Synthesis and antimicrobial activity of some new thiazolyl thiazolidine-2,4-dione derivatives

Article abstract of DOI:10.1016/j.bmc.2007.06.049

In this study, a series of thiazolyl thiazolidine-2,4-dione derivatives (Va-f and VIa-f) were synthesized and evaluated for their antibacterial and antifungal activities against Staphylococcus aureus (ATCC 25923), methicillin resistant S. aureus (MRSA ATC

Full text of DOI:10.1016/j.bmc.2007.06.049

Bioorganic & Medicinal Chemistry 15 (2007) 6012–6017
Synthesis and antimicrobial activity of some new thiazolyl
thiazolidine-2,4-dione derivatives
b
a
c
c
Oya Bozdag˘-Dundar,a, Ozen Ozgen, Arzu Menteßse, Nurten Altanlar, Onur Atlı,
*
¨
¨
¨
Engin Kendib and Rahmiye Ertana
aAnkara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100 Tandog˘an, Ankara, Turkey
bHacettepe University, Department of Physics Engineering, 06800 Beytepe, Ankara, Turkey
cAnkara University, Faculty of Pharmacy, Department of Microbiology, Tandog˘an, Ankara, Turkey
Received 9 April 2007; revised 21 June 2007; accepted 26 June 2007
Available online 29 June 2007
Abstract—In this study, a series of thiazolyl thiazolidine-2,4-dione derivatives (Va–f and VIa–f) were synthesized and evaluated for
their antibacterial and antifungal activities against Staphylococcus aureus (ATCC 25923), methicillin resistant S. aureus (MRSA
ATCC 43300), methicillin resistant S. aureus (MRSA isolate), and Escherichia coli (ATCC 23556) and C. albicans (ATCC10145).
All the compounds were found active against used microorganisms.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
positive pathogens including Staphylococci, Strepto-
cocci, and Enterococci.14 It has been known that the en-
trance of arylidene moieties at different positions of the
thiazolidine ring enhanced the antimicrobial activ-
ity.15,16 Organic compounds bearing thiazoles of differ-
ent pharmacodynamic nuclei were found to possess
potent antibacterial17 and antifungal18 activities.
Bacterial infections have increased dramatically in recent
years. Bacteria have been the cause of some of the most
deadly diseases and widespread epidemics in human civ-
ilization. Bacterial diseases such as tuberculosis, typhus,
plague, diphtheria, typhoid fever, cholera, dysentery,
and pneumonia have taken a high toll on humanity.1
Previously, we reported that the synthesis and antimicro-
bial evaluation of 3-substituted-benzyl-5-(4-chloro-2-pip-
eridin-1yl-thiazole-5-yl-methylene)-thiazolidine-2,4-dione
derivatives showed a comparable activity to that of
ampicillin against Escherichia coli.19 As part of an ongoing
research, herein, we have synthesized a new series of thiaz-
olo-substituted phenacyl-2,4-thiazolidinediones VIa–f be-
sides the antimicrobial activity and the SAR of a series of
newly (VIa–f) and previously synthesized thiazolo-substi-
tuted benzyl-2,4-thiazolidinedione derivatives Va–f20 were
described in order to reveal the lead optimization against
the tested various bacteria and the fungus C. albicans.
The introduction of antibiotics in the 1940 s was thought
to have eliminated the scourge of all infectious diseases.
However, due to the widespread use and misuse of anti-
biotics, bacterial resistance to antibiotics has become a
serious public health problem. Some of these resistant
strains, such as vancomycin-resistant enterococci
(VRE) and multidrug resistant Staphylococcus aureus
(MRSA), are capable of surviving the effects of most,
if not all, antibiotics currently in use.2–6 With the
increase in resistance of bacteria to antibiotic treatment,
attention has focused on developing novel approaches
to antimicrobial therapy.7–13
1,3-Thiazolidines are the new class of antimicrobial
agents with activity against broad spectrum of Gram-
2. Results and discussion
2.1. Chemistry
Keywords: Thiazolidine-2,4-diones; Thiazole derivatives; Antimicro-
bial activity; Single-X-ray structure.
Thiazolyl-2,4-thiazolidinedione compounds Va–f, VIa–
f were synthesized according to the synthetic pathway
described in Scheme 1. 2,4-dichlorothiazole-5-carbalde-
*
Corresponding author. Tel.: +90 312 2126805/2167; fax: +90 312
2131081; e-mail: bozdag@pharmacy.ankara.edu.tr
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.06.049

O. Bozdag˘-Du¨ndar et al. / Bioorg. Med. Chem. 15 (2007) 6012–6017
6013
O
O
ArCOCH2Br
Ar CO CH2
N
KN
O
S
S
O
IVa-f
KOH
O
O
S
Cl
H
O
POCl3 / DMF
HN
O
N
S
S
Ar CO CH2
N
Cl
Cl
I
II
S
N
O
ArCH2Br
O
Cl
VIa-f
Ar CH2
N
S
IIIa-f
O
O
S
Ar CH2
N
Cl
S
N
O
Cl
Va-f
Scheme 1. General synthesis of Va–f, VIa–f.
hyde (II) was obtained with 2,4-TZD15 (I) and N,N-
dimethylformamide in phosphoryl
chloride.21
the chloro and dichloro substituents at the para-posi-
tion and ortho/para-position of the aryl groups at N-
3 position of the TZD ring, respectively. The
Substituted benzyl-2,4-thiazolidinediones IIIa–f were
obtained by 2,4-TZD (1) and appropriate benzyl halide
derivatives in NaOH/ethanol. Substituted phenacyl-
2,4-thiazolidinediones IVa–f were synthesized by react-
ing potassium 2,4-thiazolidinedione with appropriate
phenacylbromide derivatives in hot methanol. The con-
densation of 2,4-dichlorothiazole-5-carbaldehyde II
with substituted benzyl-2,4-thiazolidinediones IIIa–f
and phenacyl-2,4-thiazolidinediones IVa–f in the
presence of sodium acetate/acetic acid glacial by Knoe-
venagel reaction led to thiazolo-substituted benzyl-2,4-
thiazolidinediones Va–f20and thiazolo-substituted
phenacyl-2,4-thiazolidinediones VIa–f, respectively.
stereoisomers (VIc and VIe) were isolated using silica
gel column chromatography. H NMR spectrums of
1
VIc-1 and VIe-1 were very similar to those of VIc-2
and VIe-2 except for the signal due to the methine pro-
ton, respectively. The methine proton of the VIc-1 and
VIe-1 appeared at a lower field than that of the VIc-2
and VIe-2. It was reported that the methine proton,
deshielded by the adjacent C@O, was detected at
7.70–7.75 ppm in 1H NMR spectra as observed for
analogues 5-arylidene-2,4-TZDs.25 In E isomers, due
to the lesser deshielding effect of 1-S of the TZD ring,
such a proton should resonate at lower chemical shift
values.26 The calculated values of the methyne
protons of VIc-1/VIe-1 and VIc-2/VIe-2 were seen as
In the literature, it was reported that in reactions using
unsubstituted imidazolidinediones and benzaldehydes
in acidic medium, the main product was the Z iso-
mer.22 The coupled 13C NMR study of arylidene thia-
zolidinediones and imidazolidinediones also showed
that the Z isomer was formed.23,24 In this study, only
one isomer was obtained except VIc and VIe having
a singlet at 8.05–8.04 ppm and 7.34–7.33 ppm,
respectively.
Furthermore, the X-ray diffractometric analysis of a
representative compound VIc-1 unambiguously con-
firmed the Z configuration at the chiral axis (Fig. 1).
Figure 1. X-ray structure of VIc-1.

6014
O. Bozdag˘-Du¨ndar et al. / Bioorg. Med. Chem. 15 (2007) 6012–6017
Methyne protons for compounds VIa,b,d,f were seen at
8.04–8.06 ppm as a singlet. In Mass spectra, all the com-
pounds have M+22 ion peak with MS ESI method.
and MRSA ATCC 43300 with a MIC value of 6.25
and 12.5 lg/ml, respectively. While compounds Va, Vf,
VId were more potent against MRSA ATCC 43,300,
compounds Vd, VIc-2 were more potent against MRSA
(isolate).
2.2. In vitro antibacterial and antifungal activity
All the newly synthesized thiazolyl-2,4-thiazolidinedione
compounds Va–f, VIa–f were tested for their in vitro
antibacterial activity against S. aureus (ATCC 25923),
methicillin resistant S. aureus (MRSA ATCC 43300),
methicillin resistant S. aureus (MRSA isolate) as
Gram-positive bacteria, E. coli (ATCC 23556) as
Gram-negative bacterium, and the antifungal activity
was evaluated against C. albicans (ATCC10145). The
MIC values were determined by twofold serial dilution
technique27 in Mueller–Hinton broth and Sabouraud
dextrose agar for the antibacterial and antifungal assays,
respectively. In comparison with the antimicrobial activ-
ity, ampicillin and ciprofloxacin were used as the refer-
ence antibacterial agents, miconazole was used as the
reference antifungal agent. All the biological results of
the tested compounds are given in Table 1. The com-
bined data were reported that the synthesized com-
pounds Va–f, VIa–f showing MIC values between 50
and 6.25 lg/ml were able to have an in vitro inhibitory
effect against the screened microorganisms.
All of the compounds indicated significant inhibitory ef-
fect with MIC values between 6.25 and 12.5 lg/ml
against S. aureus ATCC 23556 as well; suprisingly, the
derivatives Vb–d, Vf, VIa–VIc-1 showed comparable
activity with ampicillin. Structure–activity relationships
revealed that attaching an electron-withdrawing group
such as halogen or nitro on position R of phenyl ring
which has to bind with a methylene bridge instead of
acetyl to TZD played a very important role to increase
the activity. It should be pointed out that while the con-
figuration of VIe did not change the activity against
either MRSA ATCC 43300 or S. aureus strains, the Z
configuration of VIc was found to have onefold better
dilution than E configuration. Additionally, the com-
pounds VIb and VId, which have a fluorine and bromine
at the para-position of phenacyl groups, respectively,
were found to be more active than ampicillin against
Gram-negative bacterium E. coli ATCC 23556, as for
other compounds except VIc-2 showed similar activity.
All of the derivatives indicated very significant anti-
fungal activity against C. albicans ATCC10145, the
MICs ranged from 6.25 to 12.5 lg/ml even they were
higher than that of standard drug, miconazole. The
structure–activity relationships showed that the anti-
fungal activity of the substituents at the phenyl ring is
H, Cl, Br,o,p-di-Cl > F, NO2 for benzylic 2,4-TZD com-
pounds. As for phenacyl 2,4-TZD compounds, it is
Cl,Br > H, F,o,p-di-Cl, NO2. This kind of structure
could be guide for further antifungal studies.
As seen in Table 1, although none of the compounds
showed more activity against methicillin resistant S.
aureus (MRSA ATCC 43300) than ampicilin, the deriv-
atives Va–c, Vf, VIa–VIc-1, VId were found to be signif-
icantly potent with a MIC value of 6.25 lg/ml. It can be
concluded that a chlorine atom at position R1 slightly
decreased an inhibitory effect. Furthermore, compounds
Vb, Vc, VIa, VIb, VIc-1 and Ve, VIe-1, VIe-2, VIf
showed similar activity against either MRSA (isolate)
Table 1. Antibacterial and antifungal activity of the compounds Va–f , VIa–f (MIC, minimum inhibitory concentration lg/ml)
O
S
R
Cl
X
N
S
N
R1
O
Cl
Compound
X
R
R1
MRSA
ATCC 43300
MRSA
(isolate)
S. aureus
ATCC 25923
E. coli
ATCC 23556
C. albicans
ATCC10145
Va
Vb
—
—
H
H
H
H
H
Cl
H
H
H
H
H
H
Cl
Cl
H
6.25
6.25
6.25
12.5
12.5
6.25
6.25
6.25
6.25
12.5
6.25
12.5
12.5
12.5
6.25
6.25
6.25
12.5
12.5
6.25
6.25
6.25
6.25
12.5
12.5
12.5
12.5
6.25
6.25
6.25
12.5
6.25
6.25
6.25
6.25
12.5
12.5
12.5
12.5
25
25
6.25
12.5
6.25
6.25
6.25
12.5
12.5
12.5
6.25
6.25
6.25
12.5
12.5
6.25
F
Vc
Vd
—
—
Cl
Br
Cl
NO2
H
25
25
Ve
Vf
—
—
25
25
VIa
VIb
CO
CO
CO
CO
CO
CO
CO
CO
25
F
6.25
25
50
VIc-1
VIc-2
VId
Cl
Cl
Br
Cl
Cl
NO2
6.25
25
25
VIe-1
VIe-2
VIf
12.5
a
12.5
a
12.5
a
25
a
Miconazole
Ampicillin
Ciprofloxacin
25
a
1.56
a
1.56
a
6.25
a
25
a
0.78
a No tested.

O. Bozdag˘-Du¨ndar et al. / Bioorg. Med. Chem. 15 (2007) 6012–6017
6015
On the other hand, when we generally glanced at all of
the values for C. albicans it should be pointed out that
isomeric compounds VIc-1/VIc-2 and VIe-1/VIe-2 did
not show any difference in activity.
structure factors) for compound VIc-1 have been depos-
ited with the Cambridge Crystallographic Data Centre
as supplementary publication No. CCDC 626234 Copies
of the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: +44 1223 336033; e-mail: depositcdc.cam.ac.uk).
3. Conclusion
4.2. Synthesis of 2,4-dichlorothiazole-5-carbaldehyde (II)
We report the synthesis and antimicrobial activity of a
new series of thiazolyl thiazolidine-2,4-diones (Va–f
and VIa–f). In this study only one isomer was obtained
except VIc and VIe having the chloro and dichloro sub-
stituents at the para-position and ortho/para-position of
the phenacyl group in phenacyl thiazolyl TZD com-
pounds, respectively. All the compounds were found
to be moderately potent against screened microorgan-
isms. In particular, the antifungal effects of all tested
compounds were higher than that of standard drug,
miconazole. According to this study, it should be
pointed out that benzyl or phenacyl groups on the
TZD ring did not play a noticeable role for increasing
the activity.
N,N-Dimethylformamide (1.61 g, 0.021 mol) was added
dropwise during 5 min to a stirred suspension of 2,4-
TZD (I) (2.5 g, 0.021 mol) in phosphoryl chloride
(19.74 g, 0.129 mol) at 10–20 ꢁC. After the addition the
resulting mixture was kept at ambient temperature for
1 h, after which it was heated to 80–90 ꢁC and stirred
at this temperature for a further 1 h. The mixture was
heated under reflux and stirred at this temperature
(ꢀ115 ꢁC) until gas evolution ceased (ꢀ4 h). After cool-
ing, the reaction mixture was stirred slowly onto ice. The
product was extracted with dichloromethane (3· 50 ml)
and the extracts were combined, washed successively
with aqueous NaHCO3 and water, then dried on anhy-
drous Na2SO4 and distilled off under reduced pressure.
The crude product was crystallized from light petroleum
(1.6 g, 41.13%). Mp: 48 ꢁC (Ref. 21 mp: 48–49 ꢁC).
4. Experimental
4.1. Chemistry
4.3. 3-[2-(2,4-Dichloro-phenyl)-2-oxo-ethyl]-thiazolidine-
2,4-dione (IVe)
Melting points were determined with a Buchi SMP-20
¨
melting point apparatus (Essen, Germany) and are
uncorrected. All instrumental analyses were performed
in Central Lab. of Pharmacy Faculty of Ankara Univer-
sity. IR spectra were recorded on a Jasco FT/IR-420
spectrometer (Easton, USA) as potassium bromide
discs. 1H NMR spectra were measured with a VARIAN
Mercury 400 FT-NMR spectrometer (Palo Alto, CA,
USA) in CDCl3. All chemical shifts were reported as d
(ppm) values. Mass spectra were recorded on Waters
Micromass ZQ (Waters Corporation, Milford, MA,
USA) by using ESI (+) method. Elementary analyses
were determined on a Leco CHNS 932 analyzer (Leco,
St. Joseph, MI, USA) and satisfactory results 0.4%
of calculated values (C, H, N) were obtained. For the
chromatographic analysis Merck Silica Gel 60 (230–
400 mesh ASTM = American Society for Testing and
Materials) was used. The chemical reagents used in syn-
thesis were purchased from E. Merck (Darmstadt, Ger-
many) and Aldrich (Milwaukee, MI, USA). 2,4-TZD
(I),15 2,4-dichlorothiazole-5-carbaldehyde (II),21 and
substituted phenacyl-2,4-TZD (IVa, IVc, IVf,28 IVb,29
IVd23) were synthesized according to the literature.
A solution of KOH (0.957 g, 0.017 mol) in CH3OH
(10 ml) was added dropwise to a suspension of 2,4-
TZD (2.0 g, 0.017 mol) in 15 ml of CH3OH. Ten min-
utes after this addition omega,2,4-trichloroacetophe-
none (3.816 g, 0.017 mol) was added. The mixture was
allowed to stand at room temperature over 5 min then
refluxed during 5 h. The crude product was removed
by filtration, washed with H2O and ether. The residue
was crystallized from ethanol (yield: 2.12 g, 40.84%;
1
mp 150 ꢁC). H NMR (CDCl3): d = 4.07 (s, 2H, CH2),
4.94 (s, 2H, N–CH2), 7.34 (dd, 1H, J5 ,6 = 8.40 Hz,
0
0
J5 ,3 = 2.00 Hz, 50-H), 7.46 (d, 1H, J3 ,5 = 2.00 Hz, 30-
0
0
0
0
H), 7.66 (d, 1H, J6 ,5 = 8.40 Hz, 60-H). MS (ESI) m/z
(rel intensity): 326.6 (M+22, 65%), Anal. for
C11H7Cl2NO3S: Calcd C, 43.42; H, 2.30; N, 4.61; S,
10.53. Found C, 43.20; H, 2.30; N, 4.74; S, 10.52.
0
0
4.4. Synthesis of compounds VIa–f
A mixture of 2,4-dichloro-thiazole-5-carbaldehyde (II)
(0.001 mol) and IVa–f (0.001 mol) was heated at 130–
140 ꢁC in the presence of 0.5 ml acetic acid glacial and
sodium acetate (0.001 mol) for 5 h. The reaction mixture
was extracted with CHCl3 (3· 50 ml) and the organic
layer was washed with water, dried over anhydrous
Na2SO4, and evaporated to dryness. The residue was
purified by column chromatography silica gel 60 (230–
400 mesh ASTM) using hexane/dichloromethane (1:1)
as eluant.
Crystals suitable for X-ray analysis were obtained by
recrystallization of compound VIc-1 from dimethylform-
amide/isopropanol (1:5) The data collection was
performed on a CAD-4 diffractometer employing graph-
˚
ite-monochromated CuKa radiation (k = 1.54184 A).
Three standard reflections were measured every 2 h.
The structure was solved by direct methods. The refine-
ment was made with anisotropic temperature factors
for all non-hydrogen atoms. The hydrogen atoms were
generated geometrically. An empirical W scan absorption
correction was applied. Crystallographic data (excluding
4.4.1. 3-(2-Phenyl-2-oxo-ethyl)-5(2,4-dichloro-thiazole-5yl-
methylenyl)-thiazolidine-2,4-dione (VIa). Yield: 51.32%,
1
mp: 168.4 ꢁC, H NMR (CDCl3): d = 5.18 (s, 2 H, CH2),
7.51–7.55 (m, 2H, 30, 50-H), 7.64–7.66 (m, 1H, 40-H),

6016
O. Bozdag˘-Du¨ndar et al. / Bioorg. Med. Chem. 15 (2007) 6012–6017
7.97–7.99 (m, 2H, 20, 60-H), 8.04 (s, 1H, @CH), MS (ESI)
m/z (rel intensity): 420.9 (M+22, 100%), Anal. for
C15H8Cl2N2O3S2: Calcd C, 45.12; H, 2.02; N, 7.02; S,
16.06. Found C, 44.97; H, 2.12; N, 7.10; S, 16.52.
4.4.8. 3-[2-(4-Nitro-phenyl)-2-oxo-ethyl]-5-(2,4-dichloro-thi-
azole-5-yl-methylenyl)-thiazolidine-2,4-dione (VIf). Yield:
1
64.56%, mp: 159 ꢁC, H NMR (CDCl3): d = 5.19 (s, 2H,
CH2), 8.06 (s, 1H, @CH), 8.16 (d, 2H, 30, 50-H), 8.39 (d,
2H, 20, 60-H ), MS (ESI) m/z (rel intensity): 465.99
(M+22, 100%), Anal. for C15H7Cl2N3O5S2 0.2H2O: Calcd
C, 40.21; H, 1.65; N, 9.38; S, 14.29. Found C, 39.83; H,
1.73; N, 9.23; S, 14.19.
4.4.2. 3-[2-(4-Fluoro-phenyl)-2-oxo-ethyl]-5-(2,4-dichloro-thi-
azole-5-yl-methylenyl)-thiazolidine-2,4-dione (VIb). Yield:
1
22.91%, mp: 189 ꢁC, H NMR (CDCl3): d = 5.14 (s, 2H,
CH2), 7.19–7.23 (m, 2H, 30, 50-H), 8.00–8.03 (m, 2H, 20,
60-H ), 8.05 (s, 1H, @CH), MS (ESI) m/z (rel intensity):
438.9 (M+22, 100%), Anal. for C15H7Cl2FN2O3S2: Calcd
C, 43.18; H, 1.69; N, 6.71; S, 15.37. Found C, 42.77; H,
1.83; N, 6.73; S, 15.35.
4.5. Microbiology
For the antibacterial and antimycotic assays, the
compounds were dissolved in dimethylformamide/
propyleneglycol (0.5:9.5). Further dilutions of the
compounds and standard drugs in the test medium
were prepared at the required quantities of 100, 50,
25, 12.5, 6.25, 3.12, 1.56, 0.78 lg/ml concentrations
with Mueller–Hinton broth and Sabouraud dextrose
broth. The minimum inhibitory concentrations
(MIC) were determined using the twofold serial dilu-
tion technique.27 A control test was also performed
containing inoculated broth supplemented with only
ethanol at the same dilutions used in our experiments
and found inactive in the culture medium. All the
compounds were tested for their in vitro growth
inhibitory activity against different bacteria and the
yeasts Candida albicans ATCC 10145, Origins of
bacterial strains are S. aureus ATCC 29253, S. aureus
(MRSA) ATCC 43300, S. aureus (MRSA) (isolate) as
Gram-positive and E. coli ATCC 23556 as Gram-
negative bacteria. ATCC strains of the microorgan-
isms used in this study were obtained from the
culture collection of Refik Saydam Health Institution
of Health Ministry, Ankara, and maintained at the
Microbiology Department of Faculty of Pharmacy
of Ankara University. Ampicillin, ciprofloxacin,
and miconazole were used as control drugs. The data
on the antimicrobial activity of the compounds and
the control drugs as MIC (lg/ml) values are given
in Table 1.
4.4.3. (Z)3-[2-(4-Chloro-phenyl)-2-oxo-ethyl]-5-(2,4-dichlo-
ro-thiazole-5-yl-methylenyl)-thiazolidine-2,4-dione (VIc-1).
Yield: 29.39%, mp: 172.4 ꢁC, 1H NMR (CDCl3):
d = 5.13 (s, 2H, CH2), 7.51 (d, 2H, 30, 50-H), 7.92 (d,
2H, 20, 60-H ), 8.05 (s, 1H, @CH), MS (ESI) m/z (rel inten-
sity): 436.4 (M+H, 70%), Anal. for C15H7Cl3N2O3S2:
Calcd C, 41.54; H, 1.63; N, 6.46; S, 14.79. Found C,
41.32; H, 1.81; N, 6.61; S, 14.69.
4.4.4. (E)3-[2-(4-Chloro-phenyl)-2-oxo-ethyl]-5-(2,4-dichlo-
ro-thiazole-5-yl-methylenyl)-thiazolidine-2,4-dione (VIc-2).
Yield: 6.3%, mp: 309.5–312 ꢁC, 1H NMR (CDCl3):
d = 5.11 (s, 2H, CH2), 7.34 (s, 1H, @CH), 7.51 (d, 2H,
30, 50-H), 7.92 (d, 2H, 20, 60-H ). MS (ESI) m/z (rel inten-
sity): 436.3 (M+H, 25%), Anal. for C15H7Cl3N2O3S2:
Calcd C, 41.54; H, 1.63; N, 6.46; S, 14.79. Found C,
41.24; H, 1.82; N, 6.44; S, 14.66.
4.4.5. 3-[2-(4-Bromo-phenyl)-2-oxo-ethyl]-5-(2,4-dichlo-
ro-thiazole-5-yl-methylenyl)-thiazolidine-2,4-dione (VId).
Yield: 34.27%, mp: 177.4 ꢁC, 1H NMR (CDCl3):
d = 5.13 (s, 2H, CH2), 7.68 (d, 2H, 30, 50-H), 7.84 (d,
2H, 20, 60-H ), 8.04 (s, 1H, @CH), MS (ESI) m/z (rel
intensity):
500.9
(M+22,
100%),
Anal.
for
C15H7BrCl2N2O3S2. 0.7H2O: Calcd C, 36.69; H, 1.71;
N, 5.71; S, 13.05. Found C, 36.52; H, 1.59; N, 5.67; S,
12.91.
4.4.6. (Z)3-[2-(2,4-Dichloro-phenyl)-2-oxo-ethyl]-5-(2,4-
dichloro-thiazole-5-yl-methylenyl)-thiazolidine-2,4-dione
(VIe-1). Yield: 29.17%, mp: 181.7 ꢁC, 1H NMR
(CDCl3): d = 5.12 (s, 2H, CH2), 7.39 (dd, 1H,
5. Antibacterial and antifungal assays
The cultures were obtained from Mueller–Hinton
broth (Difco) for all the bacterial strains after 24 h
of incubation at 37 1 ꢁC. C. albicans were main-
tained in Sabouraud dextrose broth (Difco) after incu-
bation for 24 h at 25 1 ꢁC. Testing was carried out
in Mueller–Hinton broth and Sabouraud dextrose
broth (Difco) at pH 7.4 and the twofold serial dilution
technique was applied. The final inoculum size was
105 CFU/ml for the antibacterial assay and 104 CFU/
ml for the antifungal assay. A set of tubes containing
only inoculated broth was used as controls. For the
antibacterial assay after incubation for 24 h at
37 1 ꢁC and after incubation for 48 h at 25 1 ꢁC
for the antifungal assay, the last tube with no growth
of microorganism and/or yeast was recorded to repre-
sent the MIC expressed in mg/ml. Every experiment in
the antibacterial and antifungal assays was replicated
twice.
J5 ,6 = 8.40 Hz, J5 ,3 = 2.00 Hz, 50-H), 7.52 (d, 1H,
0
0
0
0
J3 ,5 = 2.00 Hz, 30-H), 7.72 (d, 1H, J6 ,5 = 8.00 Hz, 60-
H), 8.04 (s, 1H, @CH), MS (ESI) m/z (rel intensity):
490.9 (M+22, 100%), Anal. for C15H6Cl4N2O3S2: Calcd
C, 38.48; H, 1.29; N, 5.98; S, 13.70. Found C, 38.26; H,
1.40; N, 6.07; S, 13.98.
0
0
0
0
4.4.7. (E)3-[2-(2,4-Dichloro-phenyl)-2-oxo-ethyl]-5-(2,4-
dichloro-thiazole-5-yl-methylenyl)-thiazolidine-2,4-dione
(VIe-2). Yield: 4.86%, mp: 179.80 ꢁC, 1H NMR
(CDCl3): d = 5.10 (s, 2H, CH2), 7.33 (s, 1H, @CH),
7.39 (dd, 1H, J5 ,6 = 8.40 Hz, J5 ,3 = 2.00 Hz, 50-H),
0
0
0
0
7.52 (d, 1H, J3 ,5 = 2.00 Hz, 30-H), 7.72 (d, 1H,
0
0
J6 ,5 = 8.40 Hz, 60-H), MS (ESI) m/z (rel intensity):
490.9 (M+22, 21%), 468.9 (M+H, 21%), Anal. for
C15H6Cl4N2O3S2: Calcd C, 38.48; H, 1.29; N, 5.98; S,
13.70. Found C, 38.95; H, 1.39; N, 6.08; S, 13.31.
0
0

O. Bozdag˘-Du¨ndar et al. / Bioorg. Med. Chem. 15 (2007) 6012–6017
6017
13. Oliva, B.; Miller, K.; Caggiano, N.; O’Neill, A. J.; Cuny,
G. D.; Hoemann, M. Z.; Hauske, J. R.; Chopra, I.
Antimicrob. Agents Chemother. 2003, 47, 458.
14. Nasr, M. N.; Gineinah, M. M.; El-Bendary, E. R. Arch.
Pharm. 2003, 336, 560.
Acknowledgment
This work was supported by Research Organization of
Ankara University, Turkey (No. 2005-0803048).
15. DeLima, M. C. A.; Costa, D. L. B.; Goes, A. J. S.;
Galdino, S. L.; Pitta, I. R.; Luu-Duc, C. Pharmazie 1992,
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