Synthesis of O-prenylated and O-geranylated derivatives of 5-benzylidene2,4-thiazolidinediones and evaluation of their free radical scavenging activity as well as effect on some phase II antioxidant/detoxifying enzymes

Article abstract of DOI:10.1016/j.bmcl.2006.12.040

A series of 5-arylidene-2,4-thiazolidinediones and its geranyloxy or prenyloxy derivative were synthesized and studied for their radical scavenging activity using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. Their comparable scavenging activities were expr

Full text of DOI:10.1016/j.bmcl.2006.12.040

Bioorganic & Medicinal Chemistry Letters 17 (2007) 1149–1154
Synthesis of O-prenylated and O-geranylated derivatives of
5-benzylidene2,4-thiazolidinediones and evaluation of their
free radical scavenging activity as well as effect on some
phase II antioxidant/detoxifying enzymes
Sk. Ugir Hossain and Sudin Bhattacharya*
Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road,
Kolkata 700 026, West Bengal, India
Received 21 July 2006; revised 21 November 2006; accepted 12 December 2006
Available online 15 December 2006
Abstract—A series of 5-arylidene-2,4-thiazolidinediones and its geranyloxy or prenyloxy derivative were synthesized and studied for
their radical scavenging activity using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. Their comparable scavenging activities were
expressed as IC50 value. Compounds 2c, 2d, 4d, and 6a showed appreciable radical scavenging activities. The vanillin based thiazo-
lidinedione compound 2c displayed highest activity comparable to that of a-tocopherol. But in vivo, compound 6a showed better
results in inducing phase II detoxifying/antioxidative enzyme.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Thiazolidinediones (TZDs) have been the subject of
extensive researches because of their deep involvement
in the regulation of different physiological processes.
Thiazolidinedione derivatives have been shown to pos-
sess potent immunostimulatory property, antiarthritic
activity as well as oncostatic activity.1 TZDs such as
troglitazone, pioglitazone, and rosiglitazone are potent
reducer of plasma glucose level in vivo. Besides their
anti-diabetic potency, these TZDs have been shown to
exert anti-inflammatory effects on vascular cells.2 TZDs
were also found to inhibit the production of inflamma-
tory cytokines and the expression of inducible nitric
oxide syntheses in monocytes/macrophages.3,4 It has
been shown that TZDs suppress the growth of several
cancer cell lines including colon, breast, and prostate
in vivo and in vitro.5–7 TZDs were also found to inhibit
angiogenesis.8 Some thiazolidinedione derivatives also
showed Cu2+ mediated lipid-peroxidation inhibitory
activity9 and were found to inhibit serum ALT, AST
as well as c-GTP levels significantly during treatment
in patients with type 2 diabetes10. TZDs are also poten-
tial cancer chemopreventive agents against colon,
breast, tongue, and gastric carcinogenesis.8
The naturally occurring prenyl alcohol geraniol has got
the potential to suppress the growth of tumor cells, both
11–15
in vitro
and in vivo,16 and that of chemically in-
duced tumors17,18. O-protecting geraniol exhibited bet-
ter antitumor activity compared to free alcohol.19 On
the other hand, addition of geraniol to ferulic acid
resulted the geranyloxy ferulic acid which was found
to be more potent than the ferulic acid.20 Also Aurap-
tene, a geranyl ether derivative of 7-hydroxyl coumarin,
was shown to be more effective in inhibiting mouse skin
tumor development than the parent hydroxyl
coumarin.21
Free radicals are being formed during normal cellular
metabolism and they are known to contribute to healthy
functions in human health and development when they
are not excessive. Formation of free radicals is not lim-
ited to normal cellular process but also occurs upon
exposure to certain chemicals (polycyclic aromatic
hydrocarbon, cadmium, lead, etc.), radiation, cigarette
smoke, and high fat diet. Exposure of a healthy cell to
free radical is known to damage structures and conse-
quently interfere with functions of enzymes and critical
macromolecule. Mammalian cells possess elaborate
Keywords: 2,4-Thiazolidinediones; Radical scavenger; Detoxifying
enzyme; Mice.
*
Corresponding author. Tel.: +91 33 2476 5101x316; e-mail:
sudinb19572004@yahoo.co.in
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.12.040

1150
S. U. Hossain, S. Bhattacharya / Bioorg. Med. Chem. Lett. 17 (2007) 1149–1154
defense mechanism to detoxify free radicals. A balance
between formation of free radicals and their detoxifica-
tion is essential for normal cellular function. When such
a balance is disrupted as a result of excessive generation
of damaging species or low levels of antioxidants, a cell
enters a state of oxidative stress and is damaged. If the
damage persists the cell will enter a state of genetic insta-
bility that can lead to chronic diseases including
cancer.22
bromide in presence of anhydrous K2CO3 and 10% tetr-
abutyl ammonium hydrogen sulfate in acetone at room
temperature. The products were obtained as oil and
purified through column chromatography. Compounds
(3a–d) and (5a–d) were then converted to (4a–d) and
(6a–d), respectively, by condensation with 2,4-thiazolid-
inedione in benzene in presence of piperidine with azeo-
tropic removal of water. Compounds (2a–d), (4a–d), and
(6a–d) were purified by column chromatography and
obtained in good yields (70–85%).
In this report, we describe the synthesis of several 5-ary-
lidene-2,4-thiazolidinedione derivatives with geranyloxy
or prenyloxy substituent on the 5-arylidene moiety of
5-arylidene-2,4-thiazolidinediones. We also report the
evaluation of their radical scavenging activities using
1,1-diphenyl-2-picrylhydrazyl (DPPH) assay and also
the effect of the two most active compounds 2c and 4d
(in DPPH assay) on some phase II antioxidative and
detoxifying enzyme (glutathione-S-transferase, superox-
ide dismutase, and catalase), as well as on lipid-peroxi-
dation level screened in vivo in Swiss albino mice. The
effect of these compounds on ALT, AST, and urea level
has also been reported here.
1H, 13C, and EIMS were used to confirm the structure
and purity of all listed compounds (2a–d, 4a–d, and
6a–d). Characteristically, a single 5-methylidene proton
was observed in the range of d 7.72–7.97 as a singlet
and NH proton was observed in the range of d12.5–
13.5 as a broad signal in CDCl3 or DMSO-d6 solution,
both observations were consistent with previously
reported data in the literature.23 The absence of 5-CH2
resonance of 2,4-thiazolidinedione confirmed the struc-
ture of the desired product (2a–d), (4a–d) and (6a–d).
The geometry of all benzylidenethiazolidine-2,4-diones
was assumed to be (Z)-isomer as observed in other
instances.24
The thiazolidinedione derivatives (2a–d) were prepared
as shown in Scheme 1. The Knoevenagel condensation
between active methylene group of 2,4-thiazolidinedione
and hydroxy benzaldehyde (1a–d) in presence of catalyt-
ic amount of piperidine (Route A) furnished the 5-ary-
lidene-2,4-thiazolidinediones (2a–d) as yellow colored
solid in 80–85% yield. Compounds (2a–d) on treatment
with either prenyl bromide or geranyl bromide in pres-
ence of K2CO3 or even NaH did not produce com-
pounds (4a–d) or (6a–d),29 each time the starting
material was recovered back. We presume that the
apparent inactivity of the phenolic group was due to
the stabilization of the phenolate anion which is attrib-
uted to the extended conjugation of the aryl moiety with
the thiazolidinedione ring. Compounds (4a–d) and (6a–
d) were finally prepared following route B. Hydroxy
benzaldehydes (1a–d) were first converted to the corre-
sponding prenyloxy (3a–d) or geranyloxy derivative
(5a–d) by treating with either prenyl bromide or geranyl
The scavenging effects of all of the synthesized com-
pounds on the DPPH free radical were evaluated. Now-
adays, antioxidants that exhibit DPPH radical
scavenging activity are increasingly receiving attention.9
They have been reported to have interesting anticancer,
anti-aging, and anti-inflammatory activities. According-
ly, a study of the syntheses of novel 5-arylidene-2,4-thia-
zolidinedione derivatives with antioxidant activity
would support the development of new drugs and
improve the treatment of various diseases.
The model of scavenging of the stable DPPH radical is
extensively used to evaluate radical scavenging activities
in less time than other methods. Compound reacts with
DPPH, which is a nitrogen centered radical with a char-
acteristic absorption at 517 nm, and convert it to stable
diamagnetic molecule 1,1-diphenyl-picryl hydrazine, due
to its hydrogen donating ability at a very rapid rate.25
R4
R3
R2
S
O
H
N
N
H
O
O
O
Route-A
S
Geranyl/Prenyl bromide
R1
R4
2a-d
(ii)
R4
R4
R1
R3
R2
CHO
R3
R2
R3
CHO
(i)
S
(ii)
O
Route-B
N
H
O
R2
H
Geranyl/Prenyl bromide
R1
N
O
O
R1
1a, R1=R3=R4=H, R2=OH
1b, R1=R2=R3=H, R4=OH
1c, R1=OCH3, R2=OH, R4=R3=H
S
4a-d
6a-d
3a-d
5a-d
1d, R1=R3=OCH3,R2=OH R4=H
Scheme 1. Reagents and condition: (i) Tetrabutyl ammonium hydrogen sulfate, potassium carbonate, Acetone, rt.

S. U. Hossain, S. Bhattacharya / Bioorg. Med. Chem. Lett. 17 (2007) 1149–1154
1151
When this electron becomes paired off, the absorption
decreases stoichiometrically with respect to the number
of electrons taken up. Such a change in the absorbance
produced in this reaction has been widely applied to test
the capacity of numerous molecules to act as free radical
scavengers.9
these compounds. The radical centered on oxygen (com-
pounds 2a–d) is stabilized by extended conjugation
which formed para quinonoid structure for 2a, 2c, and
2d, and ortho quinonoid structure for 2b. As the para
quinonoid structure has more stabilization than the
ortho quinonoid structure, compound 2b was found to
be the least active compound amongst 2a–d. The pres-
ence of the electron donating OCH3 group at the ortho
position enhanced the stabilization of the resulting oxy-
gen centered radical as the number of conjugating struc-
ture is more than that without the OCH3 group. As a
result compounds 2c and 2d were more active than 2a.
Amongst 2c and 2d the presence of an extra methoxy
group in 2d slightly reduced the stability of the radical
formed due to cross conjugation, hence 2c was found
to be the most active compound. The presence of unsat-
urated double bond as well as presence of NH group
which can donate hydrogen atom in thiazolidinedione
moiety may also contribute to the radical scavenging
activity of these compounds as evidenced from the re-
sults showed by compounds 4d and 6a where free OH
group is not available. The NH group does have the rad-
ical scavenging property as the N-protected compound
(7), prepared for some other purpose, showed practically
no DPPH scavenging activity as shown in Figure 1. The
difference of activity of 4a–d may be due to the stability
of the nitrogen centered radical. The presence of meth-
oxy group in the aromatic ring enhanced the stability
of the nitrogen centered radical due to electron conjuga-
tion effect and this effect is more when there are two
methoxy groups in the aromatic ring in compound 4d
(synergistic effect) compared to compound 4c which
The entire synthesized compounds scavenged DPPH
radical significantly in a concentration-dependent man-
ner. Their comparable scavenging activities were ex-
pressed in IC50 (concentration required for 50%
inhibition of 0.1 mM DPPH concentration) value. a-To-
copherol was used as the positive standard. The radical
scavenging activities of the synthesized compounds are
summarized in Table 1. Compounds 2c, 2d, 4d, and 6a
showed appreciable radical scavenging activity. The
activity showed by the vaniline based compound 2c
was comparable to that of a-tocopherol. The strong
activity showed by 2c and also by 2d was perhaps due
to the presence of the free OH group in the aryl moiety
of 5-arylidene-2,4-thiazolidinediones, which can donate
hydrogen atoms. After donating a hydrogen atom, com-
pounds exist in its radical form, and the electron conju-
gation effect in the structure stabilizes the radical which
favors the reaction to occur. That the presence of free
hydroxyl group in the aryl moiety is one of the factors
in determining the DPPH scavenging activity of the
compound is also described by Tominaga et al.26 where
protection of the free hydroxyl group drastically reduced
the DPPH scavenging activity. The difference in activity
amongst compounds 2a–d was due to the difference in
the stability of the oxygen centered radical formed in
Table 1. Inhibition of DPPH radical by synthesized compound
R4
R3
R2
S
O
5
NR
O
R1
Compound
R1
R2
R3
R4
R5
IC50 (lM)
a-Tocopherol
2.3
2a
2b
2c
2d
4a
4b
4c
4d
6a
6b
6c
6d
7
H
OH
H
H
H
H
H
11.97
23.49
2.49
H
H
OH
OH
H
H
OCH3
OCH3
H
H
OH
PRO
H
OCH3
H
H
H
2.85
>50
H
H
H
H
PRO
H
H
43.3
OCH3
OCH3
H
PRO
PRO
GRO
H
H
H
17.89
4.08
9.8
OCH3
H
H
H
H
H
H
H
GRO
H
H
11.97
17.57
32.13
Very high
OCH3
OCH3
H
GRO
GRO
GRO
H
H
OCH3
H
H
H
(CH2)5Br
H
IC50: concentration required for 50% reduction of 0.1 mM DPPH radical.
O
O
PRO=
,
GRO=

1152
S. U. Hossain, S. Bhattacharya / Bioorg. Med. Chem. Lett. 17 (2007) 1149–1154
Table 3. Modulation of hepatoprotecting activity by compounds 2c,
4d, & 6a in normal Swiss albino mice liver
110
100
90
80
70
60
50
40
30
20
10
0
Compound
ALT (U/I)
AST(U/I)
Urea (mg/dl)
Normal
12.7 1.3
4.8 1.5*
7.3 1.2**
6.32 1.22*
42.47 1.6
38.1 2.3*
37.99 1.6*
32.88 3.3*
18.48 0.65
13.83 0.53**
16.53 1.2*
14.69 2.1*
2c
4d
6a
2c
4d
6a
Results are expressed as means SD. n = 6 animals per group.
* Significantly different from normal control group at p < 0.01.
α-Tocopherol
7
such as superoxide dismutase (SOD), catalase (CAT),
glutathione-S-transferase (GST), and reduced Glutathi-
one (GSH), and at the same time lowering the serum
ALT and AST level at the preliminary screening dose
of 3 mg/kg in normal Swiss albino mice given orally
for 20 days as compared to the control animals. The
hepatic lipid-peroxidation level (LPO) remained
unchanged.
0
3
6
9
12 15 18 21 24 27 30 33 36 39
[ Compound ] μΜ
Figure 1. Graphical representation of % DPPH radical scavenging
activity of compounds 2c, 4d, 6a, 7, and a-tocopherol.
The vulnerability of the liver to chemical injury is due to
its anatomical proximity to the blood supply and diges-
tive tract as to its ability to biotransform and concen-
trate xenobiotics.27 Serum ALT and AST are two
marker enzymes which indicate the extent of liver injury.
In the literature it was observed that thiazolidinedione
derivative compounds were effective to inhibit serum
ALT, AST level significantly.10 In the present experi-
ment, the thiazolidinedione compounds 2c, 4d, and 6a
decreased serum ALT and AST activities, characterizing
hepatoprotective effect of the compounds lowering re-
lease of these enzymes to plasma in mice.
has one methoxy group in the aromatic ring. Com-
pounds 4a and 4b which do not have any methoxy group
showed less activity. The better activity of 4b as com-
pared to 4a may be due to the 1,7-sigmatropic shift30
of the prenyl group attached to the aromatic oxygen
atom to the carbonyl oxy atom of the thiazolidine ring,
which is possible, resulting more stable phenoxy radical.
The difference in activity amongst compounds 6a–d may
be in part due to the steric interaction between the bulky
geranyl group and the proximate methoxy group in
compounds 6c and 6d which disturbed the planarity of
the molecule as a result the stability of the nitrogen cen-
tered radical through conjugation is also disturbed. In
case of compound 6a which does not have any proxi-
mate methoxy group, such steric interaction is minimum
providing better stability of the nitrogen centered radical
by extended conjugation resulting in para quinonoid
structure which has more stabilization than the ortho
quinonoid structure formed for compound 6b. As a re-
sult compound 6a was found more active than 6b and
also the most active amongst 6a–d.
In addition, these three compounds caused decrease in
serum urea levels and did not change creatine level sug-
gesting no renal toxicity. A number of reports showed
that enhanced serum urea and creatine levels are indica-
tive of renal injury.28
Substitution of the phenolic hydrogen by the Prenyl/
Geranyl group though lowered the radical scavenging
activity to some extent still it has the potential to upreg-
ulate host antioxidant defense system in a significant
manner. Geranyloxy derivative of thiazolidinedione
(6a) showed better effect compared to prenyloxy deriva-
tive (4d) as an antioxidant by enhancing detoxifying en-
zyme as well as lowering lipid peroxidation level. In
conclusion, these synthesized compounds are found to
be highly promising to be used as antioxidants against
oxidative stress related diseases with special reference
to cancer.
The effect of the thiazolidinedione derivatives 2c, 4d, and
6a on different phase II/detoxifying enzymes as well as
on serum ALT, AST, and urea level in Swiss albino mice
was evaluated and the results are summarized in Tables
2 and 3.
The compounds (2c, 4d, and 6a) were found to be effec-
tive in enhancing the host antioxidant defense system
Table 2. Modulation of Phase II detoxifying enzymes (GST, SOD, CAT, and GSH) and lipid peroxidation by compounds 2c, 4d, and 6a in normal
Swiss albino mice liver
Compound
LPO (nmTBARS/
mg protein)
GST (nmol CDNB-GSH
minÀ1mgÀ1
GSH (nmol GSH/
mg protein)
SOD (unit of inhibition/
mg protein)
CAT (units/mg protein)
)
Normal
0.15 0.01
113.86 9.12
220.8 3.96*
140.54 11*
160.33 12*
101.17 11.84
184.09 18.4*
238.22 22.3*
245.32 11.3*
57.4 3.4
65.45 3.7*
67.07 6.6*
70.15 12.3*
12.26 0.37
16.85 1.2*
23.97 2.25*
22.32 1.2*
2c
4d
6a
0.143 0.01*
0.158 0.011*
0.148 0.013*
Results are expressed as means SD. n = 6 animals per group.
* Significantly different from normal control group at p < 0.01.

S. U. Hossain, S. Bhattacharya / Bioorg. Med. Chem. Lett. 17 (2007) 1149–1154
1153
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This work was supported by Grant from CSIR (9/
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CSIR for Senior Research Fellowship. The authors
thank Prof. Somnath Ghosh, Jadavpur University,
Kolkata, India, for providing valuable suggestions and
also thank Director, CNCI, for support in this study.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.
2006.12.040.
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29. Preparation of 5-[4-(3,7-dimethyl-octa-2,6-dienyloxy)-ben-
zylidene]-thiazolidine-2,4-dione: (6a) Geranyl bromide
(1.064 ml, 4.9 mmol) in 4 ml acetone was added dropwise
to a mixture containing 4-hydroxybenzaldehyde (300 mg,
2.45 mmol), potassium carbonate (677.3 mg), and tetra-
butylammonium hydrogen sulfate (30 mg) in 6 ml dry
acetone at room temperature under anhydrous condition.
After stirring at room temp. for 24 h, acetone was
removed in vacuo and the residue was extracted with
CHCl3. The CHCl3 extract was washed with 4%
aqueous NaOH sol (3· 10 ml) then with water and
finally dried over CaCl2, CHCl3 was removed in vacuo
to leave an oil which was purified by column chromatog-
raphy over silica gel (60–120 mesh) with CHCl3–petro-
leum ether (3:1,v/v) to give the compound 5a (150 mg,
51.6%).
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A mixture of 5a (150 mg, 0.588 mmol), 2,4-thiazolidined-
ione (82.7 mg, 0.706 mmol), and catalytic amount of
pyperidine (20 ll) in 15 ml benzene was stirred at refluxing
temperature for 24 h in dean-stark apparatus. The reac-
tion mixture was cooled at room temperature and the
solid separated filtered. The crude product was purified
through column chromatography over silica gel
(60–120 mesh) with Petroleum ether–diethyl ether
(5:2, v/v) to give the title compound (6a) as yellow color
solid. It was then crystallised from diethyl ether–petether
(60–80 ꢁC) to get an analytical sample (90 mg, 67.17%).
Yield: 67.17%, mp: 120–121 ꢁC. 1H NMR (300 MHz,
CDCl3): d 1.6 (3H, s), d 1.67 (3H, s), d 1.75 (3H, s), d
2.1 (4H, s), d 4.6 (2H, d, 6.5 Hz), d 5.1 (1H, s), d 5.47
(1H, t, 6.3 Hz), d 6.99 (2H, d, 8.7 Hz), d 7.44 (2H, d,
8.7 Hz), d 7.83 (1H, s), d 9.08 (1H, s). 13C (75 M Hz,
CDCl3): 167.87, 167.5, 161.02, 141.99, 134.52, 132.56,
125.37, 123.61, 118.68, 115.47, 65.14, 39.48, 26.18, 25.64,
17.66, and 16.68. EIMS: m/z, 357 (M+), 221
(M+ÀC10H15), 150 (M+À C10H15, CONHCO). IR (KBr)
mmax cmÀ1: 2976.0, 1743.5, 1687.6, 1583.4, 1512.1. Anal.
Found C, 67.12; H, 6.54, N, 3.88. Calcd for C20H23NO3S:
C: 67.2, H: 6.49, N: 3.92.
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