Synthesis and antimicrobial screening of 5-(benzylidene)-3- phenylthiazolidin-4-one derivatives incorporating thiazole ring

Article abstract of DOI:10.1007/s00044-013-0512-9

The present article deals with the synthesis and antimicrobial screening of a series of N-(5-(2-(5-(arylidene)-4-oxo-3-phenylthiazolidin-2-ylidene) hydrazinecarbonyl)-4-methylthiazol-2-yl)-4-methoxybenzamides (6a-o). The structures of these compounds have been elucidated by spectra (IR, ¹H NMR, ¹³C NMR, mass spectra). All the synthesized compounds were screened for in vitro antibacterial activity against Gram-positive (Staphylococcus aureus, Streptococcus pyogenes) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacteria. These compounds were also tested for their inhibitory action against three strains of fungi (Candida albicans, Aspergillus niger, Aspergillus clavatus). The thiazole derivatives discovered in this study may provide valuable therapeutic intervention for the treatment of microbial diseases, especially against bacterial and fungal infections.

Full text of DOI:10.1007/s00044-013-0512-9

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0512-9
ORIGINAL RESEARCH
Synthesis and antimicrobial screening of 5-(benzylidene)-3-
phenylthiazolidin-4-one derivatives incorporating thiazole ring
•
N. C. Desai K. M. Rajpara V. V. Joshi
•
Received: 26 August 2012 / Accepted: 24 January 2013
Ó Springer Science+Business Media New York 2013
Abstract The present article deals with the synthesis and
antimicrobial screening of a series of N-(5-(2-(5-(arylid-
ene)-4-oxo-3-phenylthiazolidin-2-ylidene)hydrazinecar-
bonyl)-4-methylthiazol-2-yl)-4-methoxybenzamides (6a–o).
The structures of these compounds have been elucidated
natural products as privileged pharmacophores. The thiaz-
olyl group is also of great importance as it appears frequently
in the structures of various natural products and biologically
active compounds like thiamine (vitamin-B) and also in
some antibiotic drugs like penicillin and micrococcin (Oncu
et al., 2004). Several thiazole-containing drugs are available
such as; nizatidine is a histamine H2-receptor antagonist that
inhibits stomach acid production, and commonly used in the
treatment of peptic ulcer disease (PUD) and gastroesopha-
geal reflux disease (GERD), nitazoxanide as antiprotozal,
sulfathiazole as antibiotic and abafungin as antifungal. The
thiazolidinone nucleus also appears frequently in the struc-
ture of various natural products, notably thiamine, com-
pounds possessing cardiac and glycemic benefits such as
troglitazone (Ghazzi et al., 1997) and many metabolic
products of fungi and primitive marine animals, including
2-(aminoalkyl)-thiazole-4-carboxylic acids (Ulrich et al.,
1987). Numerous thiazolidinone derivatives have shown
significant bioactivities such as antidiarrhoeal (Diurno et al.,
1997), anticonvulsant (Ragab et al., 1997), antimicrobial
(Sattigeri et al., 2005), antidiabetic (Norisada et al., 2004),
antihistaminic (Previtera et al., 1994), anticancer (Hav-
rylyuk et al., 2009), anti-HIV (Rawal et al., 2005), PAF
antagonist (Tanabe et al., 1991), non-peptide thrombin
receptor antagonist (Kato et al., 1999a), cardioprotective
(Kato et al., 1999b), Ca2? channel blocker (Kato et al.,
1999c), antiischemic (Adachi et al., 1999), COX inhibitory
(Ottana et al., 2002), anti-platelet activating factor (Tanabe
et al., 1995), and tumor necrosis.
1
by spectra (IR, H NMR, 13C NMR, mass spectra). All the
synthesized compounds were screened for in vitro anti-
bacterial activity against Gram-positive (Staphylococcus
aureus, Streptococcus pyogenes) and Gram-negative
(Escherichia coli, Pseudomonas aeruginosa) bacteria.
These compounds were also tested for their inhibitory
action against three strains of fungi (Candida albicans,
Aspergillus niger, Aspergillus clavatus). The thiazole
derivatives discovered in this study may provide valuable
therapeutic intervention for the treatment of microbial
diseases, especially against bacterial and fungal infections.
Keywords Antibacterial activity ꢀ Antifungal activity ꢀ
MIC ꢀ Thiazole ꢀ Thiazolidinone
Introduction
The search for new antimicrobial drugs is an area charac-
terized by active investigation with the goal of overcoming
the phenomenon of multiple drug resistance. Azoles con-
stitute immensely important members of the aromatic het-
erocycle family due to their presence in a myriad of bioactive
Certain commercially available drugs containing thia-
zole and thiazolidinone nucleus are shown in Fig. 1.
In search of new bio-active molecule, the development
of hybrid molecules through the combination of different
pharmacophores in one frame may lead to compounds with
interesting pharmacological properties (Desai et al., 2012a,
N. C. Desai (&) ꢀ K. M. Rajpara ꢀ V. V. Joshi
Division of Medicinal Chemistry, Department of Chemistry
(DST-FIST Sponsored Department), Mahatma Gandhi Campus,
Maharaja Krishnakumarsinhji Bhavnagar University,
Bhavnagar 364 002, India
e-mail: dnisheeth@rediffmail.com
123

Med Chem Res
Fig. 1 Commercially available
drug candidates containing
thiazole and thiazolidinone
nucleus
N
N
NO2
S
S
O
O
O
S
O
NH
H
H
N
N
N
N
N
H
NH NO2
N
S
Abafungin
Nizatidine
Nitazoxanide
O
S
O
S
O
HN
HN
N
N
N
O
O
O
Rosiglitazone
Pioglitazone
2012b, 2012c, 2012d, 2012e, 2012f). The co-administra-
tion of the moieties, acting by different mechanisms may
have a synergistic effect, resulting in a higher activity than
each of the components. In the light of interesting bio-
logical activities associated with thiazole derivatives and
thiazolidine compounds, it was considered worthwhile to
synthesize some hybrid molecules incorporating both thi-
azole and thiazolidine nucleus.
coupling constant of nearly 15.60 Hz. 13C NMR confirmed
the proposed structure due to the appearance of signal at
d = 171.3 ppm of carbonyl carbon as well as the appearance
of signal around d = 30.7 ppm assignable to methylene
group of thiazolidine ring. Moreover, the mass spectrum of
(5) showed a molecular ion peak at m/z = 481 (M?) corre-
sponding to a molecular formula C22H21N5O4S2. The resulting
intermediate (5) was subjected to Knoevenagel condensation
with aromatic aldehydes as mentioned above to form the
target compounds N-(5-(2-(5-(benzylidene)-4-oxo-3-phe-
nylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-methyl-
thiazol-2-yl)-4-methoxybenzamides (6a–o).
Results and discussion
Chemistry
Structures of products (6a–o) were confirmed on the basis
of their elemental analysis and spectral data. For example,
the IR spectra of compound (6a) showed characteristic
absorption bands of secondary amines at 3,275 and
3,220 cm-1. Absorption bands displayed at 1679, 1697, and
1713 cm-1 which were characteristic of carbonyl groups. Its
1H NMR spectrum revealed singlet at d = 7.80 ppm
assignable to CH=C linkage and the absence of peak at
d = 3.81 and 4.12 ppm confirmed the formation of Knoe-
venagel product. Protons of methyl group displayed a singlet
at d = 2.41 ppm. Protons of secondary amines in amide
linkages appeared as a singlet at d = 10.24 and 7.96 ppm,
which were confirmed by disappearance of peak when
exchanged with D2O. Aromatic protons showed a multiplet
centered on d = 7.14–7.97 ppm. The 13C NMR spectrum of
compound (6a) revealed twenty-three inequivalent carbons.
The carbonyl carbons displayed chemical shift at d = 166.2,
167.5, and 168.8 ppm. Another important signal was dis-
played at d = 145.4 ppm which was characteristic of
CH=C. Carbon C5 of thiazolidinone displayed chemical shift
at d = 116.7 ppm and the absence of peak at d = 30.7 ppm
confirmed the formation of Knoevenagel product. Moreover,
the mass spectrum of (6a) showed a molecular ion peak at m/
z = 569 (M?) corresponding to molecular formula C29H23N5
O4S2. The spectral data for all the compounds and C, H, N
analysis were given in the Experimental part.
The synthetic pathway to obtain the intermediate and target
compounds in this study are depicted in Scheme 1. The starting
material ethyl 2-amino-4-methylthiazole-5-carboxylate (1) was
warmed with 4-methoxybenzoyl chloride to produce ethyl
2-(4-methoxybenzamido)-4-methylthiazole-5-carboxylate (2)in
good yield. When compound (2) was reacted with hydrazine
hydrate, the N-(5-(hydrazinecarbonyl)-4-methylthiazol-2-yl)-4-
methoxybenzamide (3) was obtained which was reacted with
phenyl isothiocyanate in pyridine, afforded 4-methoxy-N-(4-
methyl-5-(2-(phenylcarbamothioyl)hydrazinecarbon-
yl)thiazol-2-yl)benzamide (4). The structure of compound
1
(4) was determined by IR, H NMR, 13C NMR, and mass
spectra. Thus, obtained product (4) was further converted
into compound (5) on treatment with monochloroacetic
acid and anhydrous sodium acetate in acetic acid. The
structure of compound N-(4-methyl-5-(2-(4-oxo-3-phenyl-
thiazolidin-2-ylidene)hydrazinecarbonyl)thiazol-2-yl)-4-
methoxybenzamide (5) was confirmed with the help of IR
spectra which showed strong absorption bands at 1687,
1694, and 1716 cm-1 due to carbonyl groups. The high
frequency region of IR spectra of this compound contains –
NH stretching vibrations at 3,276 and 3,228 cm-1. In
1
addition, H NMR revealed the appearance of peaks (two
doublets) at d = 3.81 and 4.12 ppm integrating two
protons of the methylene group of thiazolidine ring with
123

Med Chem Res
Scheme 1 Synthethic route to
methylthiazolylbenzamides
(6a–o)
O
S
O
O
O
HN
O
Pyridine, 0-5 °C
Stirring, 18 h
O
S
+
O
Cl
N
H2N
N
O
(2)
(1)
Ethanol
Refulx, 4 h
NH2NH2.H2O
O
HN
N
O
N
NH2
S
Ph-NCS
O
H
N
HN
S
N
H
S
O
N
N
Pyridine
Reflux, 6 h
H
H
O
O
(4)
(3)
Gla. AcOH
Reflux, 4 h
Anhy. CH3COONa
ClCH2COOH
R
R
O
S
O
N
O
CHO
O
N
N
N
O
H
N
N
O
HN
S
H
HN
S
1,4-Dioxane
N
S
N
Piperidine
O
Reflux, 3-4 h
(6a-o)
O
(5)
R = -H, -2-OH, -3-OH, -4-OH, -2-CH3, -3-CH3, -4-CH3, -2-OCH3, -3-OCH3, -4-OCH3, -2-Cl, -4-Cl, -2-NO2, -4-NO2, -4-F
Antimicrobial activity
significant to potent active broad-spectrum antimicrobials.
Compounds 6e (2-CH3), 6g (4-CH3) and 6j (4-OCH3)
All the newly synthesized compounds were evaluated
showed highest inhibition against E. coli. It is noteworthy
that compound 6g showed highest inhibition at MIC =
12.5 lg/mL, while compounds 6e and 6j showed inhibition
at MIC = 25 lg/mL against E. coli. Compounds 6d (4-OH)
and 6i (3-OCH3) showed very good activity and showed
inhibition at MIC = 50 lg/mL. Compounds 6g (4-CH3) and
6j (4-OCH3) displayed very good inhibition at MIC =
50 lg/mL, while incorporation of methyl group at second
position showed increment in activity and showed excellent
inhibition at MIC 25 lg/mL against P. aeruginosa. Com-
pounds 6d (4-OH) and 6g (4-CH3) exhibited very good
inhibition at MIC 50 lg/mL against S. aureus. Compounds
6g (4-CH3) and 6j (4-Cl) showed noticeable growth inhib-
itory activity against S. pyogenes at MIC = 50 lg/mL.
Minimum inhibitory concentration values of antifungal
activity exhibited similar trend as antibacterial activity.
Intermediate 3 showed poor inhibitory effect against
C. albicans and A. clavatus (MIC = 1,000 lg/mL for the
both strains). Similarly, intermediate 4 showed reduced
inhibitory effect against C. albicans and A. niger (MIC =
1,000 lg/mL for the both strains). Intermediate 5 showed
moderate inhibitory effect against A. clavatus (MIC =
250 lg/mL). Formation of Knoevenagel products (6a–o)
afforded compounds to have broad-spectrum antifungal
activity. Among tested compounds, compound 6j (4-OCH3)
displayed very good inhibition effect against C. albicans at
MIC = 50 lg/mL. Compound 6g (4-CH3) exhibited
against Gram-positive bacteria (Staphylococcus aureus,
Staphylococcus pyogenes),
Gram-negative
bacteria
(Escherichia coli, Pseudomonas aeruginosa), and fungi
(Candida albicans, Aspergillus niger and Aspergillus clav-
atus) strains. Individual minimum inhibitory concentration
(MIC, lg/mL) values of tested compounds (6a–o) against
the test microbes are listed in Tables 1 and 2 along with
MIC values of reference compounds ciprofloxacin (for
bacteria) and griseofulvin (for fungi). The results revealed
that majority of synthesized compounds showed varying
degrees of inhibition against the test panel of species. The
obtained antimicrobial activity of tested compounds could
be correlated to the structural variations and modifications.
Key precursor, hydrazide of thiazole (3) showed poor anti-
bacterial activity at MIC C1,000. Reaction of hydrazide
with phenyl isothiocyanate, afforded (4) displayed mild
antibacterial activity at MIC 500 lg/mL against tested
bacteria. Then, compound (4) was converted into compound
(5) on reaction with monochloroacetic acid and anhydrous
sodium acetate, which in turn showed again mild antibac-
terial activity against P. aeruginosa and S. pyogenes at MIC
500 lg/mL and moderately active against E. coli at MIC
250 lg/mL. Compound (5) was transformed to varying
degree of active target compounds (6a–o) by means of
Knoevenagel condensation with aromatic aldehydes. Col-
lectively, compounds (6a–o) could be considered as
123

Med Chem Res
Table 1 Results of
antibacterial screening of
compounds (6a–o)
Sr. No.
-R
Minimum inhibitory concentration (MIC) for bacteria (lg/mL) SD
E. coli
MTCC 443
P. aeruginosa
MTCC 1688
S. aureus
MTCC 96
S. pyogenes
MTCC 442
3
–
[1,000
500
1,000
[1,000
500
1,000
4
–
500
500
5
–
250
500
500
500
6a
6b
6c
6d
6e
6f
6g
6h
6i
-H
250 2.46*
100 3.51
100 1.53
50 1.05***
500 4.72
250 4.16*
100 4.72
250 3.21*
25 2.04**
250 4.16
50 2.64***
100 1.60*
250 4.05
50 1**
500 4.61
250 1.92
100 2.72*
50 2.56**
250 3.78
250 2.05*
50 1.18**
100 4.04
250 2.56*
100 2.64*
250 4.61
250 2.88**
500 4.72
500 4.46
500 3.46*
50 1.52
250 2.05*
100 3.46***
250 4.04
250 3.78**
100 2.58*
100 4.04***
50 1.20
-2-OH
-3-OH
-4-OH
-2-CH3
-3-CH3
-4-CH3
-2-OCH3
-3-OCH3
-4-OCH3
-2-Cl
25
1
100 2.58*
12.5 1.20*
250 3.78**
50 3.78***
25 1.51
2 % Dimethyl sulfoxide used
as control and its antibacterial
activity is nil or zero
100 4.16***
250 3.78*
50 2.05**
500 3.60
500 3.78
250 2.88***
500 2.58*
250 4.62
50 2.08
SD = Standard deviation,
*** P \ 0.001 extremely
significant, ** P \ 0.01
moderately significant,
* P \ 0.05 significant. All
values are presented as mean of
six experiments (n = 6). All
significant differences are
considered from control
value 0.00
6j
6k
6l
250 3.60*
500 4.04*
500 3.78***
250 4.16*
500 4.72*
25 2.05
250 2.64*
500 2.88
250 3.52**
500 1.60*
250 3.64*
25 0.98
-4-Cl
6m
6n
6o
-2-NO2
-4-NO2
-4-F
Ciprofloxacin
excellent inhibition against A. clavatus at MIC = 25 lg/mL.
Compound 6j (4-OCH3) showed very good inhibition against,
whereas compound 6g (4-CH3) showed noticeable increase in
activity and showed excellent activity at MIC = 25 lg/mL
A. clavatus fungal strain as compared standard drug griseofulvin.
Biological evaluation
Antibacterial assay
The newly synthesized compounds (6a–o) were screened for
their antibacterial activity against Gram-positive bacteria
[S. aureus (MTCC-96), Streptococcus pyogenes (MTCC-442)],
and Gram-negative bacteria [E. coli (MTCC-443), P. aeru-
ginosa (MTCC-1688)]. All MTCC cultures were collected
from Institute of Microbial Technology, Chandigarh, India.
The activity of compounds was determined as per National
Committee for Clinical Laboratory Standards (NCCLS)
protocol using Mueller–Hinton Broth (Becton–Dickinson,
USA) (Finegold and Garrod, 1995). Compounds were
screened for their antibacterial activity as primary screen-
ing in six sets against E. coli, S. aureus, P. aeruginosa, and
S. pyogenes at different concentrations of 1,000, 500, and
250 lg/mL. The compounds found to be active in primary
screening were similarly diluted to obtain 200, 125, 100,
62.5, 50, 25, and 12.5 lg/mL concentrations for secondary
screening to test in a second set of dilution against all
microorganisms. Inoculum size for test strain was adjusted
to 106 CFU/mL (Colony Forming Unit per milliliter) by
comparing the turbidity (turbidimetric method). Mueller–
Hinton Broth was used as nutrient medium to grow and
dilute the compound suspension for test bacteria. 2 %
Dimethyl sulfoxide was used as a diluent/vehicle to obtain
the desired concentration of synthesized compounds and
Structure activity relationship
Antimicrobial activity of intermediates and final compounds
revealed that thiazolidine ring along with Knowevenagel
product was essential for broad-spectrum antimicrobial
activity. Antimicrobial activity (Tables 1, 2) showed that
compounds (6a–o) represented broadly potent molecules.
Compound 6a did not lead to make either a negative or a
positive contribution to antimicrobial activity against test
panel of microorganisms. As regarded the relationships
between the structure of the heterocyclic scaffolds (6a–o)
and results of antibacterial as well as antifungal activity
clearly demonstrated that the introduction of electron
donating group on the benzene ring essential for enhancing
the activity. Compounds containing 2-CH3, 4-CH3, and
4-OCH3 exhibited pronounced activity. The introduction of
the bulky electron-withdrawing nitro group and chlorine
atom strongly reduced the antibacterial and antifungal
property. In general, compounds 6e, 6g, and 6j exhibited
more noteworthy property, which possessed either methyl or
methoxy substituted. Hydrophilicity of methyl and methoxy
group may be responsible for the cause of activity.
123

Med Chem Res
Table 2 Results of antifungal
screening of compounds (6a–o)
Sr. No.
-R
Minimum inhibitory concentration (MIC) for fungi (lg/mL) SD
C. albicans
MTCC 227
A. niger
MTCC 282
A. clavatus
MTCC 1323
3
–
1,000
[1,000
1,000
1,000
4
–
1,000
[1,000
250
5
–
1,000
1,000
6a
6b
6c
6d
6e
6f
6g
6h
6i
-H
500 4.64*
500 2.64
500 4.16
250 1.51*
100 3.60**
250 1.51
100 2.64*
100 1.60
500 4.61**
50 2.60***
500 1.18
500 2.56
1000 3.70
500 2.61*
500 3.52*
500 0.58
500 3.78**
250 4.70
250 3.46
100 4.72**
100 3.60**
250 4.64
25 3.52***
100 4.04
250 2.05*
100 4.16
250 1.60**
500 2.05**
250 3.78
500 4.72
250 1.86**
100 1.16
500 1.00
250 4.16*
100 4.50**
250 3.46
100 1.50*
250 4.04
25 2.05***
100 3.78
250 3.52**
50 3.78*
250 3.60**
500 4.72
250 1.00
500 4.04**
500 1.86
100 1.10
-2-OH
-3-OH
-4-OH
-2-CH3
-3-CH3
-4-CH3
-2-OCH3
-3-OCH3
-4-OCH3
-2-Cl
2 % Dimethyl sulfoxide used
as control and its antifungal
activity is nil or zero
SD Standard deviation,
*** P \ 0.001 extremely
significant, ** P \ 0.01
moderately significant,
* P \ 0.05 significant. All
values are presented as mean
of six experiments (n = 6).
All significant differences are
considered from control
value 0.00
6j
6k
6l
-4-Cl
6m
6n
6o
-2-NO2
-4-NO2
-4-F
Griseofulvin
standard drugs to test upon standard microbial strains.
Synthesized compounds were diluted to 1,000 lg/mL
concentration, as a stock solution. Control tube containing
no antibiotic was immediately subcultured (before inocu-
lation) by spreading a loopful evenly over a quarter of plate
of medium suitable for the growth of test organisms. The
tubes were then put for incubation at 37 °C for 24 h for
bacteria. Some 10 lg/mL suspensions were further inocu-
lated on an appropriate media and growth was noted after
24 h and 48 h. The highest dilution (lowest concentration)
preventing appearance of turbidity was considered as MIC
(lg/mL) i.e., the amount of growth from the control tube
before incubation (which represents the original inoculum)
was compared. A set of tubes containing only seeded broth
and solvent controls were maintained under identical con-
ditions so as to make sure that the solvent had no influence
on strain growth. The result of this was greatly affected by
size of inoculum. Test mixture should contain 106 CFU/
mL organisms. Standard drug used in the present study was
‘‘ciprofloxacin’’ for evaluating antibacterial activity which
showed 25, 25, 50, and 50 lg/mL MIC against E. coli, P.
aeruginosa, S. aureus, and S. pyogenes, respectively.
250 lg/mL. Compounds found to be active in primary
screening were similarly diluted to obtain 200, 125, 100,
62.5, 50, 25, and 12.5 lg/mL concentrations for secondary
screening to test in a second set of dilution against all micro-
organisms. Griseofulvin was used as a standard drug for
antifungal activity, which showed 500, 100, and 100 lg/mL
MIC against C. albicans (MTCC 227), A. niger (MTCC
282) and A. clavatus (MTCC 1323). For fungal growth, in
the present protocol, we used Sabourauds dextrose broth at
28 °C in aerobic condition for 48 h.
The cytotoxic potential of compounds 6d, 6e, 6g, 6h, and
6j was also determined in human cancer cell lines such as
A 549, HL-60 and HepG2 according protocols (Skehan et al.,
1990). All of the tested compounds did not show significant
cytotoxic activity and showed the selectivity, in that they
possess potent antibacterial and antifungal activity without
the cytotoxicity in mammalian cells (Ryu et al., 2003).
Statistical analysis
Standard deviation value was expressed in terms of SD.
On the basis of calculated value by one-way ANOVA
method followed by independent two sample t test, it was
observed that differences below 0.001 level were consid-
ered statistically significant. Compounds (6a–o) were
screened for their antibacterial and antifungal activities in
six sets (n) against bacteria and fungi used in the present
protocol.
Antifungal assay
Same compounds (6a–o) were tested for antifungal activity
as primary screening in six sets against C. albicans, A. niger,
and A. clavatus at various concentrations of 1,000, 500, and
123

Med Chem Res
Preparation of N-(5-(hydrazinecarbonyl)-4-
methylthiazol-2-yl)-4-methoxybenzamide (3)
Experimental
All reactions except those in aqueous media were carried
out by standard techniques for the exclusion of moisture.
Melting points were determined on an electrothermal
melting point apparatus and are reported uncorrected. TLC
on silica gel plates (Merck, 60, F254) was used for purity
checking and reaction monitoring. Column chromatogra-
phy on silica gel (Merck, 70–230 mesh and 230–400
mesh ASTH for flash chromatography) was applied when
necessary to isolate and purify the reaction products.
Elemental analysis (% C, H, N) was carried out by a
Perkin-Elmer 2400 CHN analyzer. IR spectra of all com-
pounds were recorded on a Perkin-Elmer FT-IR spectro-
A solution of compound (2) (2.28 g, 0.01 mol) in ethanol
(99.5 %) (20 mL) was heated under reflux with hydrazine
hydrate (1.5 g, 0.03 mol) for 4 h. The reaction mixture was
kept at room temperature and the deposited solid was fil-
tered, washed, dried, and recrystallized by ethanol (95 %).
White crystals, yield: 63 %; m.p.: 141–143 °C; IR (KBr)
m
max/cm-1: 3442, 3426 (NH2), 3262, 3226 (NH), 3074,
3035 (C–H, aromatic), 2937 (C–H, methyl), 1728 (C=O),
1682 (C=O), 1584 (C=N), 1516 (C=C), 1389 (C–H bend-
ing, methyl); 1H NMR (300 MHz, DMSO-d6, d, ppm):
2.45 (s, 3H), 3.85 (s, 3H), 7.17 (d, J = 7.8 Hz, 2H), 7.76
(brs, 1H, NH, D2O exch.), 7.97 (d, J = 7.8 Hz, 2H), 9.26
(brs, 2H, D2O exch.), 10.27 (brs, 1H, D2O exch.); 13C
NMR (100 MHz, DMSO-d6, d, ppm): 18.3 (thiazole-C4–
CH3), 54.1 (OCH3), 114.5–127.8 (Ar–C), 132.6 (thiazole-
C5), 155.7 (thiazole-C4), 161.4 (C=O), 163.4 (thiazole-C2),
163.7 (C–OCH3), 165.5 (C=O linked to phenyl ring);
LCMS (m/z): 306 (M?); Anal. Calcd. For C13H14N4O3S:
C-50.97, H-4.61, N-18.29; Found: C-50.91, H-4.55,
N-18.22 %.
1
photometer in KBr. H NMR spectra were recorded on
Varian Gemini 300 MHz and 13C NMR spectra on Varian
Mercury-400 100 MHz in DMSO-d6 as a solvent and
tetramethylsilane (TMS) as an internal standard. Mass
spectra were scanned on a Shimadzu LCMS 2010 spec-
trometer. Anhydrous reactions were carried out in oven-
dried glassware in nitrogen atmosphere.
Preparation of ethyl 2-(4-methoxybenzamido)-4-
methylthiazole-5-carboxylate (2)
Preparation of 4-methoxy-N-(4-methyl-5-(2-
(phenylcarbamothioyl)hydrazinecarbonyl)thiazol-2-
yl)benzamide (4)
To a solution of ethyl 2-amino-4-methylthiazole-5-car-
boxylate (1) (2.00 g, 0.01 mol) in anhydrous dichloro-
methane (40 mL), pyridine (2.50 g, 0.03 mol) was added,
followed by the drop wise addition of 4-methoxybenzoyl
chloride (1.90 g, 0.01 mmol) at 0–5 °C temperature. The
reaction mixture was stirred at ambient temperature for
18 h, then washed sequentially with 1 N hydrochloric acid
(15 mL), saturated aqueous sodium bicarbonate (30 mL),
and water (15 mL), dried over anhydrous sodium sulfate
and filtered. The filtrate was concentrated in vacuo. The
residue was purified by column chromatography using
hexane–ethyl acetate (4:1) as eluent to afford the title
compound. Yield: 75 %; m.p.: 168–170 °C; IR (KBr)mmax/cm-1
3285, 3247 (NH), 3076, 3046 (C–H, aromatic), 2938 (C–H,
methyl), 1726 (C=O) 1581 (C=N), 1520 (C=C), 1398 (C–H
bending, methyl); 1H NMR (300 MHz, DMSO-d6, d, ppm):
1.34 (t, J = 7.1 Hz, 3H), 2.37 (s, 3H), 3.85 (s, 3H), 4.25 (q,
J = 7.1 Hz, 2H), 7.17 (d, J = 7.6 Hz, 2H), 7.94 (t,
J = 7.4 Hz, 1H), 10.28 (brs, 1H, D2O exch.); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 16.6 (ester-CH3), 54.2
(OCH3), 64.5 (ester-CH2), 18.4 (thiazole-C4–CH3), 115.1
(thiazole-C5), 114.2-127.8 (Ar–C), 158.6 (thiazole-C4),
163.7 (thiazole-C2), 163.4 (C–OCH3), 164.5 (C=O of
ester), 168.6 (C=O of amide); LCMS (m/z): 320 (M?);
Anal. Calcd. For C15H16N2O4S: C-56.24, H-5.03, N-8.74;
Found: C-56.30, H-5.11, N-8.79 %.
To a solution of compound (3) (1.1 g, 0.05 mol) in pyri-
dine (15 mL), phenyl isothiocyanate (0.06 mol) was added
and the mixture was refluxed for 6 h. The reaction mixture
was poured on crushed ice and the separated solid product
is filtered, washed with water, dried, and recrystallized
from ethanol (95 %). Light pink crystals, yield: 75 %;
m.p.: 184–186 °C; IR (KBr) mmax/cm-1: 3276, 3254 (NH),
3068, 3045 (C–H, aromatic), 2933 (C–H, methyl), 1716,
1697 (C=O, amide), 1683 (C=O), 1588 (C=N), 1516
(C=C), 1394 (C–H bending, methyl), 1251, 1033, 994
1
(NCS); H NMR (300 MHz, DMSO-d6, d, ppm): 2.44 (s,
3H), 3.85 (s, OCH3), 6.07 (s, 1H, D2O exch.), 6.80 (t,
J = 8.0 Hz, 1H), 7.23 (t, J = 7.2 Hz, 2H), 7.17 (d,
J = 7.8 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.87 (brs, 1H,
NH, D2O exch.), 7.93 (d, J = 8.4 Hz, 2H), 8.57 (s, 1H,
D2O exch.), 10.26 (s, 1H, D2O exch.); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 18.5 (thiazole-C4–CH3),
54.6 (OCH3), 113.8–127.6 (Ar–C), 132.7 (thiazole-C5),
155.5 (thiazole-C4), 163.3 (thiazole-C2), 163.8 (C–OCH3),
166.5 (C=O linked to phenyl ring), 168.6 (C=O of amide),
179.2 (C=S); LCMS (m/z): 441 (M?); Anal. Calcd. For
C20H19N5O3S2: C-54.41, H-4.34, N-15.86; Found:
C-54.45, H-4.28, N-15.89 %.
123

Med Chem Res
Preparation of N-(4-methyl-5-(2-(4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)thiazol-
2-yl)-4-methoxybenzamide (5)
7.24 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.44 (t,
J = 8.6 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.64 (t,
J = 8.8 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.80 (s, 1H),
7.96 (brs, 1H, NH, D2O exch.), 7.97 (d, J = 7.2 Hz, 2H),
10.24 (s, 1H, D2O exch.); 13C NMR (100 MHz, DMSO-d6,
d, ppm): 18.6 (thiazole-C4–CH3), 54.7 (OCH3), 116.7
(thiazolidinone-C5), 114.2–134.8 (Ar–C), 132.7 (thiazole-
C5), 145.4 (CH=C), 150.5 (thiazolidinone-C2), 154.9
(thiazole-C4), 163.1 (thiazole-C2), 166.2 (C=O linked to
phenyl ring), 163.5 (C–OCH3), 167.5 (thiazolidinone-C4),
168.8 (C=O of amide); LCMS (m/z): 569 (M?); Anal.
Calcd. For C29H23N5O4S2: C-61.15, H-4.07, N-12.29;
Found: C-61.21, H-4.12, N-12.33 %.
A mixture containing compound (4) (0.82 g, 0.002 mol),
monochloroacetic acid (0.28 g, 0.003 mol) and anhydrous
sodium acetate (0.35 g, 0.005 mol) in glacial acetic acid
(20 mL) was refluxed for 4 h, and then poured onto cru-
shed ice. The formed precipitate was filtered, washed with
water and crystallized from acetone. Light brown crystals,
yield: 68 %; m.p.: 176–178 °C; IR (KBr) mmax/cm-1: 3276,
3228 (NH), 3076, 3051 (C–H, aromatic), 2938, 2853 (C–H,
methyl, methylene), 1716, 1694 (C=O, amide), 1687 (C=O
of thiazolidinone), 1580 (C=N), 1553 (C=C), 1407, 1453
1
(C–H bending, methyl, methylene); H NMR (300 MHz,
N-(5-(2-(5-(2-hydroxybenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-
methylthiazol-2-yl)-4-methoxybenzamide (6b)
DMSO-d6, d, ppm): 2.45 (s, 3H), 3.81 (d, J = 15.60 Hz,
1H, thiazolidin-C5–HA), 3.87 (s, 3H), 4.12 (d, J = 15.60 Hz,
1H, thiazolidin-C5–HB), 6.58 (d, J = 8.6 Hz, 2H), 6.81 (t,
J = 8.0 Hz, 1H), 7.15 (d, J = 7.2 Hz, 2H), 7.20 (t,
J = 8.4 Hz, 2H), 7.88 (brs, 1H, NH, D2O exch.), 7.94 (d,
J = 8.1 Hz, 2H), 10.19 (s, 1H, D2O exch.); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 18.5 (thiazole-C4–CH3),
30.7 (thiazolidinone-C5), 54.6 (OCH3), 114.1–136.5 (Ar–
C), 149.6 (thiazolidinone-C2), 132.3 (thiazole-C5), 154.7
(thiazole-C4), 163.5 (thiazole-C2), 163.7 (C–OCH3), 166.4
(C=O linked to phenyl ring), 169.6 (C=O of amide), 171.3
(thiazolidinone C=O); LCMS (m/z): 481 (M?); Anal.
Calcd. For C22H21N5O4S2: C-54.64, H-4.37, N-14.48;
Found: C-54.59, H-4.41, N-14.52 %.
Light brown crystals, yield: 60 %; m.p.: 189–191 °C; IR
(KBr) mmax/cm-1: 3414 (O–H, Ar–OH), 3272, 3234 (NH),
3066, 3044 (C–H, aromatic), 3010 (C–H, CH=C), 2932
(C–H, methyl), 1709 1689 (C=O of amide), 1678 (C=O of
thiazolidinone), 1580 (C=N), 1537 (C=C), 1389 (C–H
bending, methyl), 960 (C–H, CH=C); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 2.44 (s, 3H), 3.86 (s, 3H), 6.77 (d,
J = 8.4 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 7.13 (t, J =
8.2 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.24 (t, J = 8.4 Hz,
1H), 7.62 (d, J = 8.8, 1H), 7.69 (t, J = 7.0 Hz, 2H), 7.78
(d, J = 7.6 Hz, 2H), 7.89 (brs, 1H, NH, D2O exch.), 7.93
(d, J = 8.0 Hz, 2H), 7.98 (s, 1H), 9.16 (s, 1H, D2O exch.),
10.25 (s, 1H, D2O exch.); 13C NMR (100 MHz, DMSO-d6,
d, ppm): 18.3 (thiazole-C4–CH3), 54.8 (OCH3), 116.1
(thiazolidinone-C5), 113.9–129.2 (Ar–C), 132.4 (thiazole-
C5), 145.7 (CH=C), 150.3 (thiazolidinone-C2), 157.5
(C–OH), 166.3 (C=O linked to phenyl ring), 154.6 (thia-
zole-C4), 163.7 (thiazole-C2), 167.1 (thiazolidinone-C4),
168.5 (C=O of amide); LCMS (m/z): 585 (M?); Anal.
Calcd. For C29H23N5O5S2: C-62.91, H-3.80, N-11.74;
Found: C-62.87, H-3.84, N-11.80 %.
General procedure for preparation of N-(5-(2-(5-
(arylidene)-4-oxo-3-phenylthiazolidin-2-
ylidene)hydrazinecarbonyl)-4-methylthiazol-2-yl)-4-
methoxybenzamides (6a–o)
A mixture containing compound (5) (0.90 g, 0.002 mol),
substituted benzaldehydes (0.002 mol) and piperidine (2
drops) in dry dioxane (10 mL) was refluxed for 3–4 h, then
allowed to cool at room temperature. The separated crys-
tals were filtered, air dried and recrystallized from ethanol
(95 %).
N-(5-(2-(5-(3-hydroxybenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-
methylthiazol-2-yl)-4-methoxybenzamide (6c)
N-(5-(2-(5-benzylidene-4-oxo-3-phenylthiazolidin-2-
ylidene)hydrazinecarbonyl)-4-methylthiazol-2-yl)-4-
methoxybenzamide (6a)
Light brown crystals, yield: 59 %; m.p.: 202–204 °C; IR
(KBr) mmax/cm-1: 3415 (O–H, Ar–OH), 3263, 3234 (NH),
3071, 3055 (C–H, aromatic), 3010 (C–H, CH=C), 2932
(C–H, methyl), 1712, 1687 (C=O of amide), 1680 (C=O of
thiazolidinone), 1583 (C=N), 1546 (C=C), 1387 (C–H
bending, methyl), 970 (C–H, CH=C); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 2.44 (s, 3H), 3.84 (s, 3H), 6.70 (s, 1H),
6.85 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 8.7 Hz, 2H), 7.17
(d, J = 7.4 Hz, 1H), 7.22 (t, J = 8.6 Hz, 1H), 7.60
White crystals, yield: 51 %; m.p.: 231–233 °C; IR (KBr)
m
max/cm-1: 3275, 3220 (NH), 3080, 3025 (C–H, aromatic),
3005 (C–H, CH=C), 2936 (C–H, methyl), 1713, 1697
(C=O of amide), 1679 (C=O of thiazolidinone), 1578
(C=N), 1545 (C=C), 1392 (C–H bending, methyl), 969
1
(C–H, CH=C); H NMR (300 MHz, DMSO-d6, d, ppm):
2.41 (s, 3H), 3.82 (s, OCH3), 7.14 (d, J = 8.2 Hz, 2H),
123

Med Chem Res
(t, J = 8.8, 1H), 7.64 (t, J = 7.0 Hz, 2H), 7.76 (d,
J = 8.4 Hz, 2H), 7.85 (s, 1H), 7.93 (brs, 1H, NH, D2O
exch.), 7.96 (d, J = 8.1 Hz, 2H), 9.10 (s, 1H, D2O exch.),
10.16 (s, 1H, D2O exch.); 13C NMR (100 MHz, DMSO-d6,
d, ppm): 18.6 (thiazole-C4–CH3), 54.5 (OCH3), 116.4
(thiazolidinone-C5), 114.7–136.5 (Ar–C), 132.4 (thiazole-
C5), 145.2 (CH=C), 150.3 (thiazolidinone-C2), 154.6 (thi-
azole-C4), 158.2 (C–OH), 163.2 (thiazole-C2), 163.8
(C–OCH3), 165.4 (C=O linked to phenyl ring), 167.8
(thiazolidinone-C4), 168.3 (C=O of amide); LCMS (m/z):
585 (M?); Anal. Calcd. For C29H23N5O5S2: C-62.91,
H-3.80, N-11.74; Found: C-62.93, H-3.82, N-11.81 %.
J = 9.2 Hz, 2H), 7.86 (brs, 1H, NH, D2O exch.), 7.92 (d,
J = 9.0 Hz, 2H), 7.97 (s, 1H), 10.25 (s, 1H, D2O exch.);
13C NMR (100 MHz, DMSO-d6, d, ppm): 18.1 (thiazole-
C4–CH3), 19.3 (CH3), 54.2 (OCH3), 116.1 (thiazolidinone-
C5), 114.7–138.1 (Ar–C), 132.3 (thiazole-C5), 145.7
(CH=C), 150.5 (thiazolidinone-C2), 154.2 (thiazole-C4),
163.3 (thiazole-C2), 163.7 (C–OCH3), 165.8 (C=O linked
to phenyl ring), 167.4 (thiazolidinone-C4), 168.3 (C=O of
amide); LCMS (m/z): 583 (M?); Anal. Calcd. For
C30H25N5O4S2: C-61.73, H-4.32, N-12.00; Found:
C-61.81, H-4.36, N-12.06 %.
N-(5-(2-(5-(3-methylbenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl-)4-
methylthiazol-2-yl)-4-methoxybenzamide (6f)
N-(5-(2-(5-(4-hydroxybenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-
methylthiazol-2-yl)-4-methoxybenzamide (6d)
Light reddish brown crystals, yield: 58 %; m.p.:
234–236 °C; IR (KBr) mmax/cm-1: 3273, 3230 (NH), 3067,
3045 (C–H, aromatic), 3010 (C–H, CH=C), 2938 (C–H,
methyl), 1719, 1694 (C=O of amide), 1683 (C=O of thia-
zolidinone), 1584 (C=N), 1542 (C=C), 1393 (C–H bending,
Light pink crystals, yield: 52 %; m.p.: 212–214 °C; IR
(KBr) mmax/cm-1: 3413 (O–H, Ar–OH), 3273, 3243 (NH),
3067, 3043 (C–H, aromatic), 3018 (C–H, CH=C), 2933 (C–
H, methyl), 1714, 1683 (C=O of amide), 1677 (C=O of
thiazolidinone), 1584 (C=N), 1552 (C=C), 1397 (C–H
bending, methyl), 975 (C–H, CH=C); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 2.46 (s, 3H), 3.87 (s, 3H), 6.64 (d,
J = 7.4 Hz, 2H), 7.17 (d, J = 7.4 Hz, 2H), 7.25 (t,
J = 8.6 Hz, 1H), 7.58 (d, J = 7.8, 2H), 7.66 (t,
J = 7.6 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.80 (s, 1H),
7.96 (brs, 1H, NH, D2O exch.), 7.94 (d, J = 8.2 Hz, 2H),
9.08 (s, 1H, D2O exch.), 10.17 (s, 1H, D2O exch.); 13C
NMR (100 MHz, DMSO-d6, d, ppm): 18.5 (thiazole-C4–
1
methyl), 968 (C–H, CH=C); H NMR (300 MHz, DMSO-
d6, d, ppm): 2.39 (s, 3H), 2.43 (s, 3H), 3.85 (s, 3H), 7.00 (s,
1H), 7.06 (d, J = 8.1 Hz, 1H), 7.12 (t, J = 9.2 Hz, 1H),
7.19 (d, J = 8.4 Hz, 2H), 7.24 (t, J = 7.0 Hz, 1H), 7.34 (d,
J = 8.8, 1H), 7.63 (t, J = 7.6 Hz, 2H), 7.75 (d,
J = 8.4 Hz, 2H), 7.87 (s, 1H), 7.92 (brs, 1H, NH, D2O
exch.), 7.99 (d, J = 8.2 Hz, 2H), 10.21 (s, 1H, D2O exch.);
13C NMR (100 MHz, DMSO-d6, d, ppm): 18.4 (thiazole-
C4–CH3), 21.6 (CH3), 54.1 (OCH3), 116.5 (thiazolidinone-
C5), 113.6–138.2 (Ar–C), 132.5 (thiazole-C5), 145.3
(CH=C), 150.7 (thiazolidinone-C2), 154.4 (thiazole-C4),
163.1 (C–OCH3), 163.8 (thiazole-C2), 165.5 (C=O linked
to phenyl ring), 167.5 (thiazolidinone-C4), 168.7 (C=O of
amide); LCMS (m/z): 583 (M?); Anal. Calcd. For
C30H25N5O4S2: C-61.73, H-4.32, N-12.00; Found:
C-61.68, H-4.37, N-12.09 %.
CH3),
54.2
(OCH3),
116.2
(thiazolidinone-C5),
114.0–130.8 (Ar–C), 132.7 (thiazole-C5), 145.1 (CH=C),
150.7 (thiazolidinone-C2), 154.3 (thiazole-C4), 157.8
(C–OH), 163.6 (thiazole-C2), 163.9 (C–OCH3), 165.3
(linked to phenyl ring), 167.7 (thiazolidinone-C4), 168.4
(C=O of amide); LCMS (m/z): 585 (M?); Anal. Calcd. For
C29H23N5O5S2: C-62.91, H-3.80, N-11.74; Found:
C-62.84, H-3.74, N-11.72 %.
N-(5-(2-(5-(4-methylbenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-
methylthiazol-2-yl)-4-methoxybenzamide (6g)
N-(5-(2-(5-(2-methylbenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)4-
methylthiazol-2-yl)-4-methoxybenzamide (6e)
Light pink crystals, yield: 55 %; m.p.: 188–190 °C; IR
(KBr) mmax/cm-1: 3268, 3240 (NH), 3078, 3041 (C–H,
aromatic), 3007 (C–H, CH=C), 2931 (C–H, methyl), 1716,
1696 (C=O of amide), 1687 (C=O of thiazolidinone), 1588
(C=N), 1542 (C=C), 1386 (C–H bending, methyl), 968
Light yellow crystals, yield: 53 %; m.p.: 196–198 °C; IR
(KBr) mmax/cm-1: 3278, 3234 (NH), 3076, 3052 (C–H,
aromatic), 3008 (C–H, CH=C), 2930 (C–H, methyl), 1714,
1697 (C=O of amide), 1688 (C=O of thiazolidinone), 1584
(C=N), 1562 (C=C), 1401 (C–H bending, methyl), 970
1
(C–H, CH=C); H NMR (300 MHz, DMSO-d6, d, ppm):
1
(C–H, CH=C); H NMR (300 MHz, DMSO-d6, d, ppm):
2.38 (s, 3H), 2.44 (s, 3H), 3.85 (s, 3H), 7.14 (d, J = 8.2 Hz,
2H), 7.18 (d, J = 7.6 Hz, 2H), 7.23 (t, J = 9.0 Hz, 1H),
7.59 (d, J = 7.4, 2H), 7.61 (t, J = 7.8 Hz, 2H), 7.75 (d,
J = 8.4 Hz, 2H), 7.81 (s, 1H), 7.92 (brs, 1H, NH, D2O
exch.), 7.96 (d, J = 8.4 Hz, 2H), 10.08 (s, 1H, D2O exch.);
2.43 (s, 3H), 2.49 (s, 3H), 3.81 (s, 3H), 7.01 (d, J = 8.1 Hz,
1H), 7.12 (t, J = 7.4 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H),
7.26 (t, J = 8.4 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.35 (d,
J = 7.8, 1H), 7.67 (t, J = 7.2 Hz, 2H), 7.73 (d,
123

Med Chem Res
13C NMR (100 MHz, DMSO-d6, d, ppm): 18.4 (thiazole-
C4–CH3), 21.2 (CH3), 54.6 (OCH3), 116.2 (thiazolidinone-
C5), 114.2–137.8 (Ar–C), 132.6 (thiazole-C5), 145.4
(CH=C), 150.3 (thiazolidinone-C2), 154.7 (thiazole-C4),
163.1 (C–OCH3), 163.5 (thiazole-C2), 166.6 (C=O linked
to phenyl ring), 167.5 (thiazolidinone-C4), 168.5 (C=O of
amide); LCMS (m/z): 583 (M?); Anal. Calcd. For
C30H25N5O4S2: C-61.73, H-4.32, N-12.00; Found:
C-61.77, H-4.40, N-11.95 %.
C4–CH3), 54.2 (OCH3), 55.1 (OCH3), 116.3 (thiazolidi-
none-C5), 113.3–136.4 (Ar–C), 132.6 (thiazole-C5), 145.2
(CH=C), 150.4 (thiazolidinone-C2), 154.4 (thiazole-C4),
160.3 (C–OCH3), 163.2 (thiazole-C2), 163.7 (C–OCH3),
166.2 (C=O linked to phenyl ring), 167.5 (thiazolidinone-
C4), 168.8 (C=O of amide); LCMS (m/z): 599 (M?); Anal.
Calcd. For C30H25N5O5S2: C-60.09, H-4.63, N-12.26;
Found: C-60.03, H-4.70, N-12.20 %.
N-(5-(2-(5-(4-methoxybenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-
methylthiazol-2-yl)-4-methoxybenzamide (6j)
N-(5-(2-(5-(2-methoxybenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-
methylthiazol-2-yl)-4-methoxybenzamide (6h)
Light reddish crystals, yield: 50 %; m.p.: 225–227 °C; IR
(KBr) mmax/cm-1: 3280, 3232 (NH), 3078, 3048 (C–H,
aromatic), 3012 (C–H, CH=C), 2930 (C–H, methyl), 1716,
1696 (C=O of amide), 1684 (C=O of thiazolidinone), 1579
(C=N), 1532 (C=C), 1394 (C–H bending, methyl), 1202,
Light yellow crystals, yield: 58 %; m.p.: 175–177 °C; IR
(KBr) mmax/cm-1: 3274, 3236 (NH), 3078, 3041 (C–H,
aromatic), 3006 (C–H, CH=C), 2934 (C–H, methyl), 1717,
1696 (C=O of amide), 1683 (C=O of thiazolidinone), 1587
(C=N), 1537 (C=C), 1389 (C–H bending, methyl), 1216,
1
1148 (C–O–C), 978 (C–H, CH=C); H NMR (300 MHz,
1
1150 (C–O–C), 970 (C–H, CH=C); H NMR (300 MHz,
DMSO-d6, d, ppm): 2.38 (s, 3H), 3.73 (s, 3H), 3.86 (s, 3H),
6.95 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.22 (t,
J = 7.2 Hz, 1H), 7.59 (t, J = 7.2 Hz, 2H), 7.66 (d,
J = 7.4, 2H), 7.78 (d, J = 7.6 Hz, 2H), 7.83 (s, 1H), 7.92
(brs, 1H, NH, D2O exch.), 7.98 (d, J = 9.0 Hz, 2H), 10.18
(s, 1H, D2O exch.); 13C NMR (100 MHz, DMSO-d6, d,
ppm): 18.4 (thiazole-C4–CH3), 54.8 (OCH3), 55.3 (OCH3),
116.0 (thiazolidinone-C5), 114.1–131.3 (Ar–C), 132.8
(thiazole-C5), 145.7 (CH=C), 150.4 (thiazolidinone-C2),
154.7 (thiazole-C4), 159.2 (C–OCH3), 163.1 (C–OCH3),
163.7 (thiazole-C2), 165.9 (C=O linked to phenyl ring),
167.7 (thiazolidinone-C4), 168.4 (C=O of amide); LCMS
(m/z): 599 (M?); Anal. Calcd. For C30H25N5O5S2: C-60.09,
H-4.63, N-12.26; Found: C-60.14, H-4.57, N-12.34 %.
DMSO-d6, d, ppm): 2.43 (s, 3H), 3.76 (s, 3H), 3.86 (s, 3H),
6.95 (d, J = 8.0 Hz, 1H), 6.99 (t, J = 7.2 Hz, 1H), 7.13 (d,
J = 8.6 Hz, 2H), 7.20 (t, J = 7.6 Hz, 1H), 7.28 (t,
J = 8.4 Hz, 1H), 7.65 (t, J = 7.8 Hz, 2H), 7.69 (d,
J = 7.2 Hz, 1H), 7.76 (d, J = 7.4 Hz, 2H), 7.85 (brs, 1H,
NH, D2O exch.), 7.92 (d, J = 8.2 Hz, 2H), 7.97 (s, 1H),
10.17 (s, 1H, D2O exch.); 13C NMR (100 MHz, DMSO-d6,
d, ppm): 18.2 (thiazole-C4-CH3), 54.7 (OCH3), 56.1
(OCH3), 116.5 (thiazolidinone-C5), 113.7–128.8 (Ar–C),
132.5 (thiazole-C5), 145.3 (CH=C), 150.6 (thiazolidinone-
C2), 154.5 (thiazole-C4), 159.3 (C–OCH3), 163.2 (thiazole-
C2), 163.8 (C–OCH3), 166.3 (C=O linked to phenyl ring),
167.3 (thiazolidinone-C4), 168.4 (C=O of amide); LCMS
(m/z): 599 (M?); Anal. Calcd. For C30H25N5O5S2: C-60.09,
H-4.63, N-12.26; Found: C-60.17, H-4.68, N-12.30 %.
N-(5-(2-(5-(2-chlorobenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-
methylthiazol-2-yl)-4-methoxybenzamide (6k)
N-(5-(2-(5-(3-methoxybenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-
methylthiazol-2-yl)-4-methoxybenzamide (6i)
Light yellow crystals, yield: 59 %; m.p.: 169–171 °C; IR
(KBr) mmax/cm-1: 3276, 3237 (NH), 3085, 3053 (C–H,
aromatic), 3005 (C–H, CH=C), 2932 (C–H, methyl), 1712,
1693 (C=O of amide), 1687 (C=O of thiazolidinone), 1595
(C=N), 1534 (C=C), 1397 (C–H bending, methyl), 969
Light yellow crystals, yield: 54 %; m.p.: 210–203 °C; IR
(KBr) mmax/cm-1: 3273, 3228 (NH), 3082, 3054 (C–H,
aromatic), 3009 (C–H, CH=C), 2929 (C–H, methyl), 1717,
1697 (C=O of amide), 1685 (C=O of thiazolidinone), 1585
(C=N), 1560 (C=C), 1382 (C–H bending, methyl), 1206,
1
(C–H, CH=C), 754 (C–Cl); H NMR (300 MHz, DMSO-
d6, d, ppm): 2.51 (s, 3H), 3.80 (s, 3H), 7.13 (d, J = 8.2 Hz,
2H), 7.18 (t, J = 8.4 Hz, 1H), 7.25 (t, J = 7.2 Hz, 1H),
7.29 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.52 (d,
J = 7.6, 1H), 7.65 (t, J = 9.0 Hz, 2H), 7.73 (d,
J = 8.4 Hz, 2H), 7.87 (brs, 1H, NH, D2O exch.), 7.92 (d,
J = 8.0 Hz, 2H), 7.97 (s, 1H), 10.17 (s, 1H, D2O exch.);
13C NMR (100 MHz, DMSO-d6, d, ppm): 18.6 (thiazole-
C4–CH3), 54.6 (C–OCH3), 116.5 (thiazolidinone-C5),
114.7–134.5 (Ar–C), 145.4 (CH=C), 150.7 (thiazolidinone-
1
1157 (C–O–C), 968 (C–H, CH=C); H NMR (300 MHz,
DMSO-d6, d, ppm): 2.40 (s, 3H), 3.72 (s, 3H), 3.85 (s, 3H),
6.86 (d, J = 7.8 Hz, 1H), 7.13 (s, 1H), 7.18 (d, J = 8.2 Hz,
2H), 7.23 (d, J = 8.2 Hz, 1H), 7.27 (t, J = 8.6 Hz, 1H),
7.59 (t, J = 7.3, 1H), 7.65 (t, J = 7.5 Hz, 2H), 7.76 (d,
J = 7.4 Hz, 2H), 7.84 (s, 1H), 7.92 (brs, 1H, NH, D2O
exch.), 7.98 (d, J = 8.0 Hz, 2H), 10.17 (s, 1H, D2O exch.);
13C NMR (100 MHz, DMSO-d6, d, ppm): 18.4 (thiazole-
123

Med Chem Res
C2), 132.4 (thiazole-C5), 154.6 (thiazole-C4), 163.3 (thia-
zole-C2), 163.7 (C–OCH3), 165.6 (C=O linked to phenyl
ring), 167.7 (thiazolidinone-C4), 168.5 (C=O of amide);
LCMS (m/z): 604 (M?); Anal. Calcd. For C29H22ClN5
O4S2: C-57.66, H-3.68, N-11.59; Found: C-57.60, H-3.62,
N-11.54 %.
C4), 168.3 (C=O of amide); LCMS (m/z): 614 (M?); Anal.
Calcd. For C29H22N6O6S2: C-56.67, H-3.61, N-13.67;
Found: C-56.73, H-3.57, N-13.72 %.
N-(5-(2-(5-(4-nitrobenzylidene)-4-oxo-3-phenylthiazolidin-
2-ylidene)hydrazinecarbonyl)-4-methylthiazol-2-yl)-4-
methoxybenzamide (6n)
N-(5-(2-(5-(4-chlorobenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-
methylthiazol-2-yl)-4-methoxybenzamide (6l)
Dark yellowish orange crystals, yield: 53 %; m.p.:
189–191 °C; IR (KBr) mmax/cm-1: 3273, 3228 (NH), 3065,
3058 (C–H, aromatic), 3014 (C–H, CH=C), 2937 (C–H,
methyl), 1712, 1696 (C=O of amide), 1687 (C=O of thia-
zolidinone), 1573 (C=N), 1512 (C=C), 1485, 1358 (NO2),
1388 (C–H bending, methyl), 967 (C–H, CH=C); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 2.53 (s, 3H), 3.86 (s, 3H),
7.17 (d, J = 7.7 Hz, 2H), 7.24 (t, J = 7.0 Hz, 1H), 7.63 (t,
J = 8.2 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.86 (s, 1H),
7.91 (d, J = 8.6 Hz, 2H), 7.95 (brs, 1H, NH, D2O exch.),
8.03 (d, J = 8.1, 2H), 8.21 (d, J = 7.6 Hz, 2H), 10.23 (s,
1H, D2O exch.); 13C NMR (100 MHz, DMSO-d6, d, ppm):
18.5 (thiazole-C4–CH3), 116.3 (thiazolidinone-C5),
114.8–129.4 (Ar–C), 145.4 (CH=C), 132.7 (thiazole-C5),
147.0 (C–NO2), 150.1 (thiazolidinone-C2), 154.6 (thiazole-
C4), 161.5 (C=O), 163.2 (thiazole-C2), 163.7 (C–OCH3),
165.9 (C=O linked to phenyl ring), 167.6 (thiazolidinone-
C4), 168.6 (C=O of amide); LCMS (m/z): 614 (M?); Anal.
Calcd. For C29H22N6O6S2: C-56.67, H-3.61, N-13.67;
Found: C-56.63, H-3.67, N-13.62 %.
Light brown crystals, yield: 61 %; m.p.: 211–213 °C; IR
(KBr) mmax/cm-1: 3268, 3236 (NH), 3083, 3044 (C–H,
aromatic), 3009 (C–H, CH=C), 2932 (C–H, methyl), 1715,
1694 (C=O of amide), 1687 (C=O of thiazolidinone), 1584
(C=N), 1528 (C=C), 1390 (C–H bending, methyl), 978
1
(C–H, CH=C), 758 (C–Cl); H NMR (300 MHz, DMSO-
d6, d, ppm): 2.48 (s, 3H), 7.16 (d, J = 8.6 Hz, 2H), 7.25 (t,
J = 8.0 Hz, 1H), 7.41 (t, J = 7.2 Hz, 2H), 7.60 (t,
J = 9.0 Hz, 2H), 7.69 (d, J = 8.8, 2H), 7.75 (d,
J = 7.4 Hz, 2H), 7.84 (s, 1H), 7.96 (brs, 1H, NH, D2O
exch.), 10.17 (s, 1H, D2O exch.); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 18.7 (thiazole-C4–CH3), 54.3 (OCH3),
116.3 (thiazolidinone-C5), 114.7–133.8 (Ar–C), 132.2
(thiazole-C5), 145.7 (CH=C), 150.4 (thiazolidinone-C2),
154.6 (thiazole-C4), 163.2 (thiazole-C2), 163.7 (C–OCH3),
166.5 (C=O linked to phenyl ring), 167.9 (thiazolidinone-
C4), 168.7 (C=O of amide); LCMS (m/z): 604 (M?); Anal.
Calcd. For C29H22ClN5O4S2: C-57.66, H-3.68, N-11.59;
Found: C-57.72, H-3.51, N-11.64 %.
N-(5-(2-(5-(4-fluorobenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-
methylthiazol-2-yl)-4-methoxybenzamide (6o)
N-(5-(2-(5-(2-nitrobenzylidene)-4-oxo-3-phenylthiazolidin-
2-ylidene)hydrazinecarbonyl)-4-methylthiazol-2-yl)-4-
methoxybenzamide (6m)
Light yellow crystals, yield: 50 %; m.p.: 158–160 °C; IR
(KBr) mmax/cm-1: 3283, 3258 (NH), 3074, 3029 (C–H, aro-
matic), 3006 (C–H, CH=C), 2938 (C–H, methyl), 1719, 1695
(C=O of amide), 1686 (C=O of thiazolidinone), 1588 (C=N),
1536 (C=C), 1418 (C–H bending, methyl), 1132 (C–F), 972
(C–H, CH=C); 1H NMR (300 MHz, DMSO-d6, d, ppm): 2.52
(s, 3H), 3.84 (s, 3H), 7.17 (d, J = 7.4, 2H), 7.12 (d,
J = 8.4 Hz, 2H), 7.27 (t, J = 8.2 Hz, 1H), 7.64 (t,
J = 8.6 Hz, 2H), 7.71 (d, J = 7.2 Hz, 2H), 7.79 (d,
J = 8.0 Hz, 2H), 7.84 (s, 1H), 7.94 (d, J = 9.0 Hz, 2H), 7.98
(brs, 1H, NH, D2O exch.), 10.26 (s, 1H, D2O exch.); 13C
NMR (100 MHz, DMSO-d6, d, ppm): 18.1 (thiazole-C4–
CH3), 54.7 (OCH3), 116.5 (thiazolidinone-C5), 114.7–131.6
(Ar–C), 132.7 (thiazole-C5), 145.8 (CH=C), 150.4 (thiazo-
lidinone-C2), 154.6 (thiazole-C4), 161.4 (C=O), 162.3 (C–F),
163.4 (thiazole-C2), 166.3 (C=O linked to phenyl ring), 167.5
(thiazolidinone-C4), 168.4 (C=O of amide); LCMS (m/z): 587
(M?); Anal. Calcd. For C29H22FN5O4S2: C-59.27, H-3.77,
N-11.92; Found: C-59.32, H-3.72, N-11.87 %.
Orange crystals, yield: 56 %; m.p.: 234–236 °C; IR (KBr)
m
max/cm-1: 3275, 3237 (NH), 3081, 3056 (C–H, aromatic),
3015 (C–H, CH=C), 2932 (C–H, methyl), 1718, 1692
(C=O of amide), 1686 (C=O of thiazolidinone), 1587
(C=N), 1534 (C=C), 1482, 1354 (NO2), 1385 (C–H bend-
ing, methyl), 982 (C–H, CH=C); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 2.51 (s, 3H), 3.84 (s, 3H), 7.17 (d,
J = 7.2 Hz, 2H), 7.25 (t, J = 7.4 Hz, 1H), 7.64 (t,
J = 8.4 Hz, 2H), 7.75 (d, J = 9.0 Hz, 2H), 7.83 (t,
J = 7.2 Hz, 1H), 7.91 (brs, 1H, NH, D2O exch.), 7.97 (t,
J = 8.4 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 8.12 (d,
J = 7.4 Hz, 2H), 8.27 (d, J = 7.8, 1H), 8.35 (s, 1H), 10.22
(s, 1H, D2O exch.); 13C NMR (100 MHz, DMSO-d6, d,
ppm): 18.6 (thiazole-C4–CH3), 116.8 (thiazolidinone-C5),
114.5-134.8 (Ar–C), 132.7 (thiazole-C5), 148.8 (C–NO2)
145.3 (CH=C), 147.1 (C–NO2), 150.7 (thiazolidinone-C2),
154.8 (thiazole-C4), 163.1 (thiazole-C2), 163.4 (C–OCH3),
166.5 (C=O linked to phenyl ring), 167.5 (thiazolidinone-
123

Med Chem Res
Finegold SM, Garrod L (1995) Bailey and Scott’s diagnostic
microbiology, 8th edn., Chap 13. C.V. Mosby, Toronto,
pp 171–193
Conclusion
In conclusion, a series of novel thiazole compounds con-
taining a thiazolidine group were prepared successfully
through an easy, convenient, and efficient synthetic
method. Their antibacterial and antifungal activities results
showed that most of the synthesized derivatives exhibited
significant in vitro activities. The derivatives 6e, 6g, and 6j
containing methyl and methoxy groups were the most
potent compounds against all tested strains with the MIC
values ranging from 12.5 to 25 lg/mL, and exhibited much
stronger activities than the reference drugs ciprofloxacin
and griseofulvin. The type of heterocyclic framework, size
of bulky groups, hydrophilicity and nature of substituent
had a notable effect on the antimicrobial activity of the
target compounds. Further research on these potential new
antimicrobial agents is underway in our group.
Ghazzi MN, Perez JE, Antonucci TK, Driscoll JH, Huang SM, Faja
BW, Whitcomb RW (1997) Cardiac and glycemic benefits of
troglitazone treatment in NIDDM. The Troglitazone Study
Group. Diabetes 46:433–439. doi:10.2337/diabetes.46.3.433
Havrylyuk D, Zimenkovsky B, Lesyk R (2009) Synthesis and
anticancer activity of novel nonfused bicyclic thiazolidinone
derivatives. Phosphorus Sulfur Silicon Relat Elem 184:638–650.
doi:10.1080/10426500802247563
Kato Y, Kita Y, Nishio M, Hirasawa Y, Ito K, Yamanaka T,
Motoyama Y, Seki J (1999a) In vitro antiplatelet profile of
FR171113, a novel non-peptide thrombin receptor antagonist.
Eur J Pharmacol 384:197–202. doi:10.1016/S0014-2999(99)
00658-5
Kato T, Ozaki T, Ohi N (1999b) Improved synthetic methods of CP-
060S, a novel cardioprotective drug. Tetrahedron Asymmetry
10:3963–3968. doi:10.1016/S0957-4166(99)00441-3
Kato T, Ozaki T, Tamura K, Suzuki Y, Akima M, Ohi N (1999c)
Novel calcium antagonists with both calcium overload inhibition
and antioxidant activity. 2. Structure–activity relationships of
thiazolidinone derivatives. J Med Chem 42:3134–3146. doi:
10.1021/jm9900927
Norisada N, Masuzaki H, Fujimoto M, Inoue G, Hosoda K, Hayashi
T, Watanabe M, Muraoka S, Yoneda F, Nakao K (2004)
Antidiabetic and adipogenic properties in a newly synthesized
thiazolidine derivative, FPFS-410. Metabolism 53:1532–1537.
doi:10.1016/j.metabol.2004.06.020
Acknowledgments We would like to express our sincere gratitude
to the Department of Chemistry (DST-FIST Sponsored Department),
Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar
University, Bhavnagar for providing research and library facilities.
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