75
14.50
17.50
15.25
14.75
13.50
14.50
13.75
17.50
12.75
12.75
12.25
12.75
12.50
14.50
12.25
12.75
12.50
-
11.25
10.75
9.50
7.25
7.50
7.25
8.25
7.50
7.75
6.25
3.75
4.25
7.50
4.75
4.50
4.25
5.25
4.50
4.75
4.25
4.25
3.75
6.25
3.25
1.50
2.25
2.50
1.25
4.25
1.50
1.75
2.25
-
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
5a
5b
5c
6.50
7.25
7.50
6.50
9.25
6.50
6.25
6.50
-
5d
5e
5f
5g
5h
5i
5j
Streptomycin
Griseofulvin
6.25
8.75
12.50
-
the mic values of standard streptomycin for all bacteria strain and griseofulvin for all fungi strain were in the range of 1.25-3.25 and 625-12.5 μg/ml
respectively.
isoniazid and rifampicin were used as standards, mic values were 1.25 and 2.50 μg/ml respectively.
Table 2: Antiinflammatory activity of compounds 1, 2, 3(a-j), 4(a-j) and 5(a-j).
Before carageenan administration
(mean ± SEM)
Total increase in paw volume after 5
Percent
inhibition
Compound Code
hours (mean ± SEM)
0.25 ± 0.01
0.24 ± 0.03
0.23 ± 0.02
0.22 ± 0.01
0.22 ± 0.02
0.21 ± 0.03
0.23 ± 0.03
0.24 ± 0.02
0.23 ± 0.01
0.21 ± 0.01
0.20 ± 0.02
1
0.61 ± 0.01
0.62 ± 0.03
0.64 ± 0.02
0.65 ± 0.01
0.67 ± 0.02
0.60 ± 0.01
0.61 ± 0.03
0.62 ± 0.01
0.64 ± 0.03
0.66 ± 0.01
0.62 ± 0.03
21.87
25.00
28.12
31.25
31.25
34.37
28.12
25.00
28.12
34.37
37.50
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
1041

J. Chil. Chem. Soc., 57, Nº 1 (2012)
3j
0.65 ± 0.02
0.63 ± 0.01
0.65 ± 0.03
0.64 ± 0.01
0.62 ± 0.02
0.61 ± 0.03
0.62 ± 0.01
0.63 ± 0.03
0.64 ± 0.02
0.65 ± 0.01
0.64 ± 0.03
0.60 ± 0.02
0.64 ± 0.02
0.66 ± 0.02
0.68 ± 0.02
0.66 ± 0.03
0.65 ± 0.02
0.67 ± 0.02
0.64 ± 0.03
0.65 ± 0.02
0.67 ± 0.03
0.66 ± 0.02
0.68 ± 0.03
0.21 ± 0.03
0.22 ± 0.02
0.19 ± 0.01
0.18 ± 0.03
0.19 ± 0.03
0.19 ± 0.02
0.20± 0.0
34.37
31.25
40.62
43.75
40.62
40.62
37.50
40.62
56.25
53.12
56.25
50.00
56.25
59.38
59.38
59.38
62.50
56.25
62.50
68.75
65.63
-
4a
4b
4c
4d
4e
4f
4g
0.19 ± 0.02
0.14 ± 0.03
0.15 ± 0.01
0.14 ± 0.02
0.16 ± 0.02
0.14 ± 0.02
0.13 ± 0.01
0.13 ± 0.02
0.13 ± 0.02
0.12 ± 0.01
0.14 ± 0.01
0.12 ± 0.01
0.10 ± 0.03
0.11 ± 0.02
0.32 ± 0.01
0.08 ± 0.02
4h
4i
4j
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
Control
Standard phenylbutazone
75.00
NO2 > Cl > Br > H
2.- K. W. Woods, J. P. Fischer, A. Claiborne, T. Li, S. A. Thomas, Gui-Dong
Zhu, R. B. Diebold, X. Liu, Yan Shi, V. Klinghofer, E. K. Han, R. Guan,
S. R. Magnone, E. F. Johnson, J. J. Bouska, A. M. Olson, R. de Jong, T.
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Chem., 14, 6832, (2006).
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A. Pau, G. E. Grella, ll Farmaco, 58, 749, (2003).
4.- B. Cottyn, F. Acher, B. Ramassamy, L. Alvey, M. Lepoivre, Y. Frapart,
D. Stuehr, D. Mansuy, J-L Boucher, D. Vichard, Bioorg. Med. Chem., 16,
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Cerain A. de Lopez, A. Monge, M. A. Rojas, G. Yaluff, Bioorg. Med.
Chem, 14, 3467, (2006).
Results of antibacterial activity of the compounds 5c, 5e, 5h, 5i and 5j
showed good activity against B. subtilis and E. coli. Compounds 5d, 5h and 5j
showed good activity against S. aureus. Incase of antifungal activity compounds
5c, 5f, 5h, 5i and 5j showed good activity against A. niger and compounds
5e, 5h and 5j showed good activity against A. flavus while none compounds
showed significant antifungal activity against C. albicans. Comounds 5c, 5f, 5h
and 5i showed significant antitubercular activity and 5f, 5h, 5i and 5j showed
good anti-inflammatory activity in the series. Results showed compounds
containing nitro group (5h, 5i, 5j) displayed good activity against all strains
then containing chloro or bromo group.
CONCLUSIONS
In this study a new series of compounds synthesis and characterized, gave
satisfactory results. Synthesized compounds screened for their biological study
which displayed moderate to good activity.
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ACKNOWLEDGEMENT
10.- J. M. Orrling, M. R. Marzahn, H. Gutierrez-de-Teran, J. Aqvist, B. M.
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17, 4213, (2007).
The authors are thankful to SAIF, Central Drugs Research Institute,
Lucknow (India) for providing spectral and analytical data of the compounds.
We are also thankful to Head, Department of Chemistry, Dr. H. S. Gour,
University, Sagar (India) for giving the facilities to carry out the work.
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