Inhibition of gastric H+, K+-ATPase by novel thiazolidinone derivatives

Article abstract of DOI:10.1080/17415991003702621

In a program to identify new anti-ulcer compounds, a series of novel substituted thiazolidinone derivatives 5(a-j) were synthesized and screened for their in vitro H⁺, K⁺-ATPase inhibitory activity. The synthesized compounds were characterized by nuclear magnetic resonance ( ¹H-NMR), liquid chromatography-mass spectrometry (LCMS) and fourier transform infrared (FTIR) analysis. We have briefly investigated the structure-activity relation (SAR) studies and reveal that the nature of position of the fluorine atom influences the anti-ulcer activity. Among the synthesized compounds 5b, 5c and 5e showed 4 and 10-fold higher H⁺, K ⁺-ATPase activity when compared with those of other derivatives 5a, 5f, 5g and 5j, respectively. H⁺, K⁺-ATPase activity of 5b, 5c and 5e were comparable with those of known H⁺, K ⁺-ATPase blocker lansoprazole which is a potential anti-ulcer drug.

Full text of DOI:10.1080/17415991003702621

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Inhibition of gastric H+, K+-ATPase by
novel thiazolidinone derivatives
S. Chandrappa a , K. Vinaya a , B. M. Srikanta b , C. S. Ananda
Kumar a , D. S. Prasanna a , N. R. Thimmegowda a , Shylaja M.
Dharmesh b & K. S. Rangappa a
a Department of Studies in Chemistry , University of Mysore ,
Manasagangotri, Mysore, 570 006, India
b Department of Biochemistry and Nutrition , Central Food
Technological Research Institute , Mysore, 570 020, India
Published online: 26 May 2010.
To cite this article: S. Chandrappa , K. Vinaya , B. M. Srikanta , C. S. Ananda Kumar , D. S.
Prasanna , N. R. Thimmegowda , Shylaja M. Dharmesh & K. S. Rangappa (2010) Inhibition of gastric
H+, K+-ATPase by novel thiazolidinone derivatives, Journal of Sulfur Chemistry, 31:3, 189-196, DOI:
10.1080/17415991003702621
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Journal of Sulfur Chemistry
Vol. 31, No. 3, June 2010, 189–196
Inhibition of gastric H+, K+-ATPase by novel thiazolidinone
derivatives
S. Chandrappaa, K. Vinayaa, B.M. Srikantab, C.S. Ananda Kumara, D.S. Prasannaa,
N.R. Thimmegowdaa, Shylaja M. Dharmeshb and K.S. Rangappaa*
aDepartment of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore-570 006, India;
bDepartment of Biochemistry and Nutrition, Central Food Technological Research Institute,
Mysore-570 020, India
(Received 21 December 2009; final version received 14 February 2010)
In a program to identify new anti-ulcer compounds, a series of novel substituted thiazolidinone derivatives
5(a–j) were synthesized and screened for their in vitro H+, K+-ATPase inhibitory activity. The synthesized
compounds were characterized by nuclear magnetic resonance (1H-NMR), liquid chromatography-mass
spectrometry (LCMS) and fourier transform infrared (FTIR) analysis. We have briefly investigated the
structure–activityrelation(SAR)studiesandrevealthatthenatureofpositionofthefluorineatominfluences
the anti-ulcer activity. Among the synthesized compounds 5b, 5c and 5e showed 4 and 10-fold higher H+,
K+-ATPase activity when compared with those of other derivatives 5a, 5f, 5g and 5j, respectively. H+,
K+-ATPase activity of 5b, 5c and 5e were comparable with those of known H+, K+-ATPase blocker
lansoprazole which is a potential anti-ulcer drug.
Keywords: thiazolidinone; 5-(3-chlorophenyl)-furfural; alkyl halides; anti-ulcer; H+, K+-ATPase
enzyme
1. Introduction
The peptic ulcer and related diseases encompass a broad spectrum of clinical disorders ranging
from intense burning and pain to severe complications such as deep ulcers, strictures, etc. The
mammalian stomach is a specialized organ of the digestive tract that serves to store and process the
food for absorption by the intestine. The physiological studies (1) regarding acid secretory path-
ways have proved that the proton pump, being the ultimate mediator of acid secretion, is localized
in a specialized acid secreting tubulovesicular system of the parietal cells in the gastric mucosa.
Upon stimulation, however, this system undergoes various morphological changes accompany-
ing oxygen consumption, which elicit an acid secretory response. Besides histamine, which acts
through H2-receptors as the major stimulant, gastric and acetylcholine also have receptors on the
parietal cells (2).
The interest in thiazolidin-4-ones for medical applications is increasing strongly. (−)-2-(5-
Carboxypentyl)-thiazolidin-4-one (actithiazic acid) isolated from the culture broth of a strain
*Corresponding author. Emails: rangappaks@gmail.com, rangappaks@chemistry.uni-mysore.ac.in
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2010 Taylor & Francis
DOI: 10.1080/17415991003702621
http://www.informaworld.com

190 S. Chandrappa et al.
of streptomyces showed highly specific in vitro activity against Mycobacterium tuberculosis
(3a,b). Other substituted thiazolidin-4-ones exhibit diverse biological activities such as anti-
consultant (4), anti-diarrhea (5), anti-arthritic (6), anti-platelet activating factor activity (7a–c),
anti-histaminic (8a–c), anti-microbial (9a–c), anti-diabetic (10a,b), oxygenase inhibitory (11),
K+ channel inhibitory (12), calcium antagonist (13), cardio-protective (14), antischemic acti-
vity (15a,b) and a promising agent for treating Alzheimer’s (10b), cancer (16), AIDS (17a,b)
and hepatitis B (17a). Among the tetrahydro-1,3-thiazin-4-ones, 2-(4-chlorophenyl)-3-methyl-
tetrahydro-1,3-thiazin-4-one-1,1-dioxide (chloromezanone) is widely used as an anticoagulant
(18), tranquilizer and for muscle spasms (19). Other derivatives showed a wide range activities,
such as anti-microbial (20a,b), anti-arthritic (21), anti-rheumatic (22) and in the treatment of
cardiac arrhythmia (12), peptic ulcers (23, 24) and ocular inflammation (25). Recently, Masai et
al. (26) reported pyridyl-thiazolidinone-4-one as a gastric H+, K+-ATPase inhibitor. In the course
of our research into gastric H+, K+-ATPase inhibitors to develop effective anti-ulcer drugs, a series
of synthetic compounds 5(a–j) were synthesized.
2. Results and discussion
We have determined the inhibition of H+, K+-ATPase by individual thiazolidinone derivatives
5(a–j) that potentially inhibit the enzyme. Synthesized derivatives 5(a–j) showed the maxi-
mum inhibitory effect in 5b (IC50 = 17.4 2.1 μg/ml), 5c (IC50 = 29.0 3.2 μg/ml), and 5e
(IC50 = 18.3 2.9 μg/ml), followed by 5a (IC50 = 104.2 7.6 μg/ml), 5f (IC50 = 116.2
10.2 μg/ml), 5g (IC50 = 138.8 10.9 μg/ml) and 5j (IC50 = 300.0 22.5 μg/ml) (Table 1).
The H+, K+-ATPase enzyme, a prime component of the gastric proton pump responsible for
acid secretion in the stomach, is located in the gastric membrane vesicle and catalyzes the electro-
neutral exchange of intracellular H+ and extra cellular K+ coupled with the hydrolysis of the
cytoplasm ATP (28). Hyper-secretion of this enzyme in the stomach leads to acidity and ulcers.
Therefore, this regulatory enzyme was found to be a pharmacological target for many anti-ulcer
drugs. Synthesized thiazolidinone derivatives 5(a–j) are known to inhibit gastric H+, K+-ATPase
activity in a concentration-dependent manner (26). In the current study, we compared the H+,
K+-ATPase activity of synthesised thiazolidinone derivatives 5(a–j) with that of Lansoprazole.
The concentration required to inhibit 50% of H+, K+-ATPase activity (IC50), as calculated for 5b,
5c and 5e, showed a potential H+, K+-ATPase blocking activity with IC50 values of 17.3, 29.0
and 18.3 μg/ml, respectively, and the activity was compared with Lansoprazole (IC50 of 19.3
2.2 μg/ml), the known proton pump inhibitor. Some of the new derivatives 5a, 5f and 5g showed
4-fold lower activity and compound 5a showed a 10-fold reduction in activity when compared with
5b–e. Derivatives 5d, 5h and 5i did not show any activity. Thus, the thiazolidinone derivatives 5b,
5c and 5e were determined to be good inhibitors of the enzyme. The inhibition could be due to the
electron-withdrawing fluorine groups at the third and fourth positions in 5b, electron-withdrawing
fluorine groups at the third position in 5c and a pyridine moiety attached to thiazolidinone in 5e
upon binding to theATPase enzyme. In contrast, an electron-deficient heterocycle such as pyridine
(5e) maintains interesting levels of anti-ulcer activity. However, electron-donating groups such as
methoxy or methyl on the phenyl ring of thiazolidinone derivatives 5i and 5j reduces the activity.
Close inspections of the results reveal some interesting facts with respect to SAR studies.
Introduction of an electron-deficient acetylpyridine group at the N-position in 5e led to a more
active compound. Shifting the fluorine group at the meta position of 5c to the para position of
5g completely suppressed the activity. On the contrary, introduction of an additional fluorine
group at meta and para positions in 5b had the most potent anti-ulcer activity when compared
with monosubstituted 5c and 5g compounds. Replacing electron-withdrawing groups such as
cyano (5f) and nitro (5h) resulted in a great reduction in the activity. Finally, replacing the

Journal of Sulfur Chemistry 191
Table 1. Chemical structure, yield and melting point of the synthesized compounds 5(a–j).
Compound
R1
Yield (%)
74
MP (◦C)
172–174
IC50 (μg/ml)
5a
104.2 7.6
F
5b
79
166–168
17.4 2.1
F
F
5c
83
88
174–176
198–200
29.0 3.2
a
5d
NO2
O
N
5e
5f
76
82
76
154–156
130–132
168–170
18.3 2.9
116.2 10.2
138.8 10.9
CN
F
5g
NO2
a
a
5h
5i
73
80
161–163
169–171
OCH3
CH3
5j
77
–
163–165
–
300 22.5
19.3 2.2
Lansoprazole
–
Note: aNo significant activity.
electron-withdrawing (5b,c) by electron donating groups (5i, 5j) on to the phenyl ring decreased
the activity.
Preeti et al. (29) discussed 3D quantitative SAR (QSAR) studies, which led to the identification
of essential structural features for gastric proton pump inhibitory activity in terms of the physic-
ochemical properties and their spatial dispositions, and that the carbonyl oxygen atoms and the
nitrogen atom of compounds in proper spatial disposition are essential and crucial for the activity
of compounds. Thiazolidinone derivatives 5b, 5c and 5e possess these two carbonyl oxygen and
nitrogen atoms and showed potent H+, K+-ATPase inhibitory activity.
3. Conclusion
The aim of the present research work was to synthesize some novel substituted thiazolidinones
and to evaluate their H+, K+-ATPase inhibitory properties. Successful arrangements of functional
groups are responsible for bioactivity. Synthesis of 10 novel thiazolidinones 5(a–j), bearing an
aryl substitution at N-position, in addition to the generation of closely related structures enable
us to identify precisely the structure function activity of the H+, K+-ATPase enzyme. SAR
studies, with various chemical groups, reveal that the position and nature of the substitution

192 S. Chandrappa et al.
on the phenyl ring of thiazolidinones are crucial for H+, K+-ATPase inhibition. It is possible
that the generated compounds may involve different routes in ulcer inhibition. Hence, there is a
need for further investigation to clarify the underlying mechanism of these potential anti-ulcer
properties.
4. Experimental
Melting points were determined using SELACO-650 hot stage melting point apparatus and were
uncorrected. Infrared (IR) spectra were recorded using a Jusco FTIR-4100 series. 1H-NMR spectra
were recorded on a Shimadzu AMX 400-Bruker, 400 MHz spectrometer using DMSO-d6 as a
solvent and TMS as the internal standard (chemical shift in δ ppm). Spin multiples are given as
s (singlet), d (doublet), t (triplet) and m (multiplet). Mass and purity were recorded on a LC-
MSD-Trap-XCT. Silica gel column chromatography was performed using Merck 7734 silica gel
(60-120 mesh) and Merck-made TLC plates.
4.1. Synthesis
4.1.1. Synthesis of compound 5-((5-(4-chlorophenyl)furan-2-yl)methylene)
thiazolidine-2,4-dione 3
A mixture of thiazolidine-2,4-dione 1 (1.0 g, 8.5 mmol), 5-(3-chloro phenyl)-furfural 2 (1.75 g,
8.5 mmol) and anhydrous sodium acetate (2.1 g, 25.6 mmol) were taken in 10 ml of glacial
acetic acid. The reaction mixture was heated to 120 ◦C in an oil bath for 12 h. The progress
of the reaction was monitored by thin-layer chromatography (TLC). Then the reaction mix-
ture was cooled, filtered and washed with ether to finally get a reddish solid compound (2.10 g,
−
−
−
81%). The absence of CHO and CH2 proton peak and the presence of CH proton peak
confirms the formation of compound 3. The schematic representation of the synthesized com-
1
−
pound is shown in Scheme 1. H-NMR (DMSO-d6, 400 MHz) δ: 12.56 (bs, 1H, NH), 7.92
=
(s, 1H, CH), 7.60 (d, 2H, J = 8.2 Hz, Ar-H), 7.55 (d, 2H, J = 8.1 Hz, Ar-H), 7.35 (d, 1H,
J = 8.2 Hz, Ar-H), 6.83 (d, 1H, J = 8.1 Hz, Ar-H). IR (KBr, cm−1): 3318, 1636, 1609, 1329,
1207, 806.
S
O
S
CH3COONa, 12 h
CH3COOH, 120ºC
O
O
O
Cl
CHO
+
Cl
NH
NH
O
O
1
2
3
R-X, 4 (a–j)
r.t, 2 hr
K2CO3, DMF
O
S
O
Cl
N
O
R
5 (a–j)
Scheme 1. Synthesis of 5-((5-(4-chlorophenyl)furan-2-yl)methylene)thiazolidine-2,4-dione
derivatives.

Journal of Sulfur Chemistry 193
4.1.2. General procedure for synthesis of 5-((5-(4-chlorophenyl)furan-2-yl)methylene)
thiazolidine-2,4-dione derivatives 5(a–j)
A solution of 5-((5-(4-chlorophenyl)furan-2-yl)methylene)thiazolidine-2,4-dione 3 (1.0 eq) in dry
DMF was taken and cooled to 0–5 ◦C in an ice bath. Anhydrous potassium carbonate (3 eq) was
added to the cold mixture and stirred for 10 min. Different alkyl halides (1.1 eq) were added, and
the mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored
by TLC. When the reaction was completed, water was added to the reaction mixture and extracted
with ethyl acetate. The organic layer was washed with water and dried with anhydrous sodium
sulfate. The solvent was evaporated and the crude product obtained was purified by column
chromatography over silica gel (60–120 mesh) using hexane: ethyl acetate (8:2) as an eluent.
= −
The absence of –CO-NH and the presence of N CH2– proton peak in synthesized derivatives
5(a–j) in 1H-NMR and IR spectra confirm the identity of the products. The chemical structures
and physical data of all the synthesized compounds are given in Table 1.
4.1.3. Synthesis of 3-benzyl-5-((5-(4-chlorophenyl)furan-2-yl)methylene)
thiazolidine-2,4-dione 5a
The product obtained was a pale yellow solid from 5-((5-(4-chlorophenyl)furan-2-yl)
methylene)thiazolidine-2,4-dione 3 (0.1 g, 0.32 mmol), benzyl bromide 4a (0.06 g, 0.35 mmol)
1
=
and K2CO3 (0.132 g, 0.98 mmol). H-NMR (DMSO-d6, 400 MHz) δ: 7.95 (s, 1H, CH), 7.82
(dd, 4H, J = 8.2 Hz, Ar-H), 7.60 (m, 5H, Ar-H), 7.01 (d, 1H, J = 8.1 Hz, Ar-H), 6.65 (d, 1H,
+
J = 8.0 Hz,Ar-H), 5.14 (s, 2H, CH2). MS (ESI) m/z: 396.04 (M + H ). IR (KBr, cm−1): 1605,
−
1335, 1253, 1190, 1056, 1030, 778.
4.1.4. Synthesis of 3-(3,4-difluorobenzyl)-5-((5-(4-chlorophenyl)furan-2-yl)methylene)
thiazolidine-2,4-dione 5b
The product obtained was a pale yellow solid from 5-((5-(4-chlorophenyl)furan-2-yl)
methylene)thiazolidine-2,4-dione 3 (0.1 g, 0.32 mmol), 3,4-difluoro benzyl bromide 4b (0.074 g,
1
0.35 mmol) and K2CO3 (0.132 g, 0.98 mmol). H-NMR (DMSO-d6, 400 MHz) δ: 8.01 (s, 1H,
=
CH), 7.75 (dd, 4H, J = 8.3 Hz, Ar-H), 7.65 (m, 3H, Ar-H), 7.10 (d, 1H, J = 8.0 Hz, Ar-H),
+
−
6.65 (d, 1H, J = 8.1 Hz, Ar-H), 5.50 (s, 2H, CH2). MS (ESI) m/z: 432.04 (M + H ). IR (KBr,
cm−1): 1615, 1607, 1331, 1190, 1030, 753, 593.
4.1.5. Synthesis of 3-(3-fluorobenzyl)-5-((5-(4-chlorophenyl)furan-2-yl)methylene)
thiazolidine-2,4-dione 5c
The product obtained was a pale yellow solid from 5-((5-(4-chlorophenyl)furan-2-yl)
methylene)thiazolidine-2,4-dione 3 (0.1 g, 0.32 mmol), 3-fluoro benzyl chloride 4c (0.052 g,
1
0.35 mmol) and K2CO3 (0.132 g, 0.98 mmol). H-NMR (DMSO-d6, 400 MHz) δ: 7.95 (s, 1H,
=
CH), 7.73 (dd, 4H, J = 8 Hz, Ar-H), 7.60 (m, 4H, Ar-H), 7.03 (d, 1H, J = 8.1 Hz, Ar-H), 6.62
+
=
(d, 1H, J = 8.0 Hz, Ar-H), 5.32 (s, 2H, CH2). MS (ESI) m/z: 414.03 (M + H ). IR (KBr,
cm−1): 1657, 1611, 1502, 1329, 1209, 754, 682.
4.1.6. Synthesis of 3-(4-nitrobenzyl)-5-((5-(4-chlorophenyl)furan-2-yl)methylene)
thiazolidine-2,4-dione 5d
The product obtained was a pale yellow solid from 5-((5-(4-chlorophenyl)furan-2-yl)
methylene)thiazolidine-2,4-dione 3 (0.1 g, 0.32 mmol), 4-nitro benzyl chloride 4d (0.06 g,

194 S. Chandrappa et al.
1
0.35 mmol) and K2CO3 (0.132 g, 0.98 mmol). H-NMR (DMSO-d6, 400 MHz) δ: 8.11 (s, 1H,
=
CH), 7.83 (dd, 4H, J = 8.1 Hz,Ar-H), 7.61 (d, 2H, J = 8.0 Hz,Ar-H), 7.45 (d, 2H, J = 8.1 Hz,
−
Ar-H), 7.1 (d, 1H, J = 8.0 Hz, Ar-H), 6.7 (d, 1H, J = 8.1 Hz, Ar-H), 5.5 (s, 2H, CH2). MS
(ESI) m/z: 441.02 (M + H+). IR (KBr, cm−1): 1657, 1608, 1547, 1317, 1201, 753, 667.
4.1.7. Synthesis of 5-((5-(4-chlorophenyl)furan-2-yl)methylene)-3-(2-oxo-2-(pyridin-3-yl)
ethyl)thiazolidine-2,4-dione 5e
The product obtained was a pale yellow solid from 5-((5-(4-chlorophenyl)furan-2-yl)
methylene)thiazolidine-2,4-dione 3 (0.1 g, 0.32 mmol), 3-acetyl bromo pyridine 4e (0.1 g,
1
0.35 mmol) and K2CO3 (0.132 g, 0.98 mmol). H-NMR (DMSO-d6, 400 MHz) δ: 8.05 (s, 1H,
=
CH), 7.83 (m, 4H, J = 8.2 Hz,Ar-H), 7.70 (dd, 4H, J = 8.0 Hz,Ar-H), 7.03 (d, 1H, J = 8.0 Hz,
+
−
Ar-H), 6.65 (d, 1H, J = 8.1 Hz, Ar-H), 4.81 (s, 2H, CH2). MS (ESI) m/z: 425.03 (M + H ).
IR (KBr, cm−1): 1633, 1413, 1330, 1191, 1023, 778.
4.1.8. Synthesis of 4-((-5-((5-(4-chlorophenyl)furan-2-yl)methylene)-2,4-dioxothiazolidin-3-
yl)methyl)benzonitrile 5f
The product obtained was a pale yellow solid from 5-((5-(4-chlorophenyl)furan-2-yl)
methylene)thiazolidine-2,4-dione 3 (0.1 g, 0.32 mmol), 4-cyano benzyl bromide 4f (0.064 g,
0.35 mmol) and K2CO3 (0.132 g, 0.98 mmol). 1H-NMR (DMSO-d6, 400 MHz) δ: 7.95 (s,
=
1H, CH), 7.87 (dd, 4H, J = 8.2 Hz, Ar-H), 7.75 (dd, 4H, J = 8.1 Hz, Ar-H), 7.20 (d, 1H,
−
J = 8.0 Hz, Ar-H), 6.71 (d, 1H, J = 8.1 Hz, Ar-H), 5.23 (s, 2H, CH2). MS (ESI) m/z: 421.03
(M + H+). IR (KBr, cm−1): 1634, 1413, 1330, 1191, 1054, 778, 593.
4.1.9. Synthesis of 3-(4-fluorobenzyl)-5-((5-(4-chlorophenyl)furan-2-yl)methylene)
thiazolidine-2,4-dione 5g
The product obtained was pale yellow solid from 5-((5-(4-chlorophenyl)furan-2-yl)methylene)
thiazolidine-2,4-dione 3 (0.1 g, 0.32 mmol), 4-fluoro benzyl chloride 4g (0.052 g, 0.35 mmol) and
1
=
K2CO3 (0.132 g, 0.98 mmol). H-NMR (DMSO-d6, 400 MHz) δ: 7.96 (s, 1H, CH), 7.83 (dd,
4H, J = 8.1 Hz, Ar-H), 7.75 (d, 2H, J = 8.0 Hz, Ar-H), 7.50 (d, 2H, J = 8.2 Hz, Ar-H), 7.35
−
(d, 1H, J = 8.1 Hz, Ar-H), 6.67 (d, 1H, J = 8.2 Hz, Ar-H), 5.54 (s, 2H, CH2). MS (ESI) m/z:
414.03 (M + H+). IR (KBr, cm−1): 1641, 1607, 1414, 1329, 1192, 675, 595.
4.1.10. Synthesis of 3-(3-nitrobenzyl)-5-((5-(4-chlorophenyl)furan-2-yl)methylene)
thiazolidine-2,4-dione 5h
The product obtained was a pale yellow solid from 5-((5-(4-chlorophenyl)furan-2-yl)
methylene)thiazolidine-2,4-dione 3 (0.1 g, 0.32 mmol), 3-nitro benzyl chloride 4h (0.056 g,
1
0.35 mmol) and K2CO3 (0.132 g, 0.98 mmol). H-NMR (DMSO-d6, 400 MHz) δ: 8.18 (s, 1H,
=
CH), 7.91 (d, 2H, J = 8.3 Hz, Ar-H), 7.85 (dd, 4H, J = 8.2 Hz, Ar-H), 7.65 (m, 3H, Ar-H),
−
7.41 (d, 1H, J = 8.0 Hz, Ar-H), 6.70 (d, 1H, J = 8.0 Hz, Ar-H), 5.60 (s, 2H, CH2). MS (ESI)
m/z: 421.02 (M + H+). IR (KBr, cm−1): 1615, 1562, 1513, 1246, 1028, 746, 614.
4.1.11. Synthesis of 3-(3-methoxybenzyl)-5-((5-(4-chlorophenyl)furan-2-yl)methylene)
thiazolidine-2,4-dione 5i
The product obtained was a pale yellow solid from 5-((5-(4-chlorophenyl)furan-2-yl)
methylene)thiazolidine-2,4-dione 3 (0.1 g, 0.32 mmol), 3-methoxy benzyl chloride 4i (0.054 g,

Journal of Sulfur Chemistry 195
1
0.35 mmol) and K2CO3 (0.132 g, 0.98 mmol). H-NMR (DMSO-d6, 400 MHz) δ: 7.95 (s, 1H,
=
CH), 7.82 (dd, 4H, J = 8.2 Hz, Ar-H), 7.76 (m, 3H, Ar-H), 7.65 (d, 2H, J = 8.2 Hz, Ar-H),
−
7.35 (d, 1H, J = 8.1 Hz, Ar-H), 6.62 (d, 1H, J = 8.0 Hz, Ar-H), 5.50 (s, 2H, CH2), 3.86 (s, 3H,
+
OCH3). MS (ESI) m/z: 426.05 (M + H ). IR (KBr, cm−1): 1626, 1609, 1482, 1173, 847, 752.
−
4.1.12. Synthesis of 3-(3-methylbenzyl)-5-((5-(4-chlorophenyl)furan-2-yl)methylene)
thiazolidine-2,4-dione 5j
The product obtained was a pale yellow solid from 5-((5-(4-chlorophenyl)furan-2-yl)
methylene)thiazolidine-2,4-dione 3 (0.1 g, 0.32 mmol), 3-methyl benzyl chloride 4j (0.05 g,
1
0.35 mmol) and K2CO3 (0.132 g, 0.98 mmol). H-NMR (DMSO-d6, 400 MHz) δ: 7.93 (s, 1H,
=
CH), 7.82 (dd, 4H, J = 8.3 Hz, Ar-H), 7.75 (m, 3H, Ar-H), 7.66 (d, 2H, J = 8.2 Hz, Ar-H),
−
7.41 (d, 1H, J = 8.2 Hz, Ar-H), 6.70 (d, 1H, J = 8.0 Hz, Ar-H), 5.55 (s, 2H, CH2), 3.55 (s, 3H,
+
CH3). MS (ESI) m/z: 410.05 (M + H ). IR (KBr, cm−1): 1636, 1620, 1325, 1208, 659, 589.
−
4.2. Inhibition of gastric H+, K+-ATPase activity
Fresh sheep stomach was obtained from a local slaughterhouse in Mysore, India. The mucosa
of gastric fundus was cut off and the inner layer was scraped for parietal cells (27), which were
homogenized in 16 mM Tris buffer (pH 7.4) containing 10% Triton X-100 and centrifuged at
6000g for 10 min. The supernatant (enzyme extract) was used for the assay. Protein content was
determined according to Bradford’s method using BSA as the standard.
The enzyme extract (350 g/ml) was incubated with different fractions of synthesized novel
substituted thiazolidinones 5(a–j), in a reaction mixture containing 16 mM Tris buffer (pH 6.5),
and the reaction was initiated by adding substrate 2 mM ATP, in addition to 2 mM MgCl2 and
10 mM KCl. After 30 min of incubation at 37 ◦C, the reaction was stopped by the addition of
assay mixture containing 4.5% ammonium molybdate and 60% perchloric acid. Inorganic phos-
phate formed was measured spectrophotometrically at 400 nm. Enzyme activity was calculated
as micromoles of Pi released per hour at doses (10–50 μg/ml) of synthesized novel substituted
thiazolidinones. The results were compared with the known anti-ulcer proton potassium ATPase
inhibitor drug Lansoprazole.
Acknowledgements
The authors are grateful to UGC, Government of India for financial support to K.S.R. under the projects vide no. F.
31-143/2005(SR), UGC-SAP (Phase II) vide no. F. 540/10/2004-05 (SAP I), SMD, and B.M. Srikanta acknowledges the
support from the CSIR, Head, Department of Biochemistry and Nutrition, CFTRI, Mysore.
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