Synthesis, characterization, and biological evaluation of some N-aryl hydrazones and their 2,3-disubstituted-4-thiazolidinone derivatives

Article abstract of DOI:10.1007/s00044-012-0028-8

A series of 2,3-disubstituted 4-thiazolidinones 6 and 8a-p have been prepared by the cyclo condensation reaction of various substituted N-aryl hydrazones 5 and 7a-p with mercapto acetic acid. The intermediate N-aryl hydrazones 5 and 7a-p were synthesized

Full text of DOI:10.1007/s00044-012-0028-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-012-0028-8
ORIGINAL RESEARCH
Synthesis, characterization, and biological evaluation
of some N-aryl hydrazones and their 2,3-disubstituted-4-
thiazolidinone derivatives
•
Chidananda Nandagokula Boja Poojary Sumangala Vittal
•
•
•
Shalini Shenoy Prashanth Shetty Arulmoli Tangavelu
•
Received: 28 September 2011 / Accepted: 10 March 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A series of 2,3-disubstituted 4-thiazolidinones
6 and 8a-p have been prepared by the cyclo condensation
reaction of various substituted N-aryl hydrazones 5 and 7a–
p with mercapto acetic acid. The intermediate N-aryl
hydrazones 5 and 7a–p were synthesized by the conden-
sation of 2-bromo-5-methoxy benzohydrazide 4 with 2 or
various substituted aromatic aldehydes. The new Naph-
thalene-2-carboxaldehyde 2 has been synthesized by Vils-
meier-Haack reaction of naphthalen-1(2H)-one 1. The key
starting compound 2-bromo-5-methoxy benzohydrazide 4
was prepared from methyl 2-bromo-5-methoxybenzoate 3
by the reaction with hydrazine hydrate in alcoholic med-
ium. The formulae of the compounds were confirmed by
elemental analyses and their structures were determined
Bacillus cereus, while the antifungal activities of the
compounds against Candida albicans were tested. The
acute cytotoxicity data of compounds 7h and 8a are tested
and are found to be nontoxic up to 2,500 mg/kg.
Keywords N-aryl hydrazones ꢀ
2,3-Disubstituted-4-thiazolidinones ꢀ Anti-oxidant activity ꢀ
Anti-inflammatory activity ꢀ Analgesic activity ꢀ
Anti-microbial activities
Introduction
Five membered ring heterocycles containing nitrogen,
sulfur, and oxygen have been under investigation for a long
time because of their important medicinal properties.
Among these types of molecules, 2,3-disubstituted-4-thia-
zolidinones have been shown to have various important
biological activities (Capan et al., 1999; Vigorita et al.,
2001; Kavitha et al., 2006; Kucukguzel et al., 2006).
Compounds carrying the thiazolidinone ring have been
reported to demonstrate a wide range of pharmacological
activities which include antibacterial (Kalaiya and Parikh,
1987), antifungal (Liu et al., 2000), antiviral (Elbarbary
et al., 1994), diuretic (Harris and Turnbull, 1977; Raikwar
et al., 2008), antituberculostatic (Monian et al., 1993), anti-
HIV (Rao et al., 2004), antihistaminic (Vittoria et al.,
1992), anticancer (Dayam et al., 2006), anticonvulsant
(Rydzik et al., 1984; Troutman and Long, 1948), anti-
inflammatory (Ottana et al., 2005), and analgesic proper-
ties. Thiazolidinones possess antibacterial activity because
they contain b-lactam ring with sulfur atom in it and
derivatives inhibit the biosynthesis of the peptidoglycan
polymer essential for cell wall of bacteria on inactivation
of MurB enzyme. MurB enzyme is a unique target for
1
based on IR, H-NMR, 13C-NMR, 13C-NMR-DEPT, and
mass spectral data. The newly synthesized compounds
were evaluated for their antioxidant, anti-inflammatory,
and analgesic activities. The antibacterial activities of the
newly synthesized compounds against E. coli ATCC 8739,
S. aureus ATCC 6538, P. aeruginosa ATCC 1539, and
C. Nandagokula ꢀ B. Poojary (&) ꢀ S. Vittal
Department of Studies in Chemistry, Mangalore University,
Mangalagangothri, Karnataka 574 199, India
e-mail: bojapoojary@gmail.com
C. Nandagokula ꢀ S. Vittal ꢀ A. Tangavelu
SeQuent Scientific Limited, No. 120 A&B, Industrial Area,
Baikampady, New Mangalore 575 011, Karnataka, India
S. Shenoy
Department of Microbiology, Kasturba Medical College,
Mangalore 575 001, Karnataka, India
P. Shetty
NGSM Institute of Pharmaceutical Sciences, Deralakatte,
Mangalore 574 160, Karnataka, India
123

Med Chem Res
antibacterial activity of thiazolidinone (Fuloria et al., 2009;
Patel and Patel, 2010). In our literature search, we found
that Mannich bases of 2,3-disubstituted 4-thiazolidinones
had antimicrobial activities (Kupinic et al., 1979; Pandeya
et al., 1999, 2000) besides various other activities.
inflammatory, analgesic, antibacterial, and antifungal
activities. Toxicity study of the biologically active com-
pounds 7h and 8a are tested and are found to be nontoxic
up to 2,500 mg/kg.
Antioxidant activity (AOA) is a very important param-
eter used to characterize different plant materials. This
activity is related with compounds capable of protecting a
biological system against the potential harmful effects of
oxidative processes. Antioxidants have received increased
attention in the last years from nutritionists and medical
researchers for their potential activities in the prevention of
several degenerative diseases such as cancer and cardio-
vascular disorder, as well as aging (Ames et al., 1993;
Hertog et al., 1993; Peters et al., 2007). In recent years,
several works have been published on structure-activities
analysis on compounds with antioxidant activities.
Results and discussion
Chemistry
Synthetic pathway for the preparation of title compounds is
depicted in Schemes 1 and 2. The new 1-chloro-4-(3,
4-dichlorophenyl)-3,4-dihydronaphthalene-2-carbaldehyde
2 has been synthesized by Vilsmeier-Haack reaction of
4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1(2H)-one 1
and X-ray crystallographic data was recorded (Chidananda
et al., 2011). 2-bromo-5-methoxy benzohydrazide was
obtained by the reaction of 2-bromo-5-methoxy methyl
benzoate 3 with hydrazine hydrate in alcohol medium. The
intermediate N-aryl hydrazones 5 and 7a–p were synthe-
sized by the condensation reaction of 2-bromo-5-methoxy
benzohydrazide 4 with newly synthesized compound 2 or
various substituted aromatic aldehydes in the presence of
catalytic amount of anhydrous ZnCl2 in toluene medium.
The target molecules 2-bromo-N-[2-(substituted phenyl)-
4-oxo-1,3-thiazolidin-3-yl]-5-methoxybenzamides 6 and
The present report describes the synthesis of the title
compounds and the evaluation of their antioxidant, anti-
POCl3, DMF
Cl
O
Cl
Cl
O
60 C60 C
Cl
Cl
(1)
(2)
Scheme 1 Synthetic scheme of carbaldehyde (2)
OCH3
H3CO
Scheme 2 Synthetic scheme of
N-aryl hydrazones (5, 7a–p) and
their 2,3-disubstituted
O
4-thiazolidinones (6, 8a–p)
Br
(3)
reflux, 3 hrs
N2H4/EtOH
Cl
Cl
O
NH2
O
N
NH
O
Br
CHO /ZnCl2
Toluene, reflux
Cl
R1
Br
NH
R1
(2)
OCH3
OCH3
(4)
(7a-p)
O
NH
Toluene, reflux
R1
SHCH2CO2H, ZnCl2
Cl
N
Br
OCH3
SHCH2CO2H, ZnCl2
H3CO
Cl
S
H3CO
NH
N
O
N
S
Cl
Toluene, reflux
(5)
Br
Cl
O
O
NH
O
Br
(8a-p)
Cl
Cl
(6)
123

Med Chem Res
8a–p were prepared by the cyclo-condensation of 5 and
7a–p with mercapto acetic acid in the presence of anhy-
drous ZnCl2 in toluene medium. Formation of the products
6 and 8a–p may be rationalized by the mechanism shown
in Scheme 3.
pattern. The signal due to CH carbon of fused cyclohexene
ring showed at d, 41.99 ppm. The signal due to OCH3
carbon of bromophenyl ring appeared at d, 55.71 ppm. The
peak due to CH carbon of thiazolidinone ring appeared at
d, 60.14 ppm. The peaks due to non-quaternary carbon
atoms of the compounds were observed at d, 114.98,
118.55, 125.79, 126.01, 127.52, 128.11, 129.87, 130.23,
130.45, and 134.30 ppm. The LC mass of the compound
was also in agreement with the assigned structure.
All new compounds were characterized on the basis of
spectroscopic (1H-NMR, IR and MS) and analytical data.
The physicochemical properties and CHN analytical data
of synthesized compounds are presented in Table 1.
In the IR spectrum of the compound 6, the NH
stretching was observed at 3459.68 cm-1. The carbonyl
The formation of thiazolidinone compound 8a was
confirmed by their elemental analyses, IR, and NMR data.
IR spectrum of 8a showed absorption bands at
3461.2 cm-1 for its NH group. The carbonyl stretch of
thiazolidinone ring observed at 1722.3 cm-1. The absorp-
tion bands due to aromatic C=C bonds were appeared at
stretch of thiazolidinone ring appeared at 1696.42 cm-1
,
the C=C stretching of aromatic ring observed at
1475.2 cm-1. The C–Cl stretching of dichlorophenyl ring
observed at 816.89 cm-1 and C–Br stretching of 2-bromo-
5-methoxy phenyl ring appeared at 766.2 cm-1. The for-
mation of compound 6 was also confirmed by its 1H-NMR
spectral values. The 1H-NMR spectrum showed sharp
singlet at d, 8.65 ppm due to NH proton. The 10 aromatic
protons resonated as a complex multiplet in the region of d,
6.20–7.73 ppm. The –CH proton of thiazolidinone ring
appeared as a sharp singlet at d, 5.88 ppm. The –CH proton
of fused cyclohexene ring resonated as complex multiplet
at d, 4.15 ppm. The two protons of –CH2 of thiazolidinone
ring appeared as a sharp singlet at d, 3.71 ppm. The –CH2
proton of fused cyclohexene ring resonated as a complex
multiplet at d, 2.98 ppm. The further evidence for the
formation of the product was obtained by 13CNMR-DEPT-
135 spectral details. The signal due to CH2 carbon of fused
cyclohexene ring observed at d, 29.59 ppm in negative
phase. Similarly, the peaks due to CH2 carbon of thiazo-
lidinone ring appeared at d, 31.74 ppm in downward
1473.4 cm-1
. The absorption bands at 764.6 and
731.8 cm-1 are due to the presence of C–Br and C–Cl
groups, respectively. While, its 1H-NMR spectrum showed
sharp singlet at d, 7.92 ppm due to NH proton. The one
aromatic proton resonated as doublet at d, 7.5 ppm with a
coupling constant of 7.29 Hz. The other four aromatic
protons resonated as complex multiplet in the region d,
7.26–7.40 ppm. The one more aromatic proton appeared as
doublet at d, 7.04 ppm with a coupling constant of 2.9 Hz.
Another aromatic proton resonated as doublet of doublet at
d, 6.79–6.82 with a coupling constant of 2.9 Hz and
2.9 Hz, respectively. The –CH proton thiazolidinone ring
resonated as a sharp singlet at d, 6.55 ppm. The singlet of
CH2 proton of thiazolidinone ring appeared at d, 3.80 ppm.
The OCH3 proton appeared as a sharp singlet at d,
3.74 ppm. 13C-NMR spectrum of 8a showed signals at d,
29.80, 55.71, and 59.38 ppm due to CH2 carbon of
Scheme 3 Mechanism of
formation of the compounds 6
and 8a–p
H
..
H
CH3
N
OCH3
Br
CH3
H
O
O
H2N
HN
O
Br
O
HO
Ar
H
NH
Br
O
Ar
H
NH2
..
Br
N
O
H
N
N
-CH3OH
+
O
OCH3
H
H
OCH3
OCH3
-H2O
H
O
S
OCH3
OCH3
..
N
O
N NH
CO2H
Ar
H
NH
O
S
NH
N
Ar O
..
S
Ar
+
Br
OCH3
-H2O
HO
Br
O
Br
H
Cl
Where, Ar =
,
Cl
R1
Cl
123

Med Chem Res
Table 1 Characterization data of compounds 2, 4, 5, 6, (7a–p) and (8a–p)
Comp. R1
Mol. formula
Mol. wt. m.p. (°C)
Yield (%) Analysis found (calculated) (%)
C
H
N
2
–
C17H11Cl3O
C8H9BrN2O2
337.63
245.07
564.68
108–110 97
60.47 (60.48) 3.26 (3.28)
–
4
–
190–192 98
164–166 95
242–244 68
214–216 92
234–236 94
210–212 92
198–200 90
202–204 91
206–208 89
164–166 88
162–164 95
180–182 86
196–198 87
232–234 62
192–194 76
176–178 82
156–158 89
160–162 84
188–190 68
144–146 89
208–210 86
152–154 75
182–184 78
128*–130 80
134–136 84
150–152 74
190–192 82
220–222 85
178–180 79
248–250 65
180–182 78
192–194 78
198–200 71
234–236 82
240–242 76
39.28 (39.20) 3.77 (3.70) 11.48 (11.43)
5
–
C
C
25H18BrCl3N2O2
53.21 (53.17) 3.24 (3.21)
50.75 (50.77) 3.12 (3.16)
49.03 (49.01) 3.23 (3.29)
49.06 (49.01) 3.34 (3.29)
49.05 (49.01) 3.31 (3.29)
51.86 (51.92) 4.40 (4.36)
52.87 (52.91) 4.09 (4.16)
52.89 (52.91) 4.12 (4.16)
4.93 (4.96)
4.42 (4.39)
7.65 (7.62)
7.58 (7.62)
7.61 (7.62)
7.18 (7.12)
7.76 (7.71)
7.75 (7.71)
6
–
27H20BrCl3N2O3S 638.78
7a
7b
7c
7d
7e
7f
3-Cl–C6H4
4-Cl–C6H4
2-Cl–C6H4
2,4-diOCH3–C6H3
4-OCH3–C6H4
2-OCH3–C6H4
4-NO2–C6H4
C6H5
C15H12BrClN2O2
C15H12BrClN2O2
C15H12BrClN2O2
C17H17BrN2O4
C16H15BrN2O3
C16H15BrN2O3
C15H12BrN3O4
C15H13BrN2O3
C21H17BrN2O2
C16H15BrN2O2
C14H12BrN3O2
C15H12BrFN2O2
C20H17BrN2O3
C15H13BrN2O3
C15H13BrN2O3
367.62
367.62
367.62
393.23
363.20
363.20
378.18
333.18
409.27
347.20
334.17
351.17
413.26
349.20
349.20
379.20
441.72
441.72
441.72
467.33
437.31
437.31
452.28
407.28
483.37
421.31
408.27
425.27
487.36
423.28
423.28
453.30
7g
7h
7i
47.68 (47.64) 3.27 (3.20) 11.17 (11.11)
54.01 (54.07) 3.89 (3.93)
61.57 (61.63) 4.16 (4.19)
55.31 (55.35) 4.29 (4.35)
8.48 (8.41)
6.79 (6.84)
8.13 (8.07)
C
12H9
7j
4-Me–C6H4
C6H4N
7k
7l
50.28 (50.32) 3.66 (3.62) 12.54 (12.57)
4-F–C6H4
51.29 (51.30) 3.46 (3.44)
58.17 (58.13) 4.12 (4.15)
51.63 (51.60) 3.77 (3.75)
51.58 (51.60) 3.72 (3.75)
50.65 (50.68) 3.97 (3.99)
46.28 (46.22) 3.23 (3.19)
46.27 (46.22) 3.14 (3.19)
46.28 (46.22) 3.23 (3.19)
48.90 (48.83) 4.15 (4.10)
49.41 (49.44) 3.95 (3.92)
49.41 (49.44) 3.95 (3.92)
45.20 (45.15) 3.17 (3.12)
50.15 (50.13) 3.74 (3.71)
57.19 (57.15) 3.92 (3.96)
51.37 (51.31) 4.16 (4.07)
8.02 (7.98)
6.81 (6.78)
8.05 (8.02)
8.05 (8.02)
7.43 (7.39)
6.30 (6.34)
6.29 (6.34)
6.30 (6.34)
5.94 (5.99)
6.38 (6.41)
6.38 (6.41)
9.34 (9.29)
6.84 (6.88)
5.76 (5.80)
6.62 (6.65)
7m
7n
7o
7p
8a
8b
8c
8d
8e
8f
6-OCH3-2-naphthyl
2-OH–C6H4
4-OH–C6H4
4-OH–3–OCH3–C6H3 C16H15BrN2O4
3-Cl–C6H4
C17H14BrClN2O3S
C17H14BrClN2O3S
C17H14BrClN2O3S
C19H19BrN2O5S
C18H17BrN2O4S
C18H17BrN2O4S
C17H14BrN3O5S
C17H15BrN2O3S
C23H19BrN2O3S
C18H17BrN2O3S
C16H14BrN3O3S
C17H14BrFN2O3S
C22H19BrN2O4S
C17H15BrN2O4S
C16H14BrN3O3S
C18H17BrN2O5S
4-Cl–C6H4
2-Cl–C6H4
2,4-diOCH3–C6H3
4-OCH3–C6H4
2-OCH3–C6H4
4-NO2–C6H4
C6H5
8g
8h
8i
C
12H9
8j
4-Me–C6H4
8k
8l
C6H4N
47.11 (47.07) 3.48 (3.46) 10.26 (10.29)
4-F–C6H4
48.04 (48.01) 3.35 (3.32)
54.20 (54.22) 3.90 (3.93)
48.27 (48.24) 3.60 (3.57)
48.26 (48.24) 3.55 (3.57)
47.73 (47.69) 3.75 (3.78)
6.64 (6.59)
5.72 (5.75)
6.58 (6.62)
6.58 (6.62)
6.16 (6.18)
8m
8n
8o
8p
6-OCH3–2-naphthyl
2-OH C6H4
4-OH–C6H4
4-OH–3-OCH3–C6H3
DPPH radical scavenging activity
thiazolidinone ring, OCH3 carbon of bromophenyl ring and
CH carbon of thiazolidinone ring, respectively. The other
carbon atoms showed signals at 169.82, 165.34, 158.83,
134.90, 134.77, 134.33, 133.97, 130.47, 130.37, 128.99,
127.67, 118.93, 115.14, and 109.57 ppm. The peaks due to
the quaternary carbon atoms of the compounds were dis-
appeared on DEPT-135 13C-NMR spectrum. The LC mass
of the compound 443 (m ? 1) was also in agreement with
the assigned structure.
The synthesized compounds screened for their in vitro
AOA by DPPH scavenging method showed moderate to
good activity. Among all the synthesized compounds
8a–8c, 8e, and 8o showed significant AOA compared to
that of the standard ascorbic acid. The significant activity
of these compounds may be attributed due to the presence
of electron-withdrawing chlorine and electron-donating
123

Med Chem Res
Antifungal activity studies
hydroxyl and methoxy substitution in the phenyl rings.
Compounds 8k, 8l, and 8m have moderate activities. These
compounds contain 3-pyridyl, 4-fluoro phenyl, and
6-methoxy naphthyl groups, respectively, in their structure.
The remaining compounds 8d, 8f–j, 8n, and 8p have
insignificant activities.
The antifungal screening data revealed that all the newly
synthesized compounds were potent anti fungal agents. The
compounds 7h and 8a showed 5-fold more activity than the
standard drug flucanozole against Candida albicans fungal
strain. The compounds 7b, 7g, 7k, 7o, 8d, 8k, and 8n are
potent anti-fungal agents against Candida albicans fungal
strain. The compounds 5, 6, 7a, 7c, 7d–7f, 7j, 7n, 8c, 8e–
8m, and 8o showed moderate activity compared to standard
drug fluconazole.
Anti-inflammatory activity studies
The compounds 8g, 8i, 8j, 8k, 8m, and 8p containing
4-nitro phenyl, biphenyl, 4-methyl phenyl, pyridyl,
6-methoxy-2-naphthyl, and 4-hydroxy-3-methoxy phenyl
substituent’s, respectively, are the most potent agents of
this series against rat-foot inflammation. The compounds
8a, 8e, and 8h containing 3-chloro phenyl, 4-methoxy
phenyl and phenyl substituent’s, respectively, showed good
anti-inflammatory activity.
Acute toxicity study
The compounds 7h and 8a were tested for acute toxicity
test by following the OECD guidelines. No deaths of ani-
mals were observed at the doses of 500, 1000, 1500, 2000,
and 2500 mg/kg of body weight, and also no significant
behavioral changes were observed in experimental animals.
Analgesic activity studies
The analgesic activity study revealed that the compounds
6, 8g, 8h, 8i, 8k, 8l, 8n and 8p having 4-chloro-1-(3,4-
dichlorophenyl)-1,2-dihydronaphthalene, 4-nitro phenyl,
phenyl, biphenyl, pyridyl, 4-fluoro phenyl, 2-hydroxy
phenyl, and 4-hydroxy-3-methoxy phenyl substituent’s
showed good activity compared to the standard drug pen-
tazocin. This suggests that electron diminishing, bulkier
and electron releasing groups are responsible for the
activity. The compound 8d containing 2,4-dimethoxy
phenyl substituent showed moderate activity compared to
standard drug.
Conclusion
Several 2-bromo-5-methoxy-benzoyl-N-aryl hydrazones
and 2-bromo-N-[2-(substituted phenyl)-4-oxo-1,3-thiazoli-
din-3-yl]-5-methoxybenzamides successfully synthesized
in 65–90 % yields and are characterized by 1H-NMR, 13C-
NMR, Mass spectrometry, and IR studies. The antioxidant
property was evaluated using DPPH radical scavenging
assay. Compounds 8c, 8d, and 8i showed significant AOA.
These compounds substituted with 2-chloro phenyl, 2,4-
dimethoxy, and phenyl groups at position-2 of thiazolidi-
none ring showed higher AOA compared to others. The
remaining compounds showed moderate antioxidant
activities. The anti-inflammatory and analgesic activity
study showed that majority of the synthesized compounds
exhibit significant activities.
Antibacterial activity studies
The investigation of antibacterial screening data revealed
that all the tested compounds 4, 7a–p, and 8a–p showed
moderate to good activity. The compounds 7b, 7e, 7f, 8b,
and 8c showed very good activity toward P. aeruginosa
bacterial strain compared to standard drug penicillin. The
compounds 5, 6, 7a, 7c, 7d, 7g, 7i, 7k, 7l, 7n, 7o, 8a, 8d,
8e, 8f, 8i, 8k, 8m, 8n, 8o, and 8p good activity toward
P. aeruginosa bacterial strain. The compounds 7k and 8k
showed comparatively good activity against all the four
bacterial strains. The compounds 7g and 8i showed good
activity against E. coli, P. aeruginosa, and Bacillus cereus
bacterial strains. The compounds 7c and 7d showed good
activity against E. coli and P. aeruginosa. The compounds
8a and 8d showed good activity against P. aeruginosa and
Bacillus cereus bacterial strains. The compounds 8e, 8f,
and 8g showed good activity against Staphylococcus aureus,
P. aeruginosa, and Bacillus cereus bacterial strains.
All the newly synthesized compounds were screened for
antibacterial and antifungal activities. The antibacterial
activity study revealed that all the compounds tested
showed moderate to good antibacterial activity. The anti-
fungal activity study revealed that the compounds 7h and
8a showed 5-fold more active than the standard drug
fluconazole. Structure and biological activity relationship
of these compounds showed that the presence of phenyl
methylene group in N-aryl hydrazone and 3-chloro phenyl
group attached to position-2 of thiazolidinone ring of the
title compounds are responsible for good antifungal activ-
ity. The screening data showed that the newly synthesized
compounds have shown promising antibacterial and anti-
fungal activities against the screened organisms. Toxicity
of the compounds 7h and 8a which showed potent
123

Med Chem Res
General procedure for the conventional synthesis of 2-
antifungal activity was tested and these compounds are
found to be non toxic up to 2,500 mg/kg dose.
bromo-5-methoxy-benzoic acid hydrazide (4)
A mixture of 2-bromo-5-methoxy-benzoic acid methyl
ester 3 (0.01 mol) in ethyl alcohol and hydrazine hydrate
(0.01 mol) were refluxed for 4 h. The completion of
reaction was monitored by TLC. After reaction completion
the excess solvent was removed by distillation. The reac-
tion mass was then cooled to 5 °C, the solid separated was
filtered, dried, and recrystallized from ethyl alcohol.
C8H9BrN2O2, m.p. 190–192, yield: 98 %; FT-IR (KBr)
cm-1: 3352.4 (–NH2 Stretch), 3230.3 ([NH Stretch), 2845
(–OCH3), 1640.65 ([C=O stretch), 764 ([C–Br). 1H-
NMR: (CDCl3, d/ppm, 400 MHz), 9.52 (s, 1H, NH),
7.49–7.52 (d, 1H, ArH, J = 8.67 Hz), 6.94–6.95 (d, 1H,
ArH, J = 3.09 Hz), 6.89–6.92 (m, 1H, ArH), 4.45 (s, 2H,
–NH2), 3.77 (s, 3H, –OCH3). 13C-NMR: (CDCl3, d/ppm,
400 MHz), 166.32, 159.45, 131.39, 129.13, 121.91,
119.42, 113.73, 55.04 (OCH3 carbon), DEPT: 121.87,
119.39, 113.69, 55.01(OCH3 carbon). LCMS m/z: 246
(m ? 1, mol. wt. = 245.07, C8H9BrN2O2).
Experimental
Materials and methods
All solvents were of analytical grade and the reagents were
used as purchased. All melting points were determined by
open capillary method and are uncorrected. IR spectra were
obtained in KBr disk on a Shimadzu FT-IR 157 spec-
1
trometer. H-NMR and 13C-NMR spectra were recorded
either on a Perkin-Elmer EM-390 or on a Bruker WH-200
(400 or 300 MHz) in CDCl3 or DMSO-d6 as solvent, using
TMS as an internal standard and chemical shifts are
expressed as ppm. Mass spectra were determined on a Jeol
SX 102/Da-600 mass spectrometer/Data System using
Argon/Xenon (6 kv, 10 mA°) as the FAB gas. The accel-
erating voltage was 10 kV and spectra were recorded at
room temperature. The LCMS were recorded in MDSS-
CIEX, API 4000 spectrometer. The elemental analyses
(CHN) were performed on CHNS-O-analyzer Flash EA
1112 series. The progresses of the reactions were moni-
tored by TLC on pre-coated silica gel G plates.
General procedure for the conventional synthesis of 2-
bromo-N0-[(1E)-(substituted phenyl) methylene]-5-
methoxybenzohydrazide (5) and (7a-p)
All the spectral data’s of newly synthesized compounds
are consistent with proposed structure and microanalysis
within 0.3 of the calculated values.
A mixture of 2-bromo-5-methoxy-benzoic acid hydrazide 4
(0.01 mol) and 2/different substituted aromatic aldehydes
(0.01 mol) in toluene were refluxed in the presence of
ZnCl2 for 8 h. The completion of reaction was monitored
by TLC. After reaction completion, the reaction mass was
cooled to 0 °C and the solid separated was filtered, washed
with chilled toluene, and dried. The crude product was
purified by recrystallisation from ethyl alcohol.
General procedure for the synthesis of 1-chloro-4-(3,4-
dichlorophenyl)-3,4-dihydronaphthalene-2-
carbaldehyde (2)
To the Vilsmeier-Haack complex prepared from DMF and
POCl3 (0.03 mol) at 0 °C, the compound 1 (0.01 mol) was
added and the reaction mixture was stirred at 65 °C for 4 h.
The reaction completion was monitored by TLC. The
contents were cooled, poured into ice-cold water and
neutralized using Na2CO3 solution. The solid product that
separated was filtered, washed with cold water, and dried.
The crude product was recrystallized from ethyl acetate.
C17H11Cl3O, m.p. 108–110, yield 97 %; FT-IR (KBr)
cm-1: 3443.28 (–CHO), 1662.34 (C=O of aldehyde),
1595.81 (C=C, aromatic), 838.883 (C–Cl), 1255.43 (C–H
stretch). 1H-NMR (CDCl3, d/ppm, 300 MHz), 10.33 (s, 1H,
–CHO), 7.96-8.00 (m, 1H, dichloro phenyl ring), 7.34–7.45
(m, 3H, Benzene ring), 7.18–7.19 (d, J = 2.1 Hz, 1H,
dichloro phenyl ring), 6.92–6.98 (m, 1H of dichloro phenyl
ring and 1H of benzene ring), 4.13 (t, J = 7.5 Hz, 1H, –CH
proton of fused cyclohexene ring), 2.86–3.01(m, 2H, –CH2
proton of fused cyclohexene ring). LCMS m/z: 337 (M?,
mol. wt. = 337.63, C17H11Cl3O).
2-Bromo-N0-[(1Z)-(1-chloro-4-(3,4-dichlorophenyl)-
1,2,3,4-tetrahydronaphthalene) methylene]-5-
methoxybenzohydrazide (5)
C25H18BrCl3N2O2, m.p. 164–166, yield: 95 %; FT-IR
(KBr) cm-1: 3159.79 (NH), 822.491 (C–Cl) cm-1 1H-
.
NMR: (CDCl3, d/ppm, 400 MHz), 9.41 (s, 1H, NH proton),
8.50 (s, 1H,–CH=N proton), 7.81 (d, J = 8.06 Hz, 1H,
Benzene ring), 7.26–7.41 (m, 2H, Benzene ring), 7.12 (d,
J = 8.4 Hz, 1H, Dichloro phenyl ring), 6.76–7.47 (m, 9H,
ArH protons), 4.17 (t, J = 7.25 Hz, 1H, –CH proton of
fused cyclohexene ring), 3.78 (s, 3H, OCH3 protons),
2.67–3.32 (m, 2H, –CH2 proton of fused cyclohexene ring).
13CNMR (100 MHz, CDCl3): 163.44, 158.98, 146.48,
142.74, 138.92, 136.17, 134.98, 133.21, 132.41, 130.33,
130.08, 129.82, 129.77, 128.51, 128.04, 127.64, 127.13,
125.77(–CH=N), 118.65, 117.22, 115.24, 114.18, 109.68,
55.70 (OCH3 carbon of bromophenyl ring), 42.38 (CH
123

Med Chem Res
2-Bromo-N0-[(1Z)-(2,4-dimethoxyphenyl) methylene]-
5-methoxybenzohydrazide (7d)
carbon of fused cyclohexene ring), 31.24 (CH2 carbon of
fused cyclohexene ring). 13CNMR-DEPT-135 (100 MHz,
CDCl3): 146.48, 134.34, 130.33, 130.09, 129.82, 127.64,
127.13, 125.77(–CH=N), 118.65, 117.22, 114.17, 55.70
(OCH3 carbon of bromophenyl ring), 42.38 (CH carbon of
fused cyclohexene ring), 31.04 (CH2 carbon of fused
cyclohexene ring). LCMS m/z: 565 (m ? 1, mol.
wt. = 564.68, C25H18BrCl3N2O2).
C16H15BrN2O3, m.p. 206-208, yield: 89 %; FT-IR (KBr)
cm-1: 3220.2 ([NH stretch), 2848.2(-OCH3), 1720.1
([C=O stretch), 1668.4 (C=N stretch), 1602.6 (NH bend),
1571.4 ([C=C\ of aromatic ring), 763.5 ([C–Br). 1H-
NMR: (CDCl3, d/ppm, 400 MHz), 11.74 (s, 1H, [NH),
8.20 (s, 1H, =CH), 6.8809-7.67(m, 6H, ArH), 3.82 (s, 3H,
OCH3, 2,4-dimethoxy benzyl), 3.79 (s, 3H, –OCH3), 3.77
(s, –OCH3, 2,4-dimethoxy benzyl). LCMS m/z: 364
(m ? 1, mol. wt. = 363.20, C16H15BrN2O3).
2-Bromo-N0-[(1Z)-(3-chlorophenyl) methylene]-5-
methoxybenzohydrazide (7a)
C15H12BrClN2O2, m.p. 214–216, yield: 92 %; FT-IR (KBr)
cm-1: 3232.6 ([NH Stretch), 2844.2(–OCH3), 1658.2
([C=O stretch), 1590.6 ([NH bend), 1530.8 ([C=C\of
2-Bromo-5-methoxy-N0-[(1Z)-(4-methoxyphenyl)
methylene] benzohydrazide (7e)
1
aromatic ring), 766.3 ([C–Br), 763.1 (C–Cl). H-NMR:
C16H15BrN2O3, m.p. 202–204, yield: 91 %; FT-IR (KBr)
cm-1: 3215.9 ([NH stretch), 2845.3(–OCH3), 1715.2
([C=O stretch), 1665.9 (C=N stretch), 1600.8 (NH bend),
1569.0 ([C=C\ of aromatic ring), 764.8 ([C–Br). 1H-
NMR: (CDCl3, d/ppm, 400 MHz), 11.72 (s, 1H, [NH),
8.17 (s, 1H, =CH), 6.88–7.65(m, 7H, ArH), 3.78 (s, 3H,
–OCH3), 3.74 (s, –OCH3, p-methoxy benzyl). LCMS m/z:
364 (m ? 1, mol. wt. = 363.20, C16H15BrN2O3).
(CDCl3, d/ppm, 400 MHz), 11.97 (s, 1H,[NH), 8.26 (s, 1H,
=CH), 6.94–7.78(m, 7H, ArH), 3.80 (s, 3H, –OCH3). LCMS
m/z: 369 (m ? 2, mol. wt. = 367.62, C15H12BrClN2O2).
2-Bromo-N0-[(1Z)-(4-chlorophenyl) methylene]-5-
methoxybenzohydrazide (7b)
C15H12BrClN2O2, m.p. 234–236, yield: 94 %; FT-IR (KBr)
cm-1: 3230.3 ([NH Stretch), 2845(–OCH3), 1655.8
([C=O stretch), 1599.4 ([NH bend), 1525.0 ([C=C\ of
aromatic ring), 764 ([C–Br), 757.3 (C–Cl). 1H-NMR:
(CDCl3, d/ppm, 400 MHz), 11.95 (s, 1H, [NH), 8.24 (s,
1H, =CH), 6.93–7.75(m, 7H, ArH), 3.78 (s, 3H, –OCH3).
LCMS m/z: 369 (m ? 2, mol. wt. = 367.62, C15H12
BrClN2O2).
2-Bromo-5-methoxy-N0-[(1Z)-(2-methoxyphenyl)
methylene] benzohydrazide (7f)
C16H15BrN2O3, m.p. 206–208, yield: 89 %; FT-IR (KBr)
cm-1: 3220.2 ([NH stretch), 2848.2(–OCH3), 1720.1
([C=O stretch), 1668.4 (C=N stretch), 1602.6 (NH bend),
1571.4 ([C=C\ of aromatic ring), 763.5 ([C–Br). 1H-
NMR: (CDCl3, d/ppm, 400 MHz), 11.74 (s, 1H, [NH),
8.20 (s, 1H, =CH), 6.89–7.67(m, 7H, ArH), 3.79 (s, 3H,
–OCH3), 3.77 (s, –OCH3, p-methoxy benzyl). LCMS m/z:
364 (m ? 1, mol. wt. = 363.20, C16H15BrN2O3).
2-Bromo-N0-[(1Z)-(2-chlorophenyl) methylene]-5-
methoxybenzohydrazide (7c)
C15H12BrClN2O2, m.p. 234–236, yield: 94 %; FT-IR (KBr)
cm-1: 3230.8 ([NH Stretch), 2845.4(–OCH3), 1658.7
([C=O stretch), 1600.4 ([NH bend), 1529.3 ([C=C\ of
2-Bromo-5-methoxy-N0-[(1Z)-(4-nitrophenyl)
methylene] benzohydrazide (7g)
1
aromatic ring), 764.8 ([C–Br), 758.4 (C–Cl). H-NMR:
(CDCl3, d/ppm, 400 MHz), 12.09 (s, 1H, [NH), 8.69 (s,
1H, =CH), 8.01–8.03 (m, H, ArH of 2-bromo-5-methoxy
phenyl ring), 7.33–7.58 (m, 4H, ArH protons of 2-chloro
phenyl ring), 7.16 (d, 1H, ArH proton of 2-bromo-5-
methoxy phenyl ring, J = 2.72 Hz), 7.01 (dd, 1H, ArH
proton of 2-bromo-5-methoxy phenyl ring, J = 6.08 and
2.92 Hz), 3.78 (s, 3H, –OCH3). 13CNMR (100 MHz,
CDCl3): 169.67, 163.63, 158.96, 144.49, 140.77, 134.24,
132.15, 130.40, 128.10, 127.39, 118.02, 117.09, 115.25,
109.72, 56.21 (OCH3 carbon of bromophenyl ring).
13CNMR-DEPT-135 (100 MHz, CDCl3): 144.49, 140.77,
134.24, 132.15, 130.40, 128.10, 117.09, 115.25, 56.21
(OCH3 carbon of bromophenyl ring). LCMS m/z: 369
(m ? 2, mol. wt. = 367.62, C15H12BrClN2O2).
C15H12BrN3O4, m.p. 164–166, yield: 88 %; FT-IR (KBr)
cm-1: 3228.56 ([NH stretch), 2840.94 (–OCH3), 1732.54
([C=O stretch), 1670.21 (C=N stretch), 1610.4 (NH bend),
1576.3 ([C=C\ of aromatic ring), 758.9 ([C–Br). LCMS
m/z: 410 (m ? 1, mol. wt. = 409.27, C15H12BrN3O4).
2-Bromo-5-methoxy-N0-[(1Z)-phenylmethylene]
benzohydrazide (7h)
C15H13BrN2O3, m.p. 162–164, yield: 95 %; FT-IR (KBr)
cm-1: 3221.6 ([NH stretch), 2845.9 (–OCH3), 1675.6
([C=O stretch), 1664.2 (C=N stretch), 1601.4 (NH bend),
1568.3 ([C=C\ of aromatic ring), 761.5 ([C–Br).
123

Med Chem Res
1H-NMR: (CDCl3, d/ppm, 400 MHz), 11.69 (s, 1H,[NH),
8.22 (s, 1H, =CH), 6.82–7.73(m, 8H, ArH), 3.76 (s, 3H,
–OCH3). LCMS m/z: 334 (m ? 1, mol. wt. = 333.18,
C16H15BrN2O3).
2-Bromo-N0-[(1Z)-(2-hydroxyphenyl) methylene]-5-
methoxybenzohydrazide (7n)
C15H13BrN2O3, m.p. 156–158, yield: 89 %; FT-IR (KBr)
cm-1: 3396.98 (OH stretch), 3228.4 ([NH stretch), 2838.4
(–OCH3), 1730.4 ([C=O stretch), 1668.0 (C=N stretch),
1619.2 (NH bend), 1569.8 ([C=C\ of aromatic ring),
752.6 ([C–Br).
N0-[(1Z)-Biphenyl-4-ylmethylene]-2-bromo-5-
methoxybenzohydrazide (7i)
C21H17BrN2O2, m.p. 180–182, yield: 86 %; FT-IR (KBr)
cm-1: 3238.23 ([NH stretch), 2836.86 (-OCH3), 1725.71
([C=O stretch), 1668.91 (C=N stretch), 1618.89 (NH
bend), 1582.8 ([C=C\of aromatic ring), 765.9.9 ([C–Br).
2-Bromo-N0-[(1Z)-(4-hydroxyphenyl) methylene]-5-
methoxybenzohydrazide (7o)
C15H13BrN2O3, m.p. 160–162, yield: 84 %; FT-IR (KBr)
cm-1: 3398.82 (OH stretch), 3226.46 ([NH stretch),
2838.62 (–OCH3), 1729.4 ([C=O stretch), 1664.9 (C=N
stretch), 1608.8 (NH bend), 1568.8 ([C=C\ of aromatic
ring), 752.6 ([C–Br). LCMS m/z: 350 (m ? 1, mol.
wt. = 349.20, C15H13BrN2O3).
2-Bromo-5-methoxy-N0-[(1Z)-(4-methylphenyl)
methylene] benzohydrazide (7j)
C16H15BrN2O2, m.p. 196–198, yield: 87 %; FT-IR (KBr)
cm-1: 3225.8 ([NH stretch), 2845.2 (–OCH3), 1680.1
([C=O stretch), 1668.3 (C=N stretch), 1603.9 (NH bend),
1564.8 ([C=C\ of aromatic ring), 765.7 ([C–Br). 1H-
NMR: (CDCl3, d/ppm, 400 MHz), 11.72 (s, 1H, [NH),
8.18 (s, 1H, =CH), 6.68–7.74 (m, 7H, ArH), 3.78 (s, 3H,
–OCH3), 2.25 (s, 3H, Ar–CH3). LCMS m/z: 348 (m ? 1,
mol. wt. = 347.20, C16H15BrN2O2).
2-Bromo-N0-[(1Z)-(4-hydroxy-3-methoxyphenyl)
methylene]-5-methoxybenzohydrazide (7p)
C16H15BrN2O4, m.p. 188–190, yield: 68 %; FT-IR (KBr)
cm-1: 3400.2 (OH stretch), 3230.6 ([NH stretch), 2836.24
(–OCH3), 1730.72 ([C=O stretch), 1668.81 (C=N stretch),
1620.2 (NH bend), 1570.1 ([C=C\ of aromatic ring),
754.2 ([C–Br). LCMS m/z: 380 (m ? 1, mol. wt. =
379.20, C16H15BrN2O4).
2-Bromo-5-methoxy-N0-[(1Z)-pyridin-3-yl methylene]
benzohydrazide (7k)
General procedure for the conventional synthesis of 2-
bromo-N-[2-(substituted phenyl)-4-oxo-1,3-thiazolidin-
3-yl]-5-methoxybenzamide (6) and (8a-p)
C14H12BrN3O2, m.p. 232–234, yield: 62 %; FT-IR (KBr)
cm-1: 3232.8.56 ([NH stretch), 2836.9 (–OCH3), 1728.4
([C=O stretch), 1665.1 (C=N stretch), 1614.64 (NH bend),
1577.8 ([C=C\ of aromatic ring), 760.7 ([C–Br). LCMS
m/z: 335 (m ? 1, mol. wt. = 334.17, C14H12BrN3O2).
The mixture of compound 5 or 7a–k (0.01 mol) and thio-
glycolic acid (0.015 mol) was taken in dry 1,4 dioxane,
added pinch of anhydrous ZnCl2. The reaction mass was
refluxed for 12–16 h and the generated water was removed
using Dean-Stark apparatus. The reaction progress was
monitored by TLC. After reaction completion cooled to
room temperature and poured into crushed ice. The solid
product obtained was filtered, washed with water, dried and
recrystallized from ethanol.
2-Bromo-N0-[(1Z)-(4-fluorophenyl) methylene]-5-
methoxybenzohydrazide (7l)
C15H12BrFN2O2, m.p. 192–194, yield: 76 %; FT-IR
(KBr) cm-1: 3232.6 ([NH stretch), 2838.4 (–OCH3),
1730.24 ([C=O stretch), 1666.18 (C=N stretch), 1613.7
(NH bend), 1568.8 ([C=C\ of aromatic ring), 760.2
([C–Br). LCMS m/z: 352 (m ? 1, mol. wt. = 351.17,
C15H12BrFN2O2).
2-Bromo-N-[2-(1-chloro-4-(3,4-dichlorophenyl)-
1,2,3,4-tetrahydronaphthalene)-4-oxo-1,3-thiazolidin-
3-yl]-5-methoxybenzamide (6)
2-Bromo-5-methoxy-N0-[(1Z)-(6-methoxy-1-naphthyl)
methylene] benzohydrazide (7m)
C27H20BrCl3N2O3S, m.p. 242–244, yield: 68 %; FT-IR
(KBr) cm-1: 3459.68 (NH), 1696.42 (C=O stretch), 1475.2
(C=C of aromatic ring), 816.89 (C–Cl), 766.2 ([C–Br). 1H-
NMR: (CDCl3, d/ppm, 400 MHz), 8.65 (s, 1H, NH proton),
6.20–7.73 (m, 10H, ArH protons), 5.88 (s, 1H, –CH proton
of thiazolidinone ring), 4.15 (m, 1H, –CH proton of fused
C20H17BrN2O3, m.p. 176–178, yield: 82 %; FT-IR (KBr)
cm-1: 3229.41 ([NH stretch), 2836.9 (–OCH3), 1728.84
([C=O stretch), 1667.84 (C=N stretch), 1618.2 (NH bend),
1569.35 ([C=C\ of aromatic ring), 756.921 ([C–Br).
123

Med Chem Res
cyclohexene ring), 3.71 (s, 2H, –CH2 proton of thiazolid-
inone ring), 2.98 (m, 2H, –CH2 proton of fused cyclohex-
ene ring). 13CNMR-DEPT-135 (100 MHz, CDCl3): 29.59
(CH2 carbon of fused cyclohexene ring), 31.74 (CH2 car-
bon of thiazolidinone ring), 41.99 (CH carbon of fused
cyclohexene ring), 55.71 (OCH3 carbon of bromophenyl
ring), 60.14 (CH carbon of thiazolidinone ring), 114.98,
118.55, 125.79, 126.01, 127.52, 128.11, 129.87, 130.23,
130.45, 134.30. LCMS m/z: 639 (m ? 1, mol. wt. =
638.78, C27H20BrCl3N2O3S).
([C–Br), 732.1 (C–Cl). 1H-NMR: (CDCl3, d/ppm,
400 MHz), 10.72 (s, 1H, NH), 7.46–7.58 (m, 5H, ArH),
6.96–6.98 (m, 1H, ArH), 6.685–6.692 (m, 1H, ArH), 5.96
(s, 1H, CH, thiazolidinone ring), 3.78–4.0 (m, 2H, CH2,
thiazolidinone ring), 3.71 (s, 3H, OCH3). LCMS m/z: 443
(m ? 1, mol. wt. = 441.7, C17H14BrClN2O3S).
2-Bromo-N-[2-(2,4-dimethoxyphenyl)-4-oxo-1,3-
thiazolidin-3-yl]-5-methoxybenzamide (8d)
C19H19BrN2O5S, m.p. 182–184, yield: 78 %; FT-IR (KBr)
cm-1: 3464.4 (NH Stretch), 1712.7 (C=O stretch), 1561.6
(NH bend), 1480.0 (C=C of aromatic ring), 764.6 ([C–Br),
735.6 (C–Cl). 1H-NMR: (CDCl3, d/ppm, 400 MHz), 11.80
(s, 1H, [NH), 6.84–7.68(m, 6H, ArH), 5.94 (s, 1H, CH,
thiazolidinone ring), 4.0 (m, 2H, CH2, thiazolidinone ring),
3.84 (s, 3H, OCH3, 2,4-dimethoxy benzyl), 3.75 (s,
–OCH3, 2,4-dimethoxy benzyl). 3.73 (s, 3H, OCH3). LCMS
m/z: 468 (m ? 1, mol. wt. = 467.33, C19H19BrN2O5S).
2-Bromo-N-[2-(3-chlorophenyl)-4-oxo-1,3-thiazolidin-
3-yl]-5-methoxybenzamide (8a)
C17H14BrClN2O3S, m.p. 144–146, yield: 89 %; FT-IR
(KBr) cm-1: 3461.2 (NH Stretch), 1722.3 (C=O stretch),
1562.0 (NH bend), 1473.4 (C=C of aromatic ring), 764.6
([C–Br), 731.8 (C–Cl). 1H-NMR: (CDCl3, d/ppm,
400 MHz), 7.92 (s, 1H, NH), 7.5 (d, 1H, ArH,
J = 7.29 Hz), 7.26–7.40 (m, 4H, ArH), 7.04 (d, 1H, ArH,
J = 2.9 Hz), 6.79–6.82 (dd, 1H, ArH, J = 2.9 and 2.9 Hz),
6.55 (s, –CH, thiazolidinone ring), 3.80 (s, 2H, CH2, thia-
zolidinone ring), 3.74 (s, 3H, OCH3). 13CNMR (100 MHz,
CDCl3): 169.82, 165.34, 158.83, 134.90, 134.77, 134.33,
133.97, 130.47, 130.37, 128.99, 127.67, 118.93, 115.14,
109.57, 59.38 (CH carbon of thiazolidinone ring), 55.71
(OCH3 carbon of bromophenyl ring), 29.80 (CH2 carbon of
thiazolidinone ring). 13CNMR-DEPT-135 (100 MHz,
CDCl3): 134.33, 130.48, 130.37, 128.99, 127.67, 118.93,
115.13, 59.39 (CH carbon of thiazolidinone ring), 55.71
(OCH3 carbon of bromophenyl ring), 29.80 (CH2 carbon of
thiazolidinone ring). LCMS m/z: 443 (m ? 1, mol. wt. =
441.7, C17H14BrClN2O3S).
2-Bromo-5-methoxy-N-[2-(4-methoxyphenyl)-4-oxo-
1,3-thiazolidin-3-yl] benzamide (8e)
C18H17BrN2O4S, m.p. 128–130, yield: 80 %; FT-IR (KBr)
cm-1: 3215.9 (NH Stretch), 1715.2 (C=O stretch), 1600.8
(NH bend), 1569.0 (C=C of aromatic ring), 764.1 ([C–Br),
736.2 (C–Cl). 1H-NMR: (CDCl3, d/ppm, 400 MHz), 10.60
(s, 1H, NH), 7.27–7.49 (m, 3H, ArH), 6.88–6.96 (m, 3H,
ArH), 6.631–6.638 (d, 1H, ArH, J = 2.8 Hz), 5.87 (s, 1H,
CH, thiazolidinone ring), 3.84–3.89 (m, 2H, CH2, thiazo-
lidinone ring), 3.69–3.89 (m, 6H, 2 –OCH3 of p-methoxy
benzyl and 2-bromo-5-methoxy benzyl). LCMS m/z: 437,
438 (m, m ? 1, mol. wt. = 437.3, C18H17BrN2O4S).
2-Bromo-N-[2-(4-chlorophenyl)-4-oxo-1,3-thiazolidin-
3-yl]-5-methoxybenzamide (8b)
2-Bromo-5-methoxy-N-[2-(2-methoxyphenyl)-4-oxo-
1,3-thiazolidin-3-yl] benzamide (8f)
C17H14BrClN2O3S, m.p. 208–210, yield: 86 %; FT-IR (KBr)
cm-1: 3458.8 (NH Stretch), 1721.4 (C=O stretch), 1559.5
(NH bend), 1471.0 (C=C of aromatic ring), 764.9 ([C–Br),
730.7 (C–Cl). 1H-NMR: (CDCl3, d/ppm, 400 MHz), 10.67
(s, 1H, NH), 7.43–7.53 (m, 5H, ArH), 6.94–6.97 (m, 1H,
ArH), 6.677–6.684 (d, 1H, ArH, J = 2.8 Hz), 5.91 (s, 1H,
CH, thiazolidinone ring), 3.77–3.95 (m, 2H, CH2, thiazo-
lidinone ring), 3.70 (s, 3H, OCH3). LCMS m/z: 443 (m ? 1,
mol. wt. = 441.7, C17H14BrClN2O3S).
C18H17BrN2O4S, m.p. 134–136, yield: 80 %; FT-IR (KBr)
cm-1: 3220.7 (NH Stretch), 1723.6 (C=O stretch), 1601.5
(NH bend), 1570.6 (C=C of aromatic ring), 769.4 ([C–Br),
740.5 (C–Cl). 1H-NMR: (CDCl3, d/ppm, 400 MHz), 10.67
(s, 1H, NH), 7.30–7.46 (m, 3H, ArH), 6.89–6.98 (m, 3H,
ArH), 6.638–6.645 (d, 1H, ArH, J = 2.8 Hz), 5.92 (s, 1H,
CH, thiazolidinone ring), 3.88–3.93 (m, 2H, CH2, thiazo-
lidinone ring), 3.71–3.94 (m, 6H, 2 –OCH3 of p-methoxy
benzyl and 2-bromo-5-methoxy benzyl). LCMS m/z: 438
(m ? 1, mol. wt. = 437.3, C18H17BrN2O4S).
2-Bromo-N-[2-(2-chlorophenyl)-4-oxo-1,3-thiazolidin-
3-yl]-5-methoxybenzamide (8c)
2-Bromo-5-methoxy-N-[2-(4-nitrophenyl)-4-oxo-1,3-
thiazolidin-3-yl] benzamide (8g)
C17H14BrClN2O3S, m.p. 152–154, yield: 75 %; FT-IR
(KBr) cm-1: 3458.9 (NH Stretch), 1716.9 (C=O stretch),
1559.7 (NH bend), 1475.2 (C=C of aromatic ring), 765.1
C17H14BrN3O5S, m.p. 150–152, yield: 74 %; FT-IR (KBr)
cm-1: 3432.6 (NH Stretch), 1726.8 (C=O stretch), 1560.42
123

Med Chem Res
2-Bromo-5-methoxy-N-[2-(6-methoxy-1-naphthyl)-4-
oxo-1,3-thiazolidin-3-yl]benzamide (8m)
(NH bend), 1468.6 (C=C of aromatic ring), 761.8 ([C–Br).
LCMS m/z: 453 (m ? 1, mol. wt. = 452.38, C17H14
BrN3O5S).
C22H19BrN2O4S, m.p. 192–194, yield: 78 %; FT-IR (KBr)
cm-1: 3431.4 (NH Stretch), 1721.46 (C=O stretch),
1560.62 (NH bend), 1468.7 (C=C of aromatic ring), 754.6
([C–Br).
2-Bromo-5-methoxy-N-(4-oxo-2-phenyl-1,3-
thiazolidin-3-yl)benzamide (8h)
C17H15BrN2O3S, m.p. 190–192, yield: 80 %; FT-IR (KBr)
cm-1: 3424.7 (NH Stretch), 1718.4 (C=O stretch), 1606.4
(NH bend), 1568.3 (C=C of aromatic ring), 763.5 ([C–Br),
738.8 (C–Cl). 1H-NMR: (CDCl3, d/ppm, 400 MHz), 10.89
(s, 1H, NH), 6.63–7.56 (m, 6H, ArH), 5.90 (s, 1H, CH,
thiazolidinone ring), 3.91–3.97 (m, 2H, CH2, thiazolidi-
none ring), 3.73 (s, 3H, –OCH3). LCMS m/z: 408 (m ? 1,
mol. wt. = 407.28, C17H15BrN2O3S).
2-Bromo-N-[2-(2-hydroxyphenyl)-4-oxo-1,3-
thiazolidin-3-yl]-5-methoxybenzamide (8n)
C17H15BrN2O4S, m.p. 198–200, yield: 71 %; FT-IR (KBr)
cm-1: 3452.8 (OH Stretch), 3424.6 (NH Stretch), 1730.51
(C=O stretch), 1564.73 (NH bend), 1469.76 (C=C of aro-
matic ring), 751.8 ([C–Br). LCMS m/z: 424 (m ? 1, mol.
wt. = 423.28, C17H15BrN2O4S).
N-(2-Biphenyl-4-yl-4-oxo-1,3-thiazolidin-3-yl)-2-
bromo-5-methoxybenzamide (8i)
2-Bromo-N-[2-(4-hydroxyphenyl)-4-oxo-1,3-
thiazolidin-3-yl]-5-methoxybenzamide (8o)
C23H19BrN2O3S, m.p. 220–222, yield: 85 %; FT-IR (KBr)
cm-1: 3428.8 (NH Stretch), 1729.56 (C=O stretch),
1558.82 (NH bend), 1471.4 (C=C of aromatic ring), 756.9
([C–Br). LCMS m/z: 484 (m ? 1, mol. wt. = 483.37,
C23H19BrN2O3S).
C16H14BrN3O3S, m.p. 234–236, yield: 82 %; FT-IR (KBr)
cm-1: 3448.5 (OH Stretch), 3418.2 (NH Stretch), 1726.54
(C=O stretch), 1560.2 (NH bend), 1468.8 (C=C of aromatic
ring), 758.4 ([C–Br). LCMS m/z: 424 (m ? 1, mol. wt. =
423.28, C16H14BrN3O3S).
2-Bromo-5-methoxy-N-[2-(4-methylphenyl)-4-oxo-1,3-
thiazolidin-3-yl] benzamide (8j)
2-Bromo-N-[2-(4-hydroxy-3-methoxyphenyl)-4-oxo-
1,3-thiazolidin-3-yl]-5-methoxybenzamide (8p)
C18H17BrN2O3S, m.p. 178–180, yield: 79 %; FT-IR (KBr)
cm-1: 3432.1 (NH Stretch), 1728.6 (C=O stretch), 1602.2
(NH bend), 1562.8 (C=C of aromatic ring), 764.4 ([C–Br),
734.3 (C–Cl). 1H-NMR: (CDCl3, d/ppm, 400 MHz), 10.96
(s, 1H, NH), 6.74–7.72 (m, 7H, ArH), 5.88 (s, 1H, CH,
thiazolidinone ring), 3.85 (s, 2H, CH2, thiazolidinone ring),
3.74 (s, 3H, –OCH3). LCMS m/z: 422 (m ? 1, mol.
wt. = 421.31, C18H17BrN2O3S).
C18H17BrN2O5S, m.p. 240–242, yield: 76 %; FT-IR (KBr)
cm-1: 3450.2 (OH Stretch), 3430.7 (NH Stretch), 17296.56
(C=O stretch), 1561.25 (NH bend), 1466.3 (C=C of aro-
matic ring), 760.2 ([C–Br). LCMS m/z: 454 (m ? 1, mol.
wt. = 453.30, C18H17BrN2O5S).
2-Bromo-5-methoxy-N-(4-oxo-2-pyridin-3-yl-1,3-
thiazolidin-3-yl)benzamide (8k)
Antioxidant activity studies
DPPH free radical scavenging activity
C16H14BrN3O3S, m.p. 248–250, yield: 65 %; FT-IR (KBr)
cm-1: 3420.6 (NH Stretch), 1726.42 (C=O stretch),
1564.24 (NH bend), 1468.6 (C=C of aromatic ring), 760.7
([C–Br). LCMS m/z: 409 (m ? 1, mol. wt. = 408.27,
C16H14BrN3O3S).
1,1-Diphenyl-2-picrylhydrazyl (DPPH) is a stable free
radical which has maximum optical absorbance at 517 nm.
The reaction of DPPH with free radical scavenger causes
decline in the absorbance value at 517 nm (Singh et al.,
2002). The MDC solutions of newly synthesized com-
pounds at 200, 400, and 800 lg/mL concentrations were
prepared and 4 mL of 0.1 mM methanolic solution of
DPPH was added. The test tubes were kept at an ambient
temperature for 20 min and the absorbances were mea-
sured at 517 nm, against control. Ascorbic acid was used as
a positive control. These measurements were run in
2-Bromo-N-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-
3-yl]-5-methoxybenzamide (8l)
C17H14BrFN2O3S, m.p. 180–182, yield: 78 %; FT-IR
(KBr) cm-1: 3431.6 (NH Stretch), 1734.16 (C=O stretch),
1560.24 (NH bend), 1469.65 (C=C of aromatic ring), 751.6
([C–Br).
123

Med Chem Res
triplicate. The percentage of scavenging activity was cal-
culated as follows:
Anti-inflammatory activity studies
The anti-inflammatory activity of seventeen newly syn-
thesized thiazolidinone compounds, 6 and 8a–p were
evaluated by applying carrageenan-induced paw edema
bioassay in rats of either sex (100–140 g) (Winter et al.,
1962) using Diclo as a reference standard. Rats were
selected by random sampling technique. The test com-
pounds were administrated at dose level of 100 mg/kg
orally 30 min before the administration of carrageenan in
the right hind paw of the rats. The paw thickness was
measured using vernier callipers at 60, 120, and 180 min
after carrageenan administration. The results were pre-
sented in Table 3.
Scavenging activity (% ) ¼ ½ðADPPH ꢁ ATESTÞ=ADPPH
ꢃ 100
ꢂ
where ADPPH is the absorbance of DPPH without test
sample (control) and ATEST is the absorbance of DPPH in
the presence of test sample (Table 2).
Table 2 DPPH radical scavenging assay for thiazolidinone
derivatives
Compounds
% inhibition
Concentration (lg/mL)
200
400
800
Analgesic activity studies
8a
57.65
57.47
59.29
15.90
57.51
–
58.47
58.19
65.92
33.21
58.20
5.81
59.47
58.20
72.87
70.96
59.51
12.96
41.57
62.5
8b
The analgesic activity of the above mentioned seventeen
derivatives was also evaluated by applying tail flick
method. (Kar et al., 2003) using pentazocine as a standard
reference. Wistar albino mice of either sex (20–30 g) in the
groups of six animals each were selected by random
sampling technique. The test compounds at dose level of
100 mg/kg were administered orally by intragastric tube.
The animals were held in position by a suitable restrained
the tail extending out and the tail (up to 5 cm) was then
dipped in a beaker of water maintained at 50–55 °C. The
time in seconds taken to withdraw the tail clearly out of
water was taken as the reaction time. The reading was
8c
8d
8e
8g
8h
4.30
18.06
39.87
23.51
51.03
52.35
57.97
94.97
8i
15.28
21.57
37.80
38.32
57.83
87.57
8k
25.15
57.12
58.29
58.29
96
8l
8m
8o
Ascorbic acid
Table 3 Anti-inflammatory
activity of the compounds
6 and (8a–p)
Compound
Dose
60 min
120 min
180 min
Control
DICLO
6
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
2.175 0.1797
0.6 0.04082***
2.025 0.125
2.375 0.1436
0.625 0.04787***
2.175 0.1109
1.65 0.06455**
2.25 0.0866
1.975 0.1702
2.15 0.06455
1.75 0.1936**
1.95 0.1041
1.8 0.108*
2.275 0.1181
0.625 0.04787***
2.025 0.1377
1.6 0.07071**
2.25 0.06455
2.075 0.1315
1.9 0.178
8a
1.575 0.1377*
2.15 0.09574
1.85 0.1658
8b
8c
8d
2.125 0.06292
1.6 0.178*
8e
1.875 0.1315
2.075 0.1031
1.975 0.1109
1.75 0.1258*
2.075 0.1548
1.95 0.1443
1.9 0.1581
8f
1.825 0.08539
1.45 0.06455**
1.575 0.1702*
1.45 0.1658**
1.525 0.1652**
1.45 0.06455**
8g
8h
1.65 0.1323**
1.875 0.1548
1.9 0.108
8i
8j
8k
1.75 0.1555**
2.05 0.0866
1.89 0.098
8l
2
0.09129
2.2 0.1
Results were expressed in
mean SEM. (n = 6)
significance levels, * P \ 0.05;
** P \ 0.01; *** P \ 0.001 as
compared with the respective
control
8m
8n
1.515 0.1552**
1.88 0.1958
1.98 0.1743
2.081 0.1375
2.048 0.1045
1.78 0.0257
1.980 0.1752
1.899 0.0942
1.77 0.022
8o
1.89 0.2058
8p
1.528 0.1682**
123

Med Chem Res
recorded at 60, 80, and 120 min after administration of
compounds. A cut off point of 10 s was observed to pre-
vent the tail damage. The results were illustrated in
Table 4.
water (100 mL) and adjusting pH to 5.7] was used as the
medium for fungal growth. Normal saline was used to
make the spore suspension of the fungal strains (i.e., a
loopful of particular fungal strain was transferred to 3 mL
saline to get a suspension of the corresponding species).
Activity of each compound was compared with fluconazole
as standard. The MIC of each test compounds 5, (7a–p), 6,
and (8a–p) were determined. The results of activity studies
were given in Table 5.
Antibacterial activity studies
We investigated all the newly synthesized compounds for
their antibacterial activity against Escherichia coli (ATCC-
25922), Staphylococcus aureus (ATCC-25923), Pseudo-
monas aeruginosa (ATCC-27853), and Bacillus cereus
bacterial stains by serial plate dilution method. The mini-
mum inhibitory concentration (MIC) was noted by seeing
the lowest concentration of the drug at which there was no
visible growth. Antibacterial activity was determined by
measuring the diameter of inhibition zone. Activity of each
compound was compared with penicillin as standard (Davis
et al., 1996). Zone of inhibition was determined for all the
test compounds 5, (7a–p), 6, and (8a–p). The results of
such studies are given in Table 5.
The compounds thus synthesized have been found to
possess good antibacterial and antifungal activities.
Acute toxicity study
The acute oral toxicity study for the test compounds 7h and
8a was carried out by following the OECD guidelines
(Diener et al., 1995; Diener and Schlede, 1999). Swiss
albino mice of either sex weighing between 25 and 30 g
were selected for studies. Each group consisting of 6 mice
(overnight fasted) was kept in the colony cage at
25 2 °C with 55 % relative humidity and 12 h light/dark
cycle was maintained. A different dose from 500 to
2,500 mg/kg was selected and administered orally as a
single dose as fine suspension prepared in double distilled
water using Tween 80. The acute toxic symptoms and the
behavioral changes produced by the test compounds were
observed continuously for 4, 8, 12, and 24 h onset of toxic
symptoms and behavioral changes were also recorded.
Antifungal activity studies
The all newly synthesized compounds were screened for
their antifungal activity against one fungi Candida albicans
by the serial plate dilution method (Khan, 1997; Varma,
1998). Sabourauds agar media [prepared by dissolving
peptone (1 g), D-glucose (4 g) and agar (2 g) in distilled
Table 4 Analgesic activity of
the newly synthesized
compounds 6 and (8a–p)
Compound
Dose
60 min
120 min
180 min
Control
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
1.363 0.1297
7.075 0.1164***
3.463 0.3085**
2.825 0.6119
2.613 0.5014
1.963 0.2202
3.175 0.6139*
2.388 0.2357
2.175 0.08539
3.375 0.4789**
3.675 0.8125**
2.988 0.1477
2.038 0.07739
3.25 0.1581*
2.923 0.0837
1.954 0.2112
3.546 0.6835**
2.675 0.5634
3.468 0.5719**
1.363 0.1297
6.863 0.1919***
3.388 0.2968**
2.8 0.6268
1.363 0.1297
7.025 0.2504***
2.338 0.1329**
2.438 0.0826
2.463 0.156
Pentazocin
6
8a
8b
8c
8d
8e
8f
2.788 0.4956
2.125 0.09242
3.075 0.5622*
2.575 0.2496
2.075 0.101
2.5 0.1399
2.388 0.08985*
2.513 0.0625
2.238 0.0875
2.663 0.2831**
2.425 0.2385**
3.113 0.1491
2.225 0.07773
2.938 0.1784*
3.241 0.2771
2.53 0.1699
8g
8h
8i
3.263 0.3243**
3.563 0.7031**
3.313 0.1573**
2.088 0.07739
3.6 0.1242**
3.421 0.2653**
2.214 0.18142
3.623 0.7631**
2.775 0.4826
3.334 0.3953**
8j
8k
8l
Results were expressed in
mean SEM. (n = 6)
significance levels, * P \ 0.05;
** P \ 0.01; *** P \ 0.001 as
compared with the respective
control
8m
8n
8o
8p
2.235 0.0485*
2.532 0.225
2.841 0.4611*
123

Med Chem Res
Table 5 Antibacterial and antifungal activity of the newly synthesized compounds 5, 6, (7a-p), and (8a–p)
Compound
MIC (lg mL-1) and zone of inhibition (mm) in parentheses
Antibacterial activity
Antifungal activity
E. coli
S. aureus
P. aeruginosa
B. cereus
C. albicans
5
12.5
12.5
12.5
6.25
6.25
6.25
12.5
12.5
6.25
12.5
25
12.5
6.25
25
6.25
6.25
6.25
3.125
6.25
6.25
3.125
3.125
6.25
12.5
6.25
12.5
6.25
6.25
12.5
6.25
6.25
12.5
6.25
3.125
3.125
6.25
6.25
6.25
12.5
12.5
6.25
12.5
6.25
12.5
6.25
6.25
6.25
6.25
0.12
–
12.5
12.5
12.5
12.5
6.25
12.5
12.5
12.5
6.25
12.5
25
6.25
6.25
6.25
3.125
6.25
6.25
6.25
6.25
3.125
1.562
12.5
6.25
3.125
12.5
12.5
6.25
3.125
12.5
1.562
12.5
6.25
3.125
6.25
6.25
6.25
6.25
6.25
6.25
3.125
6.25
6.25
3.125
6.25
12.5
–
6
7a
7b
6.25
12.5
12.5
12.5
6.25
12.5
12.5
25
7c
7d
7e
7f
7g
7h
7i
7j
6.25
6.25
12.5
12.5
6.25
12.5
6.25
12.5
12.5
12.5
12.5
12.5
12.5
6.25
12.5
6.25
12.5
6.25
6.25
6.25
12.5
6.25
12.5
0.12
–
12.5
6.25
6.25
6.25
12.5
12.5
12.5
12.5
12.5
6.25
12.5
6.25
6.25
6.25
25
12.5
6.25
6.25
6.25
12.5
6.25
6.25
6.25
12.5
6.25
6.25
6.25
6.25
6.25
25
7k
7l
7m
7n
7o
7p
8a
8b
8c
8d
8e
8f
8g
8h
8i
12.5
6.25
6.25
12.5
12.5
6.25
12.5
6.25
0.12
–
6.25
12.5
6.25
6.25
12.5
12.5
12.5
6.25
0.12
–
8j
8k
8l
8m
8n
8o
8p
Pencillin (standard)
Fluconazole (standard)
8.0
Acknowledgments The one of authors, Chidananda Nandagokula is
grateful to the management of SeQuent Scientific Ltd., New Man-
galore for encouraging my research work. The authors are also
thankful to IISc, Bangalore for providing 1H-NMR and 13C-NMR
spectral facilities. Thanks are also due to CDRI-Lucknow and Punjab
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