Synthesis and biological activity of (Z) -n-(5 Benzylidene-4-oxo-2-substituted-phenylthiazolidin-3-yl)-5-((1, 3-dioxoisoindolin-2- yl)methyl)-2-hydroxybenzamide

Article abstract of DOI:10.1155/2010/586984

5-((1, 3-Dioxoisoindolin-2-yl)methyl-2-hydroxybenzohydrazide (1) undergoes facile condensation with aromatic aldehydes to afford the corresponding N'-substituted-phenyl-5-((1,3-dioxoisoindolin-2-yl) methyl)-2- hydroxybenzohydrazide (2a-h) in good yields.

Full text of DOI:10.1155/2010/586984

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
http://www.e-journals.net
2010, 7(4), 1484-1490
Synthesis and Biological Activity of
(Z) –n-(5-Benzylidene-4-oxo-2-substituted-
phenylthiazolidin-3-yl)-5-((1, 3-dioxoisoindolin-2-
yl)methyl)-2-hydroxybenzamide
M.C. PATEL* and DHAMELIYA
P.S.Science and H. D. Patel Arts College, Kadi, Gujarat, India.
dharmeshdhameliya11@yahoo.com
Received 4 December 2009; Accepted 1 February 2010
Abstract: 5-((1, 3-Dioxoisoindolin-2-yl)methyl-2-hydroxybenzohydrazide (1)
undergoes facile condensation with aromatic aldehydes to afford the
corresponding N'-substituted-phenyl-5-((1,3-dioxoisoindolin-2-yl) methyl)-2-
hydroxybenzohydrazide (2a-h) in good yields. Cyclocondensation of compounds
(2a-h) with thioglycolic acid yields 5-((1,3-dioxoisoindolin-2-yl) methyl)-2-
hydroxy-N-(4-oxo-2-substituted phenylthiazolidin-3-yl)benzamide (3a-h). These
(3a-h) compounds were further reacted with benzaldehyde in the presence of
sodium ethanolate affords, (Z) –N-(5-benzylidene-4-oxo-2-substituted phenyl-
thiazolidin-3-yl)-5-((1,3-dioxoisoindolin-2-yl)methyl)-2-hydroxybenzamide(4a-h).
The structures of these compounds were established on the basis of analytical
and spectral data. All the newly synthesized compounds were evaluated for their
antibacterial and antifungal activities.
Keywords: 5-((1,3-Dioxoisoindolin-2-yl)methyl-2-hydroxybenzohydrazide, Thiazolidin, Antibacterial activity.
Introduction
Hydrazide and their heterocyclized products display diverse biological activities including
antibacterial, antifungicidal, analgesic, anti-inflammatory properties1-15. These heterocyclic
systems find wide use in medicine, agriculture and industry. One of the hydrazides, 5-((1,3-
dioxoisoindolin-2-yl)methyl-2-hydroxybenzohydrazide and their condensed products play a
vital role in medicinal chemistry16-18. 4-Thiazolidinones and its arylidene compounds give
good pharmacological properties19-23. 4-Thiazolidinones are also known to exhibit
antitubercular24, antibacterial25, antifungal26 and anticonvulsant activities. Hence, it was
thought of interest to merge both of thiazolidinone and 5-((1,3-dioxoisoindolin-2-yl)methyl-
2-hydroxybenzohydrazide moieties which may enhance the drug activity of compounds to

1485
DHAMELIYA et al.
some extent, or they might possess some of the above mentioned biological activities. From
this point of view, the objective of the present work is to prepare new derivatives of
salicylhydrazide containing thiazolidinone moiety. Hence the present communication
comprises the synthesis of 5-((1,3-dioxoisoindolin-2-yl)methyl)-2-hydroxy-N-(4-oxo-2-
substituted phenylthiazolidin-3-yl)benzamide. The synthetic approach is shown in Scheme 1.
O
OH
NCH2
COO Me
O
[a]
O
OH
NCH2
CONHNH2
O
(1)
[b]
O
OH
H
NCH2
R
CONHN
C
[2a-h]
[c]
O
O
OH
H
C
NCH2
R
CONHN
O
C
O
S
[3a-h]
Scheme 1
(a) NH2NH2.H2O (b) RCHO (c) SHCH2COOH, Anh. ZnCl2
Where, R = (a) C6H5, (b) 4-OH-C6H4, (c) 2-OH-C6H4, (d) 4-OCH3-C6H4, (e) 4-OH-3-
OCH3-C6H3, (f) 4- Cl- C6H4, (g) 2-No2-C6H4, (h) 5-Br-2-OH-C6H3
Experimental
Melting points were determined in open capillary tubes and were uncorrected. The IR
1
spectra were recorded in KBr pellets on a Nicolet 400D spectrometer and H NMR and 13C
NMR spectra were recorded in DMSO with TMS as internal standard on a Bruker
spectrometer at 400 MHz and 100 MHz, respectively. LC-MS of selected samples taken on
LC-MSD-Trap-SL_01046.
Preparation of N'-Substituted phenyl-5-((1,3-dioxoisoindolin-2-yl)methyl)-2-
hydroxybenzohydrazide (2a-h)
General procedure
An equimolecular mixture of 5-((1,3-dioxoisoindolin-2-yl)methyl-2-hydroxybenzohydrazide (1),
(0.01 mole) and the aromatic aldehydes (a-h) in ethanol (20 mL) was refluxed on a water bath for
1.5-2.0 h. The solid separated was collected by filtration, dried and recrystallized from ethanol.
The yields, melting points and other characterization data of these compounds are given in Table 1.

Synthesis and Biological Activity
1486
Table 1. Analytical data and elemental analysis of compounds (2a-h)
Elemental analysis
% H
Molecular formula,
(Mol.wt.)
%C
%N
Compd.
Found Calcd. Found Calcd. FoundCalcd.
C24H19N3O3(397.43) 80 252 72.44 72.53 4.77
C24H19N3O4(413.43) 72 260 69.65 69.72 4.58
C24H19N3O4(413.43) 76 259 69.69 69.72 4.56
4.82 10.45 10.57
4.63 10.04 10.16
4.63 10.05 10.16
4.95 9.78 9.83
4.77 9.39 9.48
4.20 9.75 9.83
4.10 12.56 12.66
3.69 8.51 8.54
2a
2b
2c
2d
2e
2f
C25H21N3O4(249)
79 253 70.14 70.25 4.88
C25H21N3O5(443.45) 70 258 67.65 67.71 4.69
C24H18ClN3O3(431.87) 64 255 66.70 66.75 4.19
C24H18N4O5(442.42) 70 261 65.10 65.15 4.05
C24H18BrN3O4(492.32) 78 257 58.49 58.55 3.61
2g
2h
Preparation of 5-((1,3-dioxoisoindolin-2-yl)methyl)-2-hydroxy-N-(4-oxo-2-
substituted phenylthiazolidin-3-yl)benzamide (3a-h)
General procedure
A mixture N'-substituted phenyl-5-((1,3-dioxoisoindolin-2-yl) methyl)-2-hydroxybenzo
hydrazide (2a-h) (0.01 mole) in THF (50 mL) and mercapto acetic acid (thioglycolic acid)
(0.01 mole) with a pinch of anhydrous ZnCl2 was refluxed for 12 h. The solvent was then
removed to get a residue, which was dissolved in benzene and passed through a column of
silica gel using benzene: chloroform (8:2; v/v) mixture as eluent. The eluate was
concentrated and the product crystallized from alcohol to give 4-thiazolidinones (3a-h),
which were obtained in 52-65% yield. The yields, melting points and other characterization
data of these compounds are given in Table 2.
Table 2. Analytical data and elemental analysis of compounds (3a-h)
Elemental analysis
Molecular
%C
%H
%N
%S
formula,
(Mol.wt.)
Found Calcd. Found Calcd. Found Calcd. Found Calcd.
C25H19N3O5S
(473.50)
55 265 63.28 63.41 3.95 4.04 8.79 8.87 6.68 6.77
3a
3b
3c
3d
3e
3f
C25H19N3O6S
(489.50)
61 262 61.25 61.34 3.81 3.91 8.46 8.58
6.44 6.55
C25H19N3O6S
(489.50)
C26H21N3O6S
(503.53)
54 259 61.27 61.34 3.80 3.91 8.47 8.48
6 .43 6.55
64 260 61.95 62.02 4.11 4.20 8.32 8.35
6.31 6.37
C26H21N3O7S
(519)
65 264 60.02 60.11 3.98 4.07 8.02 8.09
6.11 6.17
C25H18ClN3O5S
(507.95)
58 263 59.04 59.11 3.47 3.57 8.21 8.27
6.25 6.31
C25H18N4O7S
(518.50)
52 261 56.58 56.67 3.42 3.50 10.75 10.81
6.04 6.18
3g
3h
C25H18N3O6S
(568.40)
60 258 52.79 52.83 3.07 3.19 7.26 7.39
5.58 5.64

1487
DHAMELIYA et al.
Preparation of (Z) –N-(5-benzylidene-4-oxo-2-substituted phenylthiazolidin-3-yl)-5-
((1,3-dioxoisoindolin-2-yl)methyl)-2-hydroxybenzamdie (4a-h)
An equimolar solution of 5-((1,3-dioxoisoindolin-2-yl) methyl)-2-hydroxy-N-(4-oxo-2-
substituted phenylthiazolidin-3-yl)benzamide (3a-h) and benzaldehyde in dioxane (40 mL)
in the presence of C2H5ONa were refluxed for about 3.5 h. The solvent was removed in
vacuo. The resulting product was recrystallized from methanol to yield compound (4a-h). The
yields, melting points and other characterization data of these compounds are given in Table 3.
Table 3. Analytical data and elemental analysis of compounds (4a-h)
Elemental analysis
% H %N
Found Calcd. Found Calcd. Found Calcd. Found Calcd.
Molecular
formula,
(Mol.wt.)
%C
%S
C32H23N3O5S
(514.61)
73 269 68.30 68.44 4.09 4.13 7.41 7.48 5.63 5.71
4a
4b
4c
4d
4e
4f
C32H23N3O6S
(577.61)
68 270 66.39 66.54 3.94 4.01 8.09 8.19 5.45 5.55
70 273 66.41 66.54 3.93 4.01 7.20 7.27 5.48 5.55
55 277 66.89 66.99 4.11 4.26 7.02 7.10 5.33 5.42
68 272 65.19 65.23 4.08 4.15 6.83 6.92 5.19 5.28
C32H23N3O6S
(577.61)
C33H25N3O6S
(591.63)
C33H25N3O7S
(607.63)
C32H22ClN3O5S
(596.05)
59 267 64.37 64.48 3.65
6.94 7.05 5.27 5.38
3.72
C32H22N4O7S
(606.60)
62 268 63.25 63.36 3.58 3.66 9.19 9.24 5.18 5.29
59 275 58.42 58.54 3.27 3.38 6.32 6.40 4.79 4.88
4g
4h
C32H22BrN3O6S
(656.50)
Results and Discussion
It was observed that 5-((1,3-dioxoisoindolin-2-yl)methyl-2-hydroxybenzohydrazide (1), on
condensation with aromatic aldehydes, yields N'-substitutedphenyl-5-((1,3-dioxoisoindolin-
2-yl)methyl)-2-hydroxybenzohydrazide (2a-h). The structures of (2a-h) were confirmed by
elemental analysis and IR spectra showing an absorption band at 3030-3080 cm-1 (C-H, of
Ar.), 1620-1640 (C=N), 1660-1670 cm-1 (-CONH), 3450-3550 cm-1 (-OH), 2810-2852 cm-1
1
(-OCH3). H NMR: 6.90 – 7.95 (9H, m) (Ar - H), 5.30-5.50 (1H, s) (-OH), 8.40-8.78 (1H, s)
(-CONH), 8.40-8.70 (1H, s) (-N=CH), 3.90 (3H, s) (-OCH3), 4.85 (2H, s) (CH2). The C, H, N
analysis data of all compounds are presented in Table 1.
The structures assigned to 5-((1,3-dioxoisoindolin-2-yl)methyl)-2-hydroxy-N-(4-oxo-2-
substituted phenylthiazolidin-3-yl)benzamide (3a-h) were supported by the elemental
analysis and IR spectra showing an absorption bands at 718 cm-1 (C-S-C of thiazolidinone
ring), 3075-3095 cm-1 (CH2 of thiazolidinone ring), 1690 cm-1 (C=O of thiazolidinone ring),
3030-3080 cm-1 (C-H, of Ar.), 3450-3550 cm-1 (-OH), 1660-1670 cm-1 (-CONH) for (3a)
compound. 1H NMR: 6.90-7.95 (9H, m) (Ar-H), 3.85-3.95 (2H, s) (-CH2 of the ring), 5.950-
5.959 (1H, s) (-CH), 8.20-8.22 (1H, s) (-CONH), 5.33-5.45 (1H, s) (-OH), 4.80 (2H, s)
(CH2), 3.92 (3H, s) (-OCH3). The C, H, N, S analysis data of all compounds are presented in
Table 2.

Synthesis and Biological Activity
1488
The IR spectra of (4a-h) are almost resemble those of the corresponding (3a-h) only
discernable difference observed that the new band (but not strong) at 1625 cm-1 (-C=CH-Ar)
1
is observed in all the spectra of (4a-h) Which might be responsible. H NMR: 6.90-7.95
(9H, m) (Ar-H), 7.75 (1H, s) (-CH), 8.20-8.28 (1H, s) (-CONH), 5.30-5.45 (1H, s) (-OH),
4.88 (2H, s) (CH2), 3.95 (3H, s) (-OCH3). The C, H, N, S analysis data of all compounds are
presented in Table 3.
The examination of elemental analytical data reveals that the elemental contents are
consistence with the predicted structure shown in Scheme 1. The IR data also direct for
assignment of the predicted structure. The final structure of all compounds is confirmed by
LC-MS. LC-MS data of samples 4b and 4e give the molecular ion peak (m/z) at 579 and 610
respectively. These values are corresponds to their molecular weight.
Biological screening
Antibacterial activities
The antibacterial activities of all the compounds were studied against gram-positive bacteria
(Staphylococcus aureus and Bacillus subtilis) and gram-negative bacteria (E.coli and
klebsiella promioe) at a concentration of 50 µg/mL by agar cup plate method. A methanol
system was used as control in this method. Similar conditions using tetracycline as a control
was used standard for comparison. The area of inhibition of zone measured in cm.
Compounds 3c, 3e, 3g, 4b, 4d and 4f were found more toxic for microbes. Other compounds
found to be less or moderate active than tetracycline Tables 4 & 5.
Table 4. Antibacterial activity of compounds (3a-h)
Gram +Ve Gram -Ve
Staphylococcus aureus Bacillus subtilis E.coli Klebsiella promioe
Compounds
55
53
63
54
64
63
70
63
62
51
60
70
57
65
54
59
61
69
68
55
61
60
68
61
69
55
81
53
65
62
56
71
67
68
64
78
3a
3b
3c
3d
3e
3f
3g
3h
Tetracycline
Table 5. Antifungal Activity of Compounds (3a-h)
Zone of Inhibition at 1000 ppm, %
Aspergillus
Nigrospora
Botrydepladia
Thiobromine
Rhizopus
Nigricum
Fusarium
oxyporium
Compounds
Sp.
72
63
59
61
60
70
63
62
Niger
71
58
61
59
73
65
71
68
64
69
67
60
59
69
63
70
64
68
67
69
70
63
69
65
69
68
3a
3b
3c
3d
3e
3f
60
61
63
58
62
68
3g
3h

1489
DHAMELIYA et al.
Antifungal activities
The fungicidal activity of all the compounds was studied at 1000 ppm concentration in vitro.
Plant pathogenic organisms used were Nigrospora Sp, Aspergillus niger, Botrydepladia
thiobromine, Rhizopus nigricum and Fusarium oxyporium. The antifungal activity of all the
compounds (3a-h) & (4a-h) were measured on each of these plant pathogenic strains on a
potato dextrose agar (PDA) medium. Such a PDA medium contained potato 200 g, dextrose
20 g, agar 20 g and water. Five days old cultures were employed. The compounds to be
o
tested were suspended (1000 ppm) in a PDA medium and autoclaved at 120 C for 15 min.
at 15 atm. pressure. These media were poured into sterile Petri plates and the organisms
were inoculated after cooling the Petri plates. The percentage inhibition for fungi was
calculated after five days using the formula given below:
Percentage of inhibition = 100(X-Y) / X
Where, X = Area of colony in control plate Y = Area of colony in test plate.
The fungicidal activity displayed by various compounds (3a-h) and (4a-h) is shown in
Tables 6 and 7.
Table 6. Antibacterial activity of compounds (4a-h)
Gram +Ve
Staphylococcus
Gram -Ve
Compounds
Bacillus
subtilis
56
E.coli Klebsiella promioe
aureus
54
70
62
69
64
71
63
71
60
56
68
56
68
60
68
61
69
62
55
76
4a
4b
68
61
67
64
4c
4d
69
54
57
68
4e
4f
70
61
69
69
63
61
4g
4h
Tetracycline
60
Table 7. Antifungal activity of compounds (4a-h)
Zone of Inhibition at 1000 ppm, %
Nigrospora Aspergillus Botrydepladia Rhizopus
Fusarium
Nigricum oxyporium
Compounds
Sp.
61
64
62
59
61
59
66
71
Niger
58
Thiobromine
63
70
68
60
68
68
67
64
52
63
74
60
71
73
69
65
61
59
68
71
63
69
68
69
4a
4b
4c
4d
4e
4f
64
71
62
59
64
73
4g
4h
63
Acknowledgment
The authors are thankful to P.S.Science and H. D. Patel Arts College, Kadi, Gujarat for
providing laboratory facilities.

Synthesis and Biological Activity
1490
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