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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,



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,



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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thiazolidinones. IndianDrugs. 2005; 42(1): 47.2. Ragab FA, et al. Egypt J. Pharm. Sci.1993; 34: 387.3. Hassan HY, et al. Synthesis and antimicrobial activity of

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Soc. 1977; 54:765.5. Vittoria DM, et al. Synthesis and antihistaminic activity

of some thazolidin-4-ones. J. Med. Chem. 1992; 35:2910.

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pyrimidyltiazolidones and their selective inhibition ofNAD- depressant pyruvate oxidation. J. Pharm. Sci. 1976;

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US5:523:314. /ChemAbst, 1996; 123: 13816.9. Panetta JA, et al. United States Patent. 1997;

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11. Henry JB. Clinical and diagnosis management bylaboratory methods. W. B. Saunders, H. B. J.International, 1991.