Synthesis and biological evaluation of novel condensed pyrimidinylmethylsulfinylbenzimidazoles as antiulcer agent

Article abstract of DOI:10.1007/s00044-012-0358-6

Current therapies to treat gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), and other acid-related diseases either prevent stimulation of the parietal cell (H₂-receptor antagonists) or inhibit gastric H⁺/K⁺

Full text of DOI:10.1007/s00044-012-0358-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:3719–3727
DOI 10.1007/s00044-012-0358-6
ORIGINAL RESEARCH
Synthesis and biological evaluation of novel condensed
pyrimidinylmethylsulfinylbenzimidazoles as antiulcer agent
•
Prashik B. Dudhe Kishor S. Jain Vikas K. Raskar
•
•
•
Atul S. Deodhe Jasminkumar G. Patel
•
•
Manisha S. Phoujdar Muthu K. Kathiravan
Received: 16 May 2012 / Accepted: 8 November 2012 / Published online: 4 December 2012
Ó Springer Science+Business Media New York 2012
Abstract Current therapies to treat gastroesophageal
reflux disease (GERD), peptic ulcer disease (PUD), and
other acid-related diseases either prevent stimulation of the
parietal cell (H2-receptor antagonists) or inhibit gastric H?/
K?-ATPase (proton pump inhibitors). The inhibition of
acid production by proton pump inhibitors (PPI’s) provides
more effective relief of symptoms and healing. A series of
novel 4-substituted-2-(1H-benzimidazol-2-yl)methylsulfi-
nylpyrimidines were synthesized as target compounds and
antiulcer activity was done using parameters like total
acidity, pH, and total gastric acid volume by pylorus liga-
tion method on Wistar rats. Three different dose levels
were employed for testings. The target compounds
4-substituted-2-(1H-benzimidazol-2-yl)methylsulfinylpyr-
imidines were effective for ulcer treatment and among
them compounds 10c, 10d, 8b, and 8c exhibited potent
antisecretory activity. Overall, compounds 10c, 10d, 8b,
and 8c can be looked upon as potential leads for further
development and investigations.
Keywords Antiulcer agents ꢀ H?/K?-ATPase ꢀ
Omeprazole ꢀ pH ꢀ Total acidity ꢀ Total gastric acid volume
Introduction
Peptic ulcer affects a large portion of the world population
and is induced by factors such as stress, smoking, nutri-
tional deficiencies, use of non-steroidal antiinflammatory
drugs, etc. The pathophysiology of acid-peptic disease is
attributed to the imbalance between aggressive factors (like
acid, pepsin, H. pylori infection) and local mucosal
defenses (like secretion of bicarbonate, mucus, and pros-
taglandins). (Reddy et al., 2010) The inhibition of gastric
acid secretion is a key therapeutic target for ulcer diseases,
gastroesophageal reflux disease (GERD), Zollinger–Ellison
syndrome (Z–E) and gastritis (Bariwal et al., 2008; Jain
et al., 2007). The gastric H?/K?-ATPase located in the
parietal cells is responsible for the final step of acid
secretion in the stomach. Proton pump is the ultimate
mediator of gastric acid secretion by parietal cells. With the
identification of H?/K?-ATPase as the primary gastric
proton pump, it was proposed that activation of H?
secretion occurred by incorporation of H?/K?-ATPase rich
tubulovesicles into the apical plasma membrane and are
re-sequestered back into the cytoplasmic compartment on
return to the resting state. Inhibition of the protons
pumping H?/K?-ATPase as a means of controlling gastric
Kishor S. Jain, Vikas K. Raskar contributed equally for the research
work.
P. B. Dudhe (&) ꢀ V. K. Raskar ꢀ A. S. Deodhe ꢀ
J. G. Patel ꢀ M. S. Phoujdar ꢀ M. K. Kathiravan
Sinhgad College of Pharmacy, Vadgaon Bk, Pune, India
e-mail: dudhe.prashik@gmail.com
V. K. Raskar
e-mail: vikasraskar2@gmail.com
A. S. Deodhe
e-mail: atuldeodhe@gmail.com
J. G. Patel
e-mail: patel.jasmin60@gmail.com
M. S. Phoujdar
e-mail: mphoujdar@hotmail.com
M. K. Kathiravan
e-mail: drmkkathir@gmail.com
K. S. Jain
Sinhgad Institute of Pharmaceutical Sciences,
Lonavala, Pune, India
e-mail: ks_jainin@yahoo.co.in
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Med Chem Res (2013) 22:3719–3727
pH is the main target in the pharmacological treatment of
acid-related diseases (Zimmermann et al., 2007). Cur-
rently, this is achieved by use of H2-receptor antagonists or
H?/K?-ATPase inhibitors, popularly referred as proton
pump inhibitors (PPI’s). Clinically used PPI’s include
omeprazole (1), lansoprazole (2), pantoprazole (3) (Block
and Beale, 2004). Chemically, the basic pharmacophore
possesses benzimidazole ring and a pyridine ring con-
nected to each other by a methylsulfinyl chain Fig. 1.
PPI’s especially of the pyridylmethylsulfinylbenzimidazoles
(PMSB) types have irreversible effect on gastric acid secretion.
The PPI’s bind covalently to the cysteine-813 and cysteine-822
residues of the H?/K?-ATPase, which leads to the inhibition of
acid secretion (Munson et al., 2005). In spite of therapeutic
effect they suffer from drawbacks like: achlorhydria, affect
digestion and nutrition, drug interactions, cause gastric polyps
and carcinoma, hypergastrinemia, etc. (Katzung and McQuaid,
2004). Therefore, there is a need to develop better analogs of the
existing PPI’s and thus overcome the drawbacks of the currently
available PPI’s. By modifying the structure of omeprazole (1),
earlier workers from our laboratories have reported a series of
pyrimidinemethylsulfinylbenzimidazoles as reversible PPI’s.
However, some of the test compounds showed good antiulcer
activity (Bariwal et al., 2008). In continuation of our ongoing
work on exploring pyrimidine moiety we have replaced the
pyridine ring present in the omeprazole with the pyrimidine
ring which is less basic and retaining the methylsulfinylbenzi-
midazole. Thus, we herein report a novel series of 4-substi-
tuted-2-(1H-benzimidazole-2-yl)methylsulfinylpyrimidines
10a–i, 8a–c as potential proton pump inhibitors.
under MWI (Jain et al., 2009) Treatment of condensed
2-chloromethylthieno[2,3-d]pyrimidin-4(3H)-ones 5a–c with
appropriate 2-mercaptobenzimidazoles gave condensed
2-(1H-benzimidazol-2-yl)methylthiopyrimidin-4(3H)-ones
6a–f under basic conditions. The reactions were carried out in
microwave irradiation at 40 W for 15–40 min. Chlorination
of condensed 2-(1H-benzimidazol-2-yl)methylthiopyrimi-
din-4(3H)-ones 6a–f was done by using POCl3 under
microwave irradiation at20 W for 12–20 mintoget 4-chloro-
2-(1H-benzimidazol-2-yl)methylthiopyrimidines (Jain et al.,
2009) 7a–f. Displacement of chlorine by alkoxy group is a
nucleophilic substitution reaction (Phoujdar et al., 2007). The
alkoxy group was found to be the best choice due to its
moderate nucleophilicity and easy convertibility to chloride
functionality on a pyrimidine molecule. Displacement of
chlorine by alkoxy group was done by refluxing 4-chloro-2-
(1H-benzimidazol-2-yl)methylthiopyrimidines 7a–f with
sodium alkoxides in alcohol.
Oxidation were done by using m-CPBA in methanol and
chloroform at 0 °C to get the target compound 4-substi-
tuted-2-(1H-benzimidazol-2-yl)methylsulfinylpyrimidines.
The target compounds are summarised in Table 1 (Dubey
et al., 2005; Zhou et al., 2005; Meinwald et al., 1964; Kishi
et al., 1972; Barill et al., 1990) 10a–i, 8a–c.
Biological activity
The test compounds were evaluated for antiulcer activity in
Wistar rats (Shay et al., 1945). The ulceration was caused
by accumulation of acidic gastric juice in the stomach.
Three parameters were tested, i.e., total volume, pH, total
acidity (Kulkarni, 2005) at three dose levels using ome-
prazole as standard drug. Results obtained are summarised
in Table 2. The study revealed that at 0.0289 mM/kg body
weight p.o., compounds 10b, 10c, 10d, 8c-produced sig-
nificant reduction in total volume more than the omepra-
zole. Compounds 10e, 10f, 10g-produced significant
reduction in total volume as compared to omeprazole,
while compounds 10a, 10h, 10i, 8a, 8b remained moder-
ately effective. At a dose of 0.0579 mM/kg body weight
p.o., compounds 10c, 8b, 8c-produced significant reduction
in total volume more when compared with omeprazole.
Compounds 10d, 10g-produced significant reduction in
Results and discussion
Chemistry
The synthetic route for target compounds 10a–i, 8a–c is
outlined in Scheme 1. 2-Amino-3-carbethoxy heterocycles
4a–c were synthesized as per earlier reported methods
(Kathiravan et al., 2007). The condensed 2-chloromethylpyr-
imidin-4(3H)-ones 5a–c were synthesized through facile one
pot HCl catalyzed cyclization of appropriate 2-amino-3-car-
bethoxy substrates with slight molar excess of chloroacetonitrile
Fig. 1 Structure of proton pump inhibitors
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Med Chem Res (2013) 22:3719–3727
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Scheme 1 Reagents and
conditions: a MWI, conc. HCl,
20W; b MWI, NaOH, 40W; c
MWI, POCl3, 20W; d NaOR1,
R1 OH, Reflux; e m-CPBA,
CHCl3 and CH3OH, 0–5 °C
total volume as comparable to omeprazole, while com-
pounds 10a, 10b, 10e, 10f, 10h, 10i, 8a remained moder-
ately effective. At 0.1158 mM/kg body weight p.o.,
compounds 10d, 10g, 8b, 8c-produced significant reduction
in total volume as comparable to omeprazole. Compounds
10c, 10h, 10i, 8a remained moderately effective; while
compounds 10a, 10b, 10e, 10f remained less effective than
the omeprazole. A perusal of Table 2 reveals that none of
the compounds were effective in modifying the pH neutral
or alkaline, i.e., increasing the pH.
at R-substituent resulted in less or comparable antisecre-
tory activity than the omeprazole (10a, 10c, 10d, 10f,
10g, 10i). Replacement of chlorine atom by trifluoroeth-
oxy group resulted in less antisecretory activity than the
omeprazole (10b, 10e, 10h).
Conclusions
In summary, a series of novel 4-substituted-2-(1H-ben-
zimidazol-2-yl)methylsulfinylpyrimidines were synthe-
sized and evaluated for antiulcer activity. Most of the
compounds exhibited antisecretory activity, but none of
the compounds have effect on pH and total acidity, i.e.,
they neither increase pH nor decrease total acidity. Based
on the present results, 4-substituted-2-(1H-benzimidazol-
2-yl)methylsulfinylpyrimidines can be considered as
effective for antisecretory activity and among them
compounds 10c, 10d, 8b, and 8c-exhibited potency.
Overall, compounds 10c, 10d, 8b, and 8c can be looked
upon as potential leads for further development and
investigations.
The preliminary structure activity relationship findings
reveal that substitutions R and R1 both influence the
antisecretory activity. Compounds with hydrogen atom
(10a, 10b, 10d, 10g, 10h, 8a) at R1-substituent resulted in
less or comparable antisecretory activity than the ome-
prazole. Replacement of hydrogen atom by methoxy
group as R1-substituent resulted in more potent antise-
cretory activity than the omeprazole (10c, 8b, 8c). Com-
pounds with chlorine atom at R substituent resulted in
more potent antisecretory activity than the Omeprazole
(8b, 8c). Replacement of chlorine atom by methoxy group
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Med Chem Res (2013) 22:3719–3727
Table 1 Physical data of 4-substituted-2-(1H-benzimidazol-2-yl)methylsulfinylpyrimidines
Comp.
no.
R
R1
Mol. Formula
(Mol.wt.)
M.P. (oC) Rf Value*
Yield
(%)
10a
10b
10c
10d
10e
10f
10g
10h
10i
8a
H
H
OCH3
OCH2CF3
OCH3
OCH3
OCH2CF3
OCH3
OCH3
OCH2CF3
OCH3
Cl
C19H18N4O2S2
(398)
102-104
118-120
066-068
126-128
178-180
078-080
120-122
130-132
090-092
074-076
082-084
134-136
68
62
64
58
70
72
64
57
64
59
68
67
0.6
0.5
0.6
0.6
0.5
0.7
0.5
0.6
0.5
0.4
0.7
0.6
C20H17F3N4O2S2
(466)
OCH3
H
C20H20N4O3S2
(428)
C21H16N4O2S2
(420)
H
C22H15F3N4O2S2
(488)
OCH3
H
C22H18N4O3S2
(450)
C21H15ClN4O2S2
(455.5)
H
C22H14ClF3N4O2S2(5
23.5)
OCH3
OCH3
OCH3
OCH3
C22H17ClN4O3S2
(485.5)
C19H17ClN4O2S2
(432.5)
8b
Cl
C21H15ClN4O2S2
(454.5)
8c
Cl
C21H14Cl2N4O2S2
(490)
*Ethylacetate: hexane
Experimental
were recorded on Perkin Elmer (USA) spectrum BX2
FT-IR spectrophotometer in potassium bromide disks.
All reagents and chemicals used were of LR grade and
purchased from standard vendors and used as received.
Melting points were determined on scientific melting point
apparatus in open capillaries and were uncorrected. The 1H
NMR spectra were recorded in DMSO-d6 using NMR
Varian Mercury YH-300 MHz spectrometer and chemical
shifts are given in units as parts per million, downfield from
TMS (tetramethylsilane) as an internal standard. Mass
spectra were obtained on a Shimadzu GCMS-QP2010
spectrometer. The IR spectra of the synthesized compounds
Chemistry
General procedure synthesis of condensed
2-chloromethylpyrimidin-4(3H)-ones
A mixture of appropriate 2-amino-3-carbethoxy substrates
(4a–c; 0.01 mol) and chloroacetonitrile (1.51g, 0.02 mol)
werereactedunder microwaveirradiationfor10 minat20 W.
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3723
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Med Chem Res (2013) 22:3719–3727
General procedure synthesis of 4-substituted-2-(1H-
The progress of reaction was monitored by TLC at 5 min
intervals. After completion of the reaction (25–35 min), the
reaction mixture was allowed to cool to room temperature and
poured onto ice–water mixture (100 ml). The resultant prod-
uct was filtered, washed with chilled water and dried. The
crude product on recrystallization from dioxane yielded fine
crystals of desired compounds (5a–c).
benzimidazol-2-yl)methylsulfinylpyrimidines
4-Substituted-2-(1H-benzimidazol-2-yl)methylthiopyrimi-
dines (9a–i, 7b, 7d, 7f; 1 mol) was dissolved in methanol
and chloroform by stirring at room temperature. Thereafter,
the reaction mixture was chilled in an ice salt bath while
maintaining the temperature below 0 °C. To this clear
solution, methanolic solution of m-CPBA (1.2 mol) was
added while stirring and the reaction was continued for 20–
25 min. After completion of the reaction, the reaction was
stopped by the addition of 10 % sodium bicarbonate. The
organic layer was separated and washed with 10 % NaCl
and water (50 ml each). The organic layer was dried over
anhydrous sodium sulphate and solvent was distilled out
under reduced pressure to obtain the product. The crude
product on recrystallization from chloroform–methanol
yielded desired compounds (10a–i, 8a–c).
General procedure synthesis of condensed 2-(1H-
benzimidazol-2-yl)methylthiopyrimidin-4(3H)-ones
In a 100 ml RBF, appropriate 2-mercaptobenzimidazoles
(0.01 mol) were dissolved in NaOH (0.01 mol) solution.
To this solution, 2-chloromethylpyrimidin-4(3H)-ones
(5a–c; 0.01 mol) was added. The flask was fitted to the
condenser in the microwave chamber and the reaction
mixture was irradiated by MWI at 40 W for 15–40 min.
The progress of reaction was monitored by TLC. On
completion of reaction, the reaction mixture was cooled to
room temperature. The solid obtained was filtered at suc-
tion, washed with chilled water and dried. The crude
product on recrystallization from chloroform–methanol
yielded desired compounds (6a–f).
2-{[(1H-benzimidazol-2-yl)sulfinyl]methyl}-4-methoxy-
5,6,7,8-tetrahydrobenzo[b]-thie-no[2,3d]pyrimidine (10a)
IR (KBr)/cm: 2,941(cC–H), 1,560(cNH), 1,058(cS–O), 745(cC–S),
1,146(cC–O); MS m/e: 398(M?); 1H NMR (DMSO-d6) d ppm:
1.72 (4H, s, CH2 at 6 & 7), 2.71 (2H, s, CH2 at 8), 2.85 (2H, s,
CH2 at 5), 3.32 (3H, s, OCH3 at 4), 5.1 (2H, s, CH2 at SCH2), 5.7
(1H, s, NH), 7.3–7.8 (4H, m, Ar–H); Anal. Calcd. for
C19H18N4O2S2: C, 57.27; H, 4.55; N, 14.06. Found: C, 57.40;
H, 4.40; N, 14.20.
General procedure synthesis of 4-chloro-2-(1H-
benzimidazol-2-yl)methylthiopyrimidines
A mixture of condensed 2-(1H-benzimidazol-2-yl)methyl-
thiopyrimidin-4(3H)-ones (6a–f; 0.01 mol) and phosphorus
oxychloride (0.05 mol) were reacted under microwave
irradiation at 20 W. The progress of reaction was monitored
by TLC at every 2 min intervals. After completion of the
reaction (12–20 min), the reaction mixture was allowed to
cool to room temperature and poured onto ice–water mix-
ture (100 ml) and Neutralization by addition of NaHCO3.
The solid obtained was filtered at suction, washed with
chilled water and dried. The crude product on recrystalli-
zation from n-hexane yielded desired compounds (7a–f).
2-{[(1H-benzimidazol-2-yl)sulfinyl]methyl}-4-(2,2,2-
trifluoroethoxy)-5,6,7,8-tetrahydro-benzo[b]thieno[2,3d]
pyrimidine (10b)
IR (KBr)/cm: 2,936(cC–H), 1,560(cNH), 1,073(cS–O), 741(cC–S),
1,265(cC–F); MS m/e: 466(M?); 1H NMR (DMSO-d6) d ppm:
1.70 (4H, s, CH2 at 6, 7), 2.72 (2H, s, CH2 at 8), 2.82 (2H,
s, CH2 at 5), 3.3 (3H, s, OCH2 at 4), 5.15 (2H, s, CH2 at
SCH2), 5.8 (1H, s, NH), 7.2–7.5 (4H, m, Ar–H); Anal.
Calcd. For C20H17F3N4O2S2: C, 51.49; H, 3.67; N, 12.01.
Found: C, 51.20; H, 3.85; N, 12.34.
General procedure synthesis of 4-alkoxy-2-(1H-
benzimidazol-2-yl)methylthiopyrimidines
4-Methoxy-2-{[(5-methoxy-1H-benzimidazol-2-
yl)sulfinyl]methyl}-5,6,7,8-tetrahydro-benzo[b]thieno
[2,3-d] pyrimidine (10c)
To a solution of 4-chloro-2-(1H-benzimidazol-2-yl)meth-
ylthiopyrimidines (7a–f; 1 mol) in appropriate alcohol
added sodium methoxide (2 mol). The sodium chloride
was formed immediately. The resulting solution was
refluxed for 1.5–2.5 h. After completion of the reaction,
reaction mixture was allowed to cool at room temp. The
reaction was poured on ice–water mixture and pH was
adjusted to 7.0 with dil. HCl. The separated solid was fil-
tered and washed with cold water. The crude product on
recrystallization from chloroform–methanol yielded desired
compounds (9a–i).
IR (KBr)/cm: 2,932(cC–H), 1,507(cNH), 1,052(cS–O), 751(cC–S),
1,149(cC–O); MS m/e: 428(M?); 1H NMR (DMSO-d6) d ppm:
1.75 (4H, s, CH2 at 6, 7), 2.70 (2H, s, CH2 at 8), 2.84 (2H,
s, CH2 at 5), 3.35 (3H, s, OCH3 at 4), 5.2 (2H, s, CH2 at
SCH2), 5.8 (1H, s, NH), 7.3–7.7 (3H, m, Ar–H); Anal.
Calcd. for C20H20N4O3S2: C, 56.06; H, 4.70; N, 13.07.
Found: C, 56.34; H, 4.50; N, 13.32.
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3725
2-{[(1H-benzimidazol-2-yl)sulfinyl]methyl}-4-methoxy-
5-(4-Chlorophenyl)-4-methoxy-2-{[(5-methoxy-1H-
benzimidazol-2-yl)sulfinyl]methyl}-thieno[2,3-
d]pyrimidine (10i)
5-phenylthieno[2,3-d]pyrimidine (10d)
IR (KBr)/cm: 2,933(cC–H), 1,534(cNH), 1,011(cS–O), 695(cC–S),
1
1,124(cC–O); MS m/e: 420(M?), 404, 372, 255, 150, 45; H
IR (KBr)/cm: 2,926(cC–H), 1,500(cNH), 1,046(cS–O), 753(cC–S),
1,150(cC–O); MS m/e: 485(M?); 1H NMR (DMSO-d6) d ppm:
3.4 (3H, s, OCH3 at 4), 5.1 (2H, s, CH2 at SCH2), 5.7
(1H, s, NH), 7.2–8.0 (7H, m, Ar–H). Anal. Calcd. for
C22H17ClN4O3S2: C, 54.48; H, 3.53; N, 11.55. Found: C,
54.75; H, 3.74; N, 11.82.
NMR (DMSO-d6) dppm: 3.4 (3H, s, OCH3 at 4), 5.2 (2H, s,
CH2 at SCH2), 5.8 (1H, s, NH), 7.2–7.8 (9H, m, Ar–H). Anal.
Calcd. For C21H16N4O2S2: C, 59.98; H, 3.84; N, 13.32. Found:
C, 59.65; H, 3.95; N, 13.68.
2-{[(1H-benzimidazol-2-yl)sulfinyl]methyl}-5-phenyl-4-
(2,2,2-trifluoroethoxy)thieno[2,3-d]pyrimidine (10e)
4-Chloro-2-{[(5-methoxy-1H-benzimidazol-2-
yl)sulfinyl]methyl}-5,6,7,8-tetrahydro-benzo[b]thieno
[2,3-d] pyrimidine (8a)
IR (KBr)/cm: 3,086(cC–H), 1,537(cNH), 1,010(cS–O), 697(cC–S),
1,333(cC–F); MS m/e: 488(M?); 1H NMR (DMSO-d6) d ppm:
3.2 (3H, s, OCH2 at 4), 5.1 (2H, s, CH2 at SCH2), 5.9
(1H, s, NH), 7.1–8.0 (9H, m, Ar–H). Anal. Calcd. for
C22H15F3N4O2S2: C, 54.09; H, 3.09; N, 11.47. Found: C,
54.45; H, 3.34; N, 11.76.
IR (KBr)/cm: 2,927(cC–H), 1,560(cNH), 1,022(cS–O), 627
1
(cC–S), 749(cC–Cl); MS m/e: 432(M?); H NMR (DMSO-
d6) d ppm: 1.72 (4H, s, CH2 at 6 & 7), 2.70 (2H, s, CH2 at
8), 2.82 (2H, s, CH2 at 5), 3.3 (3H, s, OCH3), 5.2 (2H, s,
CH2 at SCH2), 5.8 (1H, s, NH), 7.3–7.7 (3H, m, Ar–H).
Anal. Calcd. for C19H17ClN4O2S2: C, 52.71; H, 3.96; N,
12.94. Found: C, 52.55; H, 3.72; N, 13.22.
4-Methoxy-2-{[(5-methoxy-1H-benzimidazol-2-
yl)sulfinyl]methyl}-5-phenylthieno-[2,3-d]pyrimidine (10f)
IR (KBr)/cm: 2,917(cC–H), 1,537(cNH), 1,046(cS–O), 697
(cC–S), 1,203(cC–O); MS m/e: 450(M?); 1H NMR (DMSO-
d6) d ppm: 3.4 (3H, s, OCH3 at 4), 5.15 (2H, s, CH2 at
SCH2), 5.7 (1H, s, NH), 7.2–8.0 (8H, m, Ar–H). Anal.
Calcd. for C22H18N4O3S2: C, 58.65; H, 4.03; N, 12.44.
Found: C, 58.86; H, 4.34; N, 12.68.
4-Chloro-2-{[(5-methoxy-1H-benzimidazol-2-
yl)sulfinyl]methyl}-5-phenylthieno[2,3-d] pyrimidine (8b)
IR (KBr)/cm: 2,925(cC–H), 1,542(cNH), 1,026(cS–O), 697(cC–S),
754(cC–Cl); MS m/e: 454(M?); 1H NMR (DMSO-d6)
d ppm: 3.2 (3H, s, OCH3 at 4), 5.3 (2H, s, CH2 at SCH2),
5.6 (1H, s, NH), 7.2–7.9 (8H, m, Ar–H). Anal. Calcd. for
C21H15ClN4O2S2: C, 55.44; H, 3.32; N, 12.31. Found: C,
55.68; H, 3.55; N, 12.55.
2-{[(1H-Benzimidazol-2-yl)sulfinyl]methyl}-5-(4-
chlorophenyl)-4-methoxythieno[2,3-d]
pyrimidine (10g)
4-Chloro-5-(4-chlorophenyl)-2-{[(5-methoxy-1H-
benzimidazol-2-yl)sulfinyl]methyl}-thieno[2,3-
d]pyrimidine (8c)
IR (KBr)/cm: 2,921(cC–H), 1,504(cNH), 1,013(cS–O), 743
(cC–S), 1,139(cC–O); MS m/e: 455(M?); 1H NMR (DMSO-
d6) d ppm: 3.3 (3H, s, OCH3 at 4), 5.25 (2H, s, CH2 at
SCH2), 5.9 (1H, s, NH), 7.1–7.8 (8H, m, Ar–H). Anal.
Calcd. for C21H15ClN4O2S2: C, 55.44; H, 3.32; N, 12.31.
Found: C, 55.74; H, 3.54; N, 12.55.
IR (KBr)/cm: 2,918(cC–H), 1,545(cNH), 1,016(cS–O), 625
1
(cC–S), 750(cC–Cl); MS m/e: 490(M?); H NMR (DMSO-
d6) d ppm: 3.4 (3H, s, OCH3 at 4), 5.4 (2H, s, CH2 at
SCH2), 5.8 (1H, s, NH), 7.1–7.9 (7H, m, Ar–H). Anal.
Calcd. for C21H14Cl2N4O2S2: C, 51.54; H, 2.88; N, 11.45.
Found: C, 51.75; H, 3.12; N, 11.78.
2-{[(1H-Benzimidazol-2-yl)sulfinyl]methyl}-5-(4-
chlorophenyl)-4-(2,2,2-trifluoroethoxy)- thieno[2,3-
d]pyrimidine (10h)
IR (KBr)/cm: 2,920(cC–H), 1,527(cNH), 1,066(cS–O), 748
(cC–S), 1,260(cC–F); MS m/e: 523(M?), 522, 506, 357,
150, 45; H NMR (DMSO-d6) d ppm: 3.4 (3H, s, OCH3
Biological activity
1
Animals
at 4), 5.2 (2H, s, CH2 at SCH2), 5.8 (1H, s, NH), 7.1–8.0
(8H, m, Ar–H). Anal. Calcd. for C22H14ClF3N4O2S2: C,
50.53; H, 2.70; N, 10.71. Found: C, 50.75; H, 2.85; N,
10.86.
Wistar rats (200–250 g) of either sex were used. The ani-
mals were housed in standard laboratory conditions main-
tained at a temperature 23 2 °C with relative humidity
123

3726
Med Chem Res (2013) 22:3719–3727
55 10 % and 12 h light and dark cycle. Animals had free
access to food (corn, wheat, whole soya beans) and water
ad libitum. All the experimental procedures and protocol
were reviewed and approved (SCOP/IAEC/Approval/
2010-11/03) by Institutional Animal Ethical Committee,
constituted under Committee for Purpose of Control and
Supervision of Experiments on Animals (CPCSEA). Animals
were shifted to the laboratory 1 h before the experiment.
All the animals were divided into 40 groups as follows:
Total acidity ¼ Vol: of NaOH consumed ꢁ N
ꢁ 100=0:1 ðmEq/100 gÞ
where N is the Normality of NaOH.
Statistical analysis
Values are presented as group means and SEM. The data
were analyzed by one-way analysis of variance (ANOVA)
and comparison of means was carried out by Dunnett’s test
with P \ 0.05 being considered statically significant.
Group 1
The control group (2.5 % acacia solution p.o.).
Standard groups were treated with omeprazole
at three dose levels (0.0289 mM/kg, 0.0579
mM/kg, 0.1158 mM/kg p.o.).
Group 2–4
Acknowledgments The authors are thankful to Prof. M. N. Navale
(Founder President) & Dr. (Mrs.) S. M. Navale (Secretary) Sinhgad
Technical Education Society, Pune, for providing us with necessary
facilities and encouraging our research work.
Groups 5–40 All groups were treated for 12 test com-
pounds at three dose levels (0.0289 mM/kg,
0.0579 mM/kg, and 0.1158 mM/kg p.o.)
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