Some new thiazolyl thiazolidinedione derivatives as aldose reductase inhibitors

Article abstract of DOI:10.1007/s00044-007-9008-9

In diabetes, increased flux through the polyol pathway has been implicated in the development of diabetic complications such as cataract, retinopathy, neuropathy, and nephropathy. Aldose reductase (AR) appears to be the key factor in the reduction of gluc

Full text of DOI:10.1007/s00044-007-9008-9

Med Chem Res (2007) 16:39–47
DOI 10.1007/s00044-007-9008-9
ORIGINAL ARTICLE
Some new thiazolyl thiazolidinedione derivatives as
aldose reductase inhibitors
¨
˘
Oya Bozdag-Du¨ndar Æ Net Das¸ Evcimen Æ Meltem Ceylan-Unlu¨soy Æ
Rahmiye Ertan Æ Mutlu Sarıkaya
Received: 15 January 2007 / Accepted: 16 March 2007 / Published online: 31 May 2007
¨
ꢀ Birkhauser Boston 2007
Abstract In diabetes, increased flux through the polyol pathway has been impli-
cated in the development of diabetic complications such as cataract, retinopathy,
neuropathy, and nephropathy. Aldose reductase (AR) appears to be the key factor in
the reduction of glucose to sorbitol. Aldose reductase inhibitors have been found to
prevent sorbitol accumulation in tissues. A series of thiazolyl-2,4-thiazolidinediones
was prepared by Knoevenagel reaction of substituted benzyl-2,4-thiazolidinediones
with chlorothiazolecarbaldehydes and were evaluated for their ability to inhibit rat
kidney AR by an in vitro spectrophotometric assay. Results showed that compounds
containing piperidine at the C-2 position of thiazole ring showed better inhibitory
activity than thiazole compounds having 4-chlorobenzylsulfanyl at the same posi-
tion.
Keywords Synthesis ꢀ Thiazole derivatives ꢀ 2,4-Thiazolidinediones aldose
reductase inhibition
Introduction
Aldose reductase (AR) is a key enzyme of the polyol pathway. The conversion of
glucose to sorbitol is slightly catalyzed by AR (Gabbay et al., 1996). AR involved in
the sorbitol pathway, which is an important mechanism in regulation of mammalian
glucose metabolism, has been known to play a significant role in the diabetic
¨
˘
O. Bozdag-Du¨ndar (&) ꢀ M. Ceylan-Unlu¨soy ꢀ R. Ertan
Department of Pharmaceutical Chemistry, Ankara University, Faculty of Pharmacy, Tandogan,
Ankara, Turkey
e-mail: bozdag@pharmacy.ankara.edu.tr
N. D. Evcimen ꢀ M. Sarıkaya
Department of Biochemistry, Ankara University, Faculty of Pharmacy, Tandogan, Ankara, Turkey

40
Med Chem Res (2007) 16:39–47
complications as diabetic cataract, retinopathy, neuropathy, and nephropathy (Pirie
and van Heyningen, 1964; Kador et al., 1985).
Aldose reductase inhibitors (ARIs) were developed to suppress sorbitol
accumulation in tissues such as lens, peripheral nerves, and kidney. Orally active
ARIs (Fig. 1) can be grouped mainly into two chemical classes: cyclic imides
(mostly hydantoins, e.g., Sorbinil) and carboxylic acids (Tolrestat).The carboxylic
acid derivatives are very active in vitro; however, in vivo they are generally less
active than imides (Costantino et al., 1999, 2000). Currently, Epalrestat (ONO-
2235) is the only ARI available on the market (Costantino et al., 1999). In addition,
topical ARI, CT-112 (5-[3-ethoxy-4-pentyloxyphenyl]-2,4-thiazolidinedione) im-
proves corneal sensation in clinical cases (Hosotani et al., 1995) and corneal
epithelial barrier function in galactose-fed rats (Yokoi et al., 1997). As a new class
of antidiabetic agents, 2,4-thiazolidinediones (2,4-TZDs) differ markedly from other
antidiabetic agents in that they are effective in normalizing glucose and lipid
metabolism associated with insulin resistance and are therefore expected to be
useful in the treatment of both type 2 diabetes mellitus and obesity (Sohda et al.,
1990; Iwamoto et al., 1991; Suter et al., 1992; Costantino et al., 1997). Some 2,4-
TZDs such as pioglitazone and rosiglitazone (Fig. 1) have been marketed for the
treatment of type 2 diabetes. On the other hand, it was reported that some 2,4-TZDs
have been patented as antihyperglycemic and ALR2 inhibitory agents with dual
activity (Costantino et al., 1997, 2000). There is a great interest in 2,4-TZD
derivatives as ARIs (Fresneau et al., 1998; Costantino et al., 2000), since they can
be viewed as hydantoin bioisosters potentially free of the hypersensitivity reactions
that are linked to the presence of the hydantoin system. Several 5-arylidene-
2,4-TZDs exerted appreciable inhibitory activity (Bruno et al., 2002).
In our previous study, the synthesis and antimicrobial evaluation of piperidine
¨
substituted thiazolyl-2,4-TZD derivatives (Va–f; Ceylan-Unlu¨soy et al., 2006) have
been described. In the present work, six additional thiazolylthiazolidinedione
O
S
N
COOH
COOH
N
S
S
O
Epalrestat
CH3O
NH
O
N
CF3
Tolrestat
F
O
CH3(CH2)4O
NH
O
S
O
CH3CH2O
Sorbinil
CT-112
O
O
O
NH
O
NH
S
N
S
N
O
O
N
Pioglitazone
Rosiglitazone
Fig. 1 Formulas of the ARI and TZD compounds

Med Chem Res (2007) 16:39–47
41
O
O
S
Cl
H
POCl3 / DMF
HN
N
S
O
Cl
I
II
X
CH2
Y
H
R
O
X1
O
S
R
X
CH2
N
H
N
S
O
Cl
X1
IIIa-b
IVa-f
O
'
2
'
3
S
X
CH2
N
R
S
N
O
X1
Cl
R=
Va-f
N
2''
3''
VIa-f
R=
S
Cl
Scheme 1. General synthesis of Va–f/VIa–f
derivatives (Scheme 1) were synthesized and all the compounds were evaluated for
their ability to inhibit rat kidney AR via an in vitro spectrophotometric assay.
Materials and Methods
Chemistry
Melting points were determined via a Bu¨chi SMP-20 melting point apparatus
(Bu¨chi, Flawil, Switzerland) and uncorrected. All instrumental analyses were
performed in the Central Laboratory of Pharmacy Faculty of Ankara University.
Infrared (IR) spectra were recorded on a Jasco FT/IR-420 spectrometer (Jasco,
1
Tokyo, Japan). H-nuclear magnetic resonance (1H-NMR) and 13C-NMR spectra
were measured with a VARIAN Mercury 400 FT-NMR spectrometer (Varian, Palo
Alto, CA) in CDCl3. All chemical shifts were reported as d (ppm) values. Mass
spectra were recorded on Waters Micromass ZQ (Waters Corporation, Milford,
MA) via the ESI (+) method. Elementary analyses were performed on a Leco CHNS
932 analyzer (Leco, St. Joseph, MI) and satisfactory results 0.4% of calculated

42
Med Chem Res (2007) 16:39–47
values (C, H, N) were obtained. For the chromatographic analysis, Merck Silica Gel
60 (230–400 mesh ASTM) was used. The chemical reagents used in synthesis were
purchased from E. Merck (Darmstadt, Germany) and Aldrich (Milwaukee, MI). 2,4-
TZD (1) (Lima et al., 1992), 2,4-dichlorothiazole-5-carbaldehyde (2) (Athmani
et al., 1992), 2-(4-chlorobenzylsulfanyl)-4-chlorothiazole-5-carbaldehyde (IIIb),
and substituted-2,4-TZD [4a (Lo and Shropshire, 1957), 4b (Lima et al., 1992), 4c
(Lo and Shropshire, 1957), 4d (Costa et al., 1995), 4e (Lo and Shropshire, 1957)]
were synthesized in our laboratory according to the literature.
Synthesis of the compounds
The synthesis (Scheme 1), detailed procedures, and characterization data for
¨
compounds Va–f have been reported previously (Ceylan-Unlu¨soy et al., 2006).
Here we present the synthetic procedure of compounds VIa–f.
Preparation of compound VIa–f. 2-(4-Chlorobenzylsulfanyl)-4-chlorothiazole-
5-carbaldehyde (IIIb). To a stirred suspension of 2,4-dichlorothiazole-5-carbalde-
hyde (II) (4.0 mmol) prepared from 2,4-TZD (Athmani et al., 1992) and potassium
carbonate (4.0 mmol) in acetonitrile (10 ml) and 4-chlorobenzylmercaptane (4.0
mmol) was added and stirred at room temperature for 12 h. The residue was purified
by column chromatography (hexane–dichloromethane) (yield: 1.03 g, 85.7%; m.p:
1
96–96.58C). Spectroscopic analysis: IR (cmꢁ1) (CO): 1661; H-NMR (CDCl3, 400
MHz, d, ppm): 4.47 (s, 2H, S–CH2), 7.31 (d, 2H, 20, 60-H), 7.35 (d, 2H, 30, 50-H),
9.90 (s, 1H, H-C=O). Anal. calcd. for C11H7Cl2NOS2 (Mr = 304.22): C: 43.43, H:
2.32, N: 4.60, S: 21.08%; found C: 43.71, H: 2.51, N: 4.52, S: 20.96%.
Synthesis of compound IVa–f. A mixture of 2,4-TZD (1) (2.34 g, 0.02 mol),
substituted benzyl halide (0.02 mol), and sodium hydroxide (0.8 g, 0.02 mol) in 20
ml of 50% ethanol was refluxed for 18 h. The crude product was crystallized from
ethanol. [IVa m.p. 62–638C (Lo and Shropshire, 1957) m.p. 618C, IVb m.p. 838C
(Lima et al., 1992) m.p. 828C), IVc m.p. 968C ( m.p. 97–988C), IVd m.p. 918C
(Costa et al., 1995; m.p. 90–918C), IVe m.p. 1178C (Lo and Shropshire, 1957; m.p.
117–1188C), IVf m.p: 1178C (Costa et al., 1995; m.p: 117–1188C)].
Synthesis of compound VIa–f. A mixture of 2-(4-chlorobenzylsulfanyl)-4-
chlorothiazole-5-carbaldehyde (IIIb) 0.001 mol) and IVa–f (0.001 mol) was heated
at ca. 1008C in the presence of 0.5 ml of glacial acetic acid and sodium acetate (0.5
mmol). The reaction mixture was extracted with CHCl3. The organic layer was
washed with water, dried over anhydrous Na2SO4, and evaporated to dryness. The
residue was purified by column chromatography (n-hexane–dichloromethane).
5-(2-(4-Chloro-benzylsulfanyl)-4-chloro-thiazol-5-yl-methylene)-3-benzyl-
thiazolidine-2,4-dione (VIa). Yield: 57.55%; m.p. 127–1288C. Spectroscopic
1
analysis: IR (KBr) tmax/cmꢁ1: 1741, 1683 (CO); H-NMR (CDCl3, 400 MHz, d,
ppm): 4.46 (s, 2H, S-CH2), 4.88 (s, 2H, N–CH2), 7.29–7.43 (m, 9H, Ar–H), 8.00 (s,
1H, H–C=C). Anal. calcd. for C21H14Cl2N2O2S3.0.1 H2O (Mr = 495.25): C: 50.92,
H: 2.87, N: 5.66, S: 19.40%; found; C: 50.65, H: 3.08, N: 5.76, S: 19.24%.
5-(2-(4-Chloro-benzylsulfanyl)-4-chloro-thiazol-5-yl-methylene)-3-(4-fluoro-
benzyl)-thiazolidine-2,4-dione (VIb). Yield: 67.46%; m.p. 1358C. Spectroscopic
1
analysis: IR (KBr) tmax/cmꢁ1: 1737, 1689 (CO); H-NMR (CDCl3, 400 MHz, d,

Med Chem Res (2007) 16:39–47
43
ppm): 4.46 (s, 2H, S–CH2), 4.84 (s, 2H, N–CH2), 6.99–7.03 (m, 2H, 20, 60-H), 7.30
(d, 2H, 2@, 6@-H), 7.34 (d, 2H, 3@, 5@-H), 7.40-7.43 (m, 2H, 30, 50-H), 7.99 (s, 1H, H–
C=C). Anal. calcd. for C21H13Cl2FN2O2S3 (Mr = 511.44): C: 49.32, H: 2.56, N:
5.48, S: 18.81%; found: C: 49.56, H: 2.74, N: 5.43, S: 18.81%.
5-(2-(4-Chloro-benzylsulfanyl)-4-chloro-thiazol-5-yl-methylene)-3-(4-chloro-
benzyl)-thiazolidine-2,4-dione (VIc). Yield: 71.03%; m.p. 1098C. Spectroscopic
1
analysis: IR (KBr) tmax/cmꢁ1: 1736, 1689 (CO); H-NMR (CDCl3, 400 MHz, d,
ppm): 4.48 (s, 2H, S–CH2), 4.82 (s, 2H, N–CH2), 7.28-7.38 (m, 8H, Ar–H), 8.00 (s,
1H, H–C=C). Anal. calcd. for C21H13Cl3N2O2S3 (Mr = 527.90): C: 47.78, H: 2.48,
N: 5.31, S: 18.22%; found: C: 47.48, H: 2.78, N: 5.22, S: 17.96%.
5-(2-(4-Chloro-benzylsulfanyl)-4-chloro-thiazol-5-yl-methylene)-3-(4-bromo-
benzyl)-thiazolidine-2,4-dione (VId). Yield : 40.78%; m.p. 102–1038C. Spectro-
1
scopic analysis: IR (KBr) tmax/cmꢁ1: 1733, 1688 (CO) ; H-NMR (CDCl3, 400
MHz, d, ppm): 4.47 (s, 2H, S–CH2), 4.82 (s, 2H, N–CH2), 7.29–7.35 (m, 6H, 20, 60,
2@, 3@, 5@, 6@-H), 7.45 (d, 2H, 30, 50-H), 7.99 (s, 1H, H–C=C). Anal. calcd. for
C21H13BrCl2N2O2S3 (Mr = 572.35): C: 44.07, H: 2.29, N: 4.89, S: 16.81%; found:
C: 43.72, H: 2.37, N: 5.02, S: 16.63%.
5-(2-(4-Chloro-benzylsulfanyl)-4-chloro-thiazol-5-yl-methylene)-3-(4-nitro-
benzyl)-thiazolidine-2,4-dione (VIe). Yield: 75.34 %; m.p. 193–1948C. Spectro-
1
scopic analysis: IR (KBr) tmax/cmꢁ1: 1733, 1676 (CO); H-NMR (CDCl3, 400
MHz, d, ppm): 4.48 (s, 2H, S–CH2), 4.96 (s, 2H, N–CH2), 7.26–7.34 (m, 4H, 2@, 3@,
5@, 6@-H), 7.59 (d, 2H, 20, 60-H), 8.04 (s, 1H, H–C=C), 8.20 (d, 2H, 30, 50-H). Anal.
calcd. for C21H13Cl2N3O4S3 (Mr = 538.45): C: 46.84, H: 2.43, N: 7.80, S: 17.87%;
found: C: 46.56, H: 2.59, N: 7.76, S: 17.80%.
5-(2-(4-Chloro-benzylsulfanyl)-4-chloro-thiazol-5-yl-methylene)-3-(2,4-di-
chloro-benzyl)-thiazolidine-2,4-dione (VIf). Yield: 61.31%; m.p: 154–1558C.
1
Spectroscopic analysis: IR (KBr) tmax/cmꢁ1 : 1739, 1679 (CO); H-NMR (CDCl3,
400 MHz, d, ppm): 4.48 (s, 2H, S–CH2), 4.99 (s, 2H, N–CH2), 7.16 (d, 1H, 2@-H),
7.22 (dd, 1H, 3@-H), 7.31 (d, 2H, 20, 60-H), 7.35 (d, 2H, 30, 50-H), 7.41 (d, 1H, 5@-H),
8.03 (s, 1H, H-C=C). Anal. calcd. for C21H12Cl4N2O2S3 (Mr = 562.34) C: 44.85, H:
2.15, N: 4.98, S: 17.11%; found: C: 44.84, H: 2.07, N: 5.24, S: 17.13%.
Biological activity
Isolation of AR. AR was isolated via the method described below. Pooled kidney
were thawed on ice and homogenized with 3 volumes of distilled water, followed by
centrifugation at 10,000 · g for 20 min. Saturated ammonium sulfate was added to
the supernatant to 40% saturation. The thick suspension was stirred for 15 min,
followed by centrifugation at 10,000 · g for 20 min. The inert protein remaining in
the supernatant was removed by increasing the ammonium sulfate concentration to
50% saturation followed by centrifuging the mixture at 10,000 · g for 20 min. The
AR was precipitated from the 50% saturated solution by adding powdered
ammonium sulfate to 75% saturation and was recovered by centrifugation at 10,000
· g for 20 min. Protein concentration was measured by the method of Bradford
(1978) with bovine serum as the standard.

44
Med Chem Res (2007) 16:39–47
Determination of AR activity. AR activity of the freshly prepared supernatant
was assayed spectrophotometrically by determining the decrease in NADPH
concentration at 340 nm via a UV-1700 Visible spectrophotometer. DL-Glyceral-
dehyde was used as the substrate. The enzyme was dissolved in 10 ml of 0.05 M
NaCI solution, and 0.1 ml was added to a quartz cuvette containing 0.2 ml of
phosphate buffer (0.067 M, pH 6.2), 0.1 ml of NADPH (2 · 10ꢁ5 M final
concentration), 0.1 ml of the test drug (10ꢁ4 M stock solution), and 2.4 ml of
distilled water to obtain a 2.9-ml solution. The reaction is started by the adding of
0.1 ml of DL-glyceraldehyde (5 · 10ꢁ5 M final concentration) to the cuvette and the
decrease in NADPH concentration was recorded at 340 nm for 5 min at 378C.
Readings were taken at intervals in the periods when the changes in absorbance
were linear (Cerelli et al., 1986).
Results and Discussion
The synthesis of the new substituted thiazolyl-2,4-TZD derivatives VIa–f is
depicted in Scheme 1. 2,4-TZD (1) was synthesized via a reaction of ClCH2COOH
and thiourea in hot water (Lima et al., 1992). 2,4-Dichlorothiazole-5-carbaldehyde
(II) was obtained with 2,4-TZD (I) and N,N-dimethylformamide in phosphoryl
chloride (Athmani et al., 1992). 2-(4-Chlorobenzylsulfanyl)-4-chlorothiazole-
5-carbaldehyde (IIIb) (Scheme 1) was synthesized by reacting II with 4-chlorob-
enzyl mercaptane in potassium carbonate–acetonitrile. Substituted benzyl-2,4-TZDs
(IVa–f) were obtained by the reaction of 2,4-TZD (I) and appropriate benzyl halide
derivatives in NaOH–ethanol [IVa (Lo and Shropshire, 1957), IVb (Lima et al.,
1992), IVc (Lo and Shropshire, 1957), IVd (Costa et al., 1995), IVe (Lo and
Shropshire, 1957), and IVf (Lo and Shropshire, 1957)]. Thiazolyl-2,4-TZDs VIa–f
were prepared via the Knoevenagel reaction in the presence of sodium acetate–
acetic acid glacial between the 2-(4-chlorobenzylsulfanyl)-4-chlorothiazole-5-
carbaldehyde (IIIb) and appropriate substituted-2,4-thiazolidinedione (IVa–f).
The structures of the synthesized thiazolidinedione compounds were fully
characterized by elementary analysis, 1H-NMR, and IR findings. IR spectra of these
new VIa–f derivatives presented the 2,4-TZD C4=O and C2=O stretching bonds at
1
1733–1741 cmꢁ1, 1676–1689 cmꢁ1, respectively. In H-NMR spectra, benzylic
CH2 protons (S–CH2 and N–CH2) for VIa–f were observed between 4.46–4.48 and
4.82–4.99 ppm as a singlet, respectively. Methylene protons (=CH) were seen at
7.99–8.04 ppm as a singlet, respectively. The compounds VIa–f have no ionization
on Waters Micromass ZQ (Waters Corporation, Milford, MA) via the ESI (+)
(electrospray ionization) method.
¨
It was shown that arylidene thiazolidinediones appeared as the Z isomer (Vogeli
and Philipsborn, 1978; Albuquerque et al., 1995). In this study, only one isomer of
the compounds was obtained. X-ray diffractometric analysis was carried out for
compound 5-(2-(4-chloro-benzylsulfanyl)-4-chloro-thiazol-5-yl-methylene)-3-(2,4-
dichloro-benzyl)-thiazolidine-2,4-dione (VIf), which showed that this derivative
¨
presents the Z isomer (Ozgen et al., 2007).

Med Chem Res (2007) 16:39–47
45
Table 1 Aldose reductase inhibition by compounds Va–f/VIa–f
O
S
X
N
R
S
N
Cl
O
X1
Compounds R
Va
X
H
X1
H
Inhibition (%)
0,00 0,00
N
Vb
Vc
Vd
Ve
Vf
F
H
H
H
H
Cl
H
0,00 0,00
0,62 3,59
0,62 6,78
2,49 4,90
3,27 2,66
0,00 0,00
N
N
N
N
N
Cl
Br
NO2
Cl
H
VIa
S
S
S
S
S
S
Cl
VIb
VIc
VId
VIe
VIf
F
H
H
H
H
Cl
0,00 0,00
0,00 0,00
0,00 0,00
0,00 0,00
1,56 1,53
Cl
Cl
Cl
Cl
Cl
Cl
Br
NO2
Cl
*Values represent the mean S. D. of three individual experiments.

46
Med Chem Res (2007) 16:39–47
The in vitro AR inhibitory activity of the synthesized compounds is listed in
Table 1. The enzyme activity was assayed by spectrophotometrically monitoring the
NADPH oxidation that accompanies the reduction of DL-glyceraldehyde used as
substrate. The inhibition study was performed merely by using a 10ꢁ4
concentration of each drug.
M
It was found that compounds Va–b and VIa–e have no inhibitory effect on AR
enzyme inhibition while compounds Vc–f and VIf have slight inhibition (0.62%,
0.62%, 2.49%, 3.27%, 1.56%, respectively). This clearly showed that the dichloro
substitutents at the ortho–para position of the phenyl ring achieved AR inhibitory
activity of the compounds.
Results also showed that compounds Vc–f containing piperidine at the C-2
position of thiazole ring showed better inhibitor activity than thiazole compounds
having 4-chlorobenzylsulfanyl at the C-2 position of VIa–e
Finally, we may conclude that the weak inhibitory effect of compounds might
depend on not having an acidic proton on the TZD ring. It is well known that the
presence of an acidic functionality is an important requirement for all ARIs because
they interact, in their ionized form, with the active site of the enzyme (Urzhumtsev
et al., 1997; Lee et al., 1998), although many compounds may have inhibitory
activity with the lack of carboxyl group such as topical ARI CT-112 (5-[3-ethoxy-4-
pentyloxyphenyl]-2,4-thiazolidinedione). Because of this paradoxical result, this
study is still on progress to evaluate more TZD derivatives.
Acknowledgment This work was supported by the Research Organization of Ankara University,
Turkey (No. 2005-0803048)
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