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Asian J. Research Chem. 2(2): April.-June, 2009
,
157
ISSN 0974-4169 www.ajrconline.org
RESEARCH ARTICLE
Synthetic and Pharmacological Evaluation of Some Pyridine Containing
Thiazolidinones
Firke SD*1, Firake BM
1, Chaudhari RY
2and Patil VR
2
1KYDSCTs College of Pharmacy, Sakegaon, Tal. Bhusawal, Dist. Jalgaon, (M.S), India.
2TVESs College of Pharmacy, Faizpur, Tal. Yawal, Dist. Jalgaon, (M.S), India.
*Corresponding Author E-mail: [email protected]
ABSTRACTA series ofN-[3-(aryl/alkyl substituted)-4-oxo-1, 3-thiazolidin-2-ylidene]-2-(pyridine-2-yloxy) acetohydrazides
were synthesized using appropriate synthetic route. These compounds were synthesized by their analytical and
spectral data. All the newly synthesized compounds were examined for their antidiabetic activity using GOD-POD
method on Wistar strain rats. The acute toxicity study (LD50) values of these compounds were determined. The test
compounds showed significant antidiabetic activity on evaluation.
KEY WORDS: Thiazolidinone, Pyridine, Antidiabetic activity.
INTRODUCTION:A number of thiazolidinone derivatives have been reported
to possess diversified activities including hypoglycemic
action.1
Thiazolidinone ring is a main pharamacophoric
group responsible for antidiabetic activity. Therefore, it was
planned to choose thiazolidinone as a lead molecule for
molecular modification to enhance the specificity and
potency of action and to reduce the toxicity. Compounds
carrying the thiazolidinone ring have been reported to
demonstrate a wide range of pharmacological activities
which include anticonvulsant2, antimicrobial
3,
antiinflammatory4
, antihistaminic5
, anti-hypertensive6
, andhypnotic
7, antidiabetic
8, 9activities. Heterocyclic ring like
pyridine ring also plays important role in antidiabetic
activity of some drugs (pioglitazone, rosiglitazone). In
general, pyridine ring and substituted thiazolidinone ring
are essential for antidiabetic activity. The proposed work
involves syntheses of some novel N-[3-(aryl/alkyl
substituted)-4-oxo-1, 3-thiazolidin-2-ylidene]- -(pyridine-2-
yloxy) acetohydrazides with the aim of obtaining the new
antidiabetic agents.
Ethyl (pyridine-2-yloxy) acetate (compound 2) was
synthesized in an excellent yield by electrophillic
substitution on 2-hydroxy pyridine using ethyl
chloroacetate under the reflux condition. Compound 2
on amination with hydrazine hydride yield 2-(pyridine-
2-yloxy) acetohydrazide 3. Reaction of3 with alkyl/aryl
isothiocynate in ethanol gives compounds 4-8. The
cyclization reaction of4-8 with chloroacetic acid in
Received on 06.04.2009 Modified on 21.05.2009
Accepted on 15.06.2009 AJRC All right reservedAsian J. Research Chem. 2(2): April.-June, 2009 page 157-161
boiling ethanol containing fused sodium acetate gives
the correspondingN-[3-(aryl/alkyl substituted)-4-oxo-1,
3-thiazolidin-2-ylidene]-2-(pyridine-2-yloxy)
acetohydrazides (9-13). The synthetic route is depicted
in Scheme 1.
Thus in the present investigation, five different
derivatives ofN-[3-(aryl/alkyl substituted)-4-oxo-1, 3-
thiazolidin-2-ylidene]-2-(pyridine-2-yloxy)
acetohydrazides were synthesized and evaluated for their
antidiabetic activity.
EXPERIMENTAL:Melting points and boiling points were determined in
open capillaries and were uncorrected. Purity of the
compounds was ascertained by TLC plates using silica gel
G coated glass plates using chloroform-methanol as
irritant and iodine vapour as detecting agent. IR spectra
were recorded using KBr pellets on FTIR 8101,
Shimadzu, Japan,1H NMR spectra and Mass spectra
(FAB-MS) were recorded on Varian 300 MHz instrument
and 70eV on Jeol D-300 spectrometer (Jeol Ltd, Tokyo,
Japan). All the solvents and chemicals used for the
synthesis were of S. d. Finechemicals Limited, Mumbai.
The starting materials were obtained from Lancaster
Limited and Alkali Metals Limited, Hyderabad.
Synthesis of 2: To a mixture of triethylamine (5.32 g,
0.0525 mol) and 2-hydroxy pyridine (5 g, 0.0525 mol), a
solution of ethyl chloroacetate (5.6ml, 0.0525 mol) in
1:4 Dioxane (50 ml) was added drop wise. The
temperature was maintained at 90C for 1 hr and then
the reaction mixture was stirred for 7-8 hrs. The excess
solvent was removed under reduced pressure. Then the
reaction mixture was poured in ice-cold water and was
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Table 1: Physical data of N-(substituted aryl/alkyl)-2-[(pyridine-2- yloxy) acetyl] carbothioamides (4-11).
Compound No. Name of aliphatic / aromatic isothiocynate Yield Rfvalue m.p.(0c) (Uncorrected)
4 Phenyl 95% 0.68 262-264
5 Ethyl 93% 0.65 116-118
6 p-chlorophenyl 89% 0.59 226-228
7 2, 4- dichlorophenyl 88% 0.60 215-216
8 Methyl 90% 0.64 136-137
Table 2: Physical and analytical data of compounds.
Compound No. R Molecular formula m.p.(0C) uncorrected Yielda (%) Mass[M+2]
9 Phenyl C16H14N4O3S 84-86 65 342b
10 Ethyl C12H14N4O3S 116-118 62 294
11 p-chlorophenyl C16H13N4O3S 130-132 55 376b
12 2,4-dichlorophenyl C16H12N4O3S 116-118 62 410b
13 Methyl C11H12N4O3S 118-120 59 279a All the compounds were recrystalized from ethanol. b Values represent [M+2] due to appearance of an isotopic peak.
Table 3: Intraday Effect of Different Aryl/ Alkyl Substituted Thiazolidinone Derivatives on Serum Glucose at 1 st day.
Average Serum Glucose Level (mg/dL) at (1st day)
Compound No. 0 hr 1 hr 3 hr 5 hr 7 hr
Control 275.151.87 276.120.78 269.212.22 266.023.10 262.012.43
Alloxan 270.62.80 275.231.87 289.401.01 296.083.12 302.612.09
Standard 282.002.80 242.271.63 201.424.21 159.110.99 122.155.63
9 276.023.36 245.422.50 212.123.10 170.211.56 126.061.23
10 294.315.32 274.103.21 247.021.02 191.380.19 138.150.96
11 298.324.23 290.430.49 261.233.10 220.315.20 181.262.14
12 294.431.93 288.112.63 276.402.90 253.240.62 245.221.83
13 283.111.23 276.102.01 243.171.94 196.161.03 148.190.96
The values are presented as mean S. E. M. of six determinationsp
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Scheme 1: General scheme for syntheses of compounds 9-13 (R= phenyl, ethyl, p-chlorophenyl, 2, 4- dichlorophenyl, methyl)
N O H
C l C H 2 C O O C 2 H 5
N O CH
2
O
O C2
H5
N H2
N H2
H2
O
N O CH
2
NH
O
N H2
R N C S
N O CH
2
O
NH
NH
N H
S
C l C H 2 C O O H
N O CH
2
NH
O
N
R
SN
O
R
R e f lu xT E A
R e f lu
E th y l( p y rid in e -2 - y lo x y )a c e ta t e 2 -( p y rid in e -2 - y lo x y )
a c e to h y d ra z id e
9 0 c
R e f lu x
N -( s u b s t i tu te d a ry l / a lk y l)- 2 -[ (p y rid in e -2 - y lo x y ) a c e ty l ]a c e to h y d ra z id e
N ' [3 - (a lk y l / a ry l s u b s t i t u te d )-4 - o x o -1 ,3 - th ia z o l id in - 2 -y l id in e ]-2 - (p y ri d in e -2 - y lo x y )a c e to h y d ra z id e .
s o d iu m a c e ta te
( 2 )
( 3 )
( 9 - 1 3 )
( 1 )
2 - h y d ro x y p y r id i n e
( 4 - 8 )
1 2 h
1 0 h
2 -3 h
1 ho
The yield and physical data are summarized in Table 1.
4: IR: 3382, 3355 cm-1
(NHNH2), 1720 cm-1
(C=O), 1360
cm-1
(C=S);1H NMR (CDCl3): 7.58 (m, 4H, Ar.), 4.82
(s, 2H, OCH2), 7.78 (s, 1H, CONH), 6.34 (t, 1H,
pyridine C-3), 7.72 (q, 1H, pyridine C-4), 6.79 (q, 1H,
pyridine C-5), 7.76 (t, 1H, pyridine C-6).
5: IR: 3212, 3225 cm-1
(NH), 1730 cm-1
(C=O), 1365 cm-
1(C=S);
1H NMR (CDCl3): 1.28 (m, 3H, CH3), 4.72 (s,
2H, OCH2), 7.75 (s, 1H, CONH), 6.44 (t, 1H, pyridine
C-3), 7.76 (q, 1H, pyridine C-4), 6.69 (q, 1H, pyridine
C-5), 7.66 (t, 1H, pyridine C-6).
6: IR: 3217, 3232 cm-1
(NH), 1736 cm-1
(C=O), 1315 cm-
1(C=S);
1H NMR (CDCl3): 7.39-7.65 (m, 4H, ArH),
4.72 (s, 2H, OCH2), 7.75 (s, 1H, CONH), 6.34 (t, 1H,
pyridine C-3), 7.73 (q, 1H, pyridine C-4), 6.62 (q, 1H,
pyridine C-5), 7.76 (t, 1H, pyridine C-6).
7: IR: 3219, 3222 cm-1
(NH), 1734 cm-1
(C=O), 1315 cm-
1(C=S);
1H NMR (CDCl3): 7.29-7.65 (m, 3H, ArH),
4.73 (s, 2H, OCH2), 7.75 (s, 1H, CONH), 6.44 (t, 1H,
pyridine C-3), 7.73 (q, 1H, pyridine C-4), 6.65 (q, 1H,
pyridine C-5), 7.73 (t, 1H, pyridine C-6).
8: IR: 3216, 3215 cm-1
(NH), 1735 cm-1
(C=O), 1362 cm-
1(C=S);
1H NMR (CDCl3): 1.18(m, 2H, CH2), 4.70 (s,
2H, OCH2), 7.73 (s, 1H, CONH), 6.54 (t, 1H, pyridine
C-3), 7.72 (q, 1H, pyridine C-4), 6.72 (q, 1H, pyridine
C-5), 7.76 (t, 1H, pyridine C-6).
Syntheses of 9-13: A mixture of the N-(substituted
aryl/alkyl)-N(-2-pyridine-2-yloxy) acetyl
thiosemicarbazides (3.03g, 0.01 mol), chloroacetic acid
(0.93g, 0.01 mol) and sodium acetate (0.81g, 0.01 mol) in
ethanol (60 ml) was refluxed for 10 hrs. The mixture was
cooled and diluted with enough water to develop turbidity
and left overnight for complete separation of the product.
Then the compounds were filtered and recrystallized fromethanol. The yield and physical data are summarized in
Table 2.
9. IR: 3220 cm-1
(N-H), 1720 cm-1
(C=O), 1585 cm-1
(C=N), 3010 cm-1
(C-H);1H NMR :( CDCl3) 6.38,
7.75, 6.68, 7.79 (C-H, 2-pyridine), 3.76, 4.83, 3.24
(CH2), 7.0 (-NH-), 1.20(CH3); FAB-MS: (m/z,
100%): 342 ([M+], 100%)
10. IR: 3325 cm-1
(N-H), 1722 cm-1
(C=O), 1583 cm-1
(C=N), 3015 cm-1
(C-H);1H NMR :( CDCl3) 6.38,
7.69, 6.68, 7.75 (C-H, 2-pyridine), 3.76, 4.83 (CH2),
7.0 (-NH-), 7.14, 7.06, 7.06, 7.14, 7.07 (Phenyl ring);
FAB-MS: (m/z, 100%): 294 ([M+], 100%)
11. IR: 3400 cm-1
(C-H str. pyridine), 1552 cm-1
(N-H
str.), 1730 cm-1
, 1650 cm-1
(C=O), 1525 cm-1
(C=N),
3035 cm-1
(C-H, Aromatic str.), 1208 cm-1
(C-O-C str.);1H NMR (CDCl3) 6.38, 7.69, 6.68, 7.75 (C-H, 2-
pyridine), 3.81, 4.83 (CH2), 7.0 (-NH-), 7.58, 7.25,
7.25, 7.58, (Phenyl ring); FAB-MS: (m/z, 100%): 378
([M++2], 100%)).
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12: IR: 3410 cm-1
(C-H str. pyridine), 1552 cm-1
(N-H
str.), 1710 cm-1
, 1640 cm-1
(C=O), 1580 cm-1
(C=N),
3020 cm-1
(C-H, Aromatic str.), 1260 cm-1
(C-O-C str.);1H NMR (CDCl3) 6.38, 7.69, 6.68, 7.75 (C-H, 2-
pyridine), 3.81, 4.83 (CH2), 7.0 (-NH-), 7.26, 7.13,
7.52 (Phenyl ring); FAB-MS: (m/z, 100%): 412 ([M+
+2], 100%.
13. IR: 3326 cm-1 (N-H), 1729 cm-1 (C=O), 1583 cm-1(C=N), 3025 cm
-1(C-H);
1H NMR :( CDCl3) 6.38,
7.69, 6.68, 7.75 (C-H, 2-pyridine), 3.76, 4.83 (CH2),
7.0 (-NH-), 7.14, 7.06, 7.06, 7.14, 7.07 (Phenyl ring);
FAB-MS: (m/z, 100%): 294 ([M+], 100%)
PHARMACOLOGICAL EVALUATION:
Antidiabetic activity:
Animals:Wistar albino rats of either sex weighing between 150
200 g were used for the study. The animals were housed
in standard environmental conditions of temperature
(2520
C), humidity (5510%) and light (12:12 hr light:dark cycle). Rats were supplied with standard laboratory
diet and water ad libitum. Animals were deprived of
food for at least 18 hrs but were allowed free access to
drinking water.
Cut-Off Lethal Dose (LD50):All the compounds synthesized were tested for acute
toxicity test. No toxicity was observed at the doses of
300, 1000, 2000 mg/kg of body weight but it was
observed that more than 50% of animals were died at the
dose of 2000 mg/kg of body weight. Thus for the
screening of antidiabetic activity, the dose selected was
200 mg/kg of body weight (i.e., 1\10 of the 2000 mg/kgof body weight) as per the OECD guidelines.10
Drugs Used:Metformin was given to rats at a dose of 5 mg/kg body
weight, as a reference standard.
Induction of Diabetes:A single dose (150 mg/kg, body weight) of Alloxan
monohydrate (5%w/v in sterile water) was dissolved in
normal saline used for the induction of diabetes and
injected intraperitoneally to Wistar albino rats weighing
150-200 g. The induction of diabetes was confirmed by
estimation of elevated fasting blood glucose level. The
rats having blood glucose level above 200 mg/dl of
blood were selected for the study.
Groups Design:These rats were divided into various groups with 6 rats
each. The rats in group I (control) were administered
distilled water orally. Group II was treated as the
diabetic control (Alloxan 150 mg/kg, i.p.). Group III
was treated with metformin (5mg/kg, orally), while
groups IV, V, VI, VII, VIII were treated with test
compounds. Treatment with compounds was started on
the 6th
day of Alloxan treatment (i.e. Day 1) and was
continued for 8th
day (i.e. Day 3), 12th
day (i.e. Day 7) of
Alloxan treatment. Before this treatment, intraday serum
glucose estimation was also carried out (i.e. after 0hr,
1hr, 3hr, 5hr, and 7hr on the 6th day of Alloxan
treatment). All the drugs were given orally as a single
dose. All the groups were subjected to serum glucose
estimation by withdrawing 0.5 ml of blood from the
retro orbital plexus under light ether anesthesia. Theblood glucose concentration was estimated in
spectrophotometer at 505 nm.
Sample Collection:Blood was collected from retro orbital plexus of the eye
under light ether anesthesia using capillary tube. Blood
was collected in fresh vials containing sodium fluoride
and sodium oxalate as anti coagulant.
All the compounds synthesized were tested for
antidiabetic activity, the fasting serum glucose levels
were determined according to GOD-POD method.11
RESULTS AND DISCUSSION:In the present investigation, different derivatives ofN-
[3-(aryl/alkyl substituted)-4-oxo-1, 3-thiazolidin-2-
ylidene]-2-(pyridine-2-yloxy) acetohydrazides (9-13)
were synthesized and evaluated for their physical,
analytical and spectral data (Table 2).
The structures of compounds 9-13 were confirmed on
the basis of spectral data. IR spectrum showed
absorption peaks at 1552 cm-1
and 1650 cm-1
for the N-
H stretching and C=O stretching of amide groups
respectively. The
1
H-NMR spectrum exhibited signalsattributed to the proton at 6.38, 7.69, 6.68, 7.75
indicating the presence of pyridine ring, while the
signals at 7.0 indicated the presence of acetohydrazide
linkage.
The results of antidiabetic activity of test compounds
were given in Table 3, 4. Compounds No. 9 and 10 were
found to be most efficient i.e. 48% and 52% reduction of
serum glucose level respectively at 200 mg/kg dose.
CONCLUSION:A series of N-[3-(4-alkyl/aryl substituted)-4-oxo-1, 3-
thiazolidin-2 ylidene]-2-(pyridine-2-yloxy)acetohydrazides were synthesized using appropriate
synthetic route and screened for antidiabetic activity. It
can be concluded that, the number of compounds
showed antidiabetic activity, out of which 9 and 10
showed appreciable antidiabetic activity. Thus research
work was undertaken for substitution at 3 position of
thiazolidinone ring. The encouraging results showed
may lead to the development of novel antidiabetic drugs
if explored further.
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Pyridines bearing thiazoline and thiazolidinones moieties.Chem. Pharm. Bull. 1998; 46(5): 863.
4. Patel PB, Trivedi JJ.Synthesis of 2-aryl-3-aryloxyethyl-4-thazolidinones and their 1, 1-dioxides. J. Ind. Chem.
Soc. 1977; 54:765.5. Vittoria DM, et al. Synthesis and antihistaminic activity
of some thazolidin-4-ones. J. Med. Chem. 1992; 35:2910.
6. Omar AM, Eshba NH. J. Pharm. Sci. 1984;73: 1166.7. Chaudhary M, et al. CNS depressant activity of
pyrimidyltiazolidones and their selective inhibition ofNAD- depressant pyruvate oxidation. J. Pharm. Sci. 1976;
65: 443.8. Bue-Vallesky, et al. United States Patent. 1996;
US5:523:314. /ChemAbst, 1996; 123: 13816.9. Panetta JA, et al. United States Patent. 1997;
US5:661:168. / Chem Abst, 1997;125: 117581.10. OECD (2000), Guidance Documents on Acute Oral
Toxicity, Environmental Health and safety MonographSeries on Testing and Assessment No 24.
11. Henry JB. Clinical and diagnosis management bylaboratory methods. W. B. Saunders, H. B. J.International, 1991.