Asian J. Research Chem. 2(2): April.

-June, 2009

ISSN 0974-4169 RESEARCH ARTICLE

www.ajrconline.org

Synthesis and Evaluation of Some New Thiazolidinedione Derivatives for Their Antidiabetic Activities
Pattan Shashikant R*1, Kekare Prajact2, NS Dighe1, SB Bhawar4, Nikalje Ana3, Pati Ashwini3 and MB Hole1
2 1

Dept. of Medicinal Chemistry, Pravara Rural College of Pharmacy, Pravaranagar Department of Medicinal Chemistry, K.L.E.S.s College of Pharmacy,Belgaum 590 010. 3 Dept. of Pharmaceutical Chemistry, Y B Chavan College of Pharmacy, Aurangabad. 4 Dept. of Pharmacology, Pravara Rural College of Pharmacy, Pravaranagar *Corresponding Author E-mail: shashipattan@yahoo.com

A new series of thiazolidinedione derivatives were synthesized by reacting under microwave irradiation. The structures of these compounds were established by means of IR, 1H-NMR and elemental analysis. All the compounds (B1-B9) were screened for antidiabetic activity on albino rats. Most of these compounds have shown significant antidiabetic activity when compared with the standard drug glibenclamide.

ABSTRACT

KEY WORDS: Thiazolidinedione, antidiabetic activity, microwave assisted synthesis.

Diabetes mellitus1 is a heterogeneous group of diseases, characterized by a state of chronic hyperglycemia2, resulting from a diversity of etiologies, environmental and genetic, acting jointly. The underlying causes of diabetes are the defective production or action of insulin, a hormone that controls carbohydrate, fat and protein metabolism. Characteristically diabetes is a long-term disease with variable clinical manifestations and progression, chronic hyperglycemia from whatever cause, leads to a number of complications including cardiovascular such as hypertension, renal, neurological such as anxiety, stress, ocular and other such inter-current infections3.Thiazolidones and thiazolidinediones were the first parent compounds in which thiazole ring was recognized. The thiazolidinediones4 used in oral combination therapy in management of patients with type II diabetes who have insufficient glycaemic control despite maximal tolerated dose of oral mono-therapy with either metformin or sulphonylurea. These observations promoted us to synthesis the title compound with presumption that incorporation of aromatic amines and thiazolidinediones nuclei would produce new compounds with significant antidiabetic properties.

INTRODUCTION:

Antidiabetic activity5: The acclimatized animals were kept fasting for 24 hrs with water ad libitm and Alloxan Monohydrate (120 mg/Kg i.p) in normal saline was administered. After one hour of alloxan administration the animals were given adlibitm. A 5% dextrose solution was given in feeding bottle for a day to overcome the early hypoglycemic phase. The blood glucose regulator was monitored after alloxination by withdrawing a drop of blood from the tail vein by Tail tipping method. The blood was dropped on the dextrostrix reagent Pad. The strip was inserted into microprocessor digital Blood Gluco Meter and readings were noted. After 72 hrs rats having blood glucose level beyond 150-mg/dl of blood were selected for the study and divided into 6 groups. The quantity of 2,4thiazolidinedione derivatives equivalent to average human intake 200-mg/ kg at a time was calculated for single dose 36 mg/kg (for acute study). The test compounds were administered orally by mixing with CMC (0.25 %) solution. The blood glucose level was monitored at different times 0 hr, 1hr, 3hr, and 6hr respectively. The antidiabetic activities of the synthesized compounds are shown in Table 1.

MATERIAL AND METHODS:

Received on 24.04.2009 Accepted on 16.06.2009

Asian J. Research Chem. 2(2): April.-June, 2009, Page 123-126

Modified on 13.05.2009 AJRC All right reserved

123

Asian J. Research Chem. 2(2): April.-June, 2009

Table No: 1 Antidiabetic activities of synthesized compounds Compound Blood glucose level mg/dl (Mean SE) . 0 hour 1 hour 3 hour B1 296.74.05 292.7 4.25 187.715.6** B2 300.50.12** 134.5 2.72 123.5 5.23 B3 320.515.81** 145.5 2.26 137.0 3.80 B4 213.58.78 140.7 3.30* 106.3 6.91 B5 B6 B7 B8 B9 283.543.76 295.37.42* 289.29.98 203.713.79 205.7549.7 233.323.8 280.69.29* 156.213.5 166.3 38.92 193.013.86 244.29.04** 123.34.3*

6 hour 148.0 7.8** 116.55.90** 123.5 1.10* 95.756.06** 124.513.16* 159.312.12 180.41.99** 101.54.5**

217.03.01 213.0 2.53 164.3 4.74* 146.02.19** Control 123.3 6.00 120.7 5.54 122.3 5.81 123.0 6.4 Standard 385.821.37 230.812.35** 156.810.87** 93.44.98** Statistical analysis is done by One-way ANOVA followed by Dunnetst test. Standard Drug: Glibenclamide. ** P<0.01 (considered as significant), *P<0.05 Table No: 2Physical data of synthesized compounds Comp. Molecular Mol. Wt. m.p. (0C) Yield formula (%) B1 C18H13N5O4S3 459.53 174-176 68% B2 C18H11N5O6S3 489.51 180-182 54% B3 C20H14N4O4S3 470.55 118-120 62% B4 C13H13N6O4S2 381.41 199-200 64% B5 C15H13N3O4S2 363.42 241-243 56% B6 C15H17N3O5S2 383.43 234-237 52% B7 C16H11N2O4S2Cl 394.86 222-223 56% B8 C14H10N4O4S2 362.39 180-182 55% B9 C12H10N4O4S3 370.43 192-193 63% All the compounds gave satisfactory elemental analysis. 0. 4 Elemental analysis Calculated(found) C H N 47.05 (46.68 ) 2.85 ( 2.57 ) 15.24 (14.96) 44.17 (43.89 ) 2.27 (1.97 ) 14.31 (13.94 ) 51.05 ( 50.76) 3.00 (2.80 ) 11.91 (11.75 ) 40.94 ( 40.77) 3.44 (3.14 ) 22.03 ( 21.56) 49.58 (49.18 ) 3.61 ( 3.33) 11.56 ( 11.26) 46.99 (46.63 ) 4.47 (4.31 ) 10.96 (10.78 ) 48.67 (48.37 ) 2.81 ( 2.56) 7.09 (6.88 ) 46.40 ( 46.32) 2.78 (2.48 ) 15.46 ( 15.21) 38.91 ( 38.55) 2.72 (2.38 ) 15.12 ( 14.96)

Table No: 3 Infra Red/ 1H-NMR spectral study of the synthesized compounds. 1 Compd. IR (cm-1) H-NMR ( , ppm) 3096.6 (Ar-CH-str.), 1691.5 (C=O-str.), 1286.4 --B1 (C-N-str.), 3452.6 (N -H str.), 620.8 (C-S-str.) 3098.2 (Ar-CH-str.), 1694.5 (C=O-str.), 1286.4 --B2 (C-N-str.), 1377.1 (N02 str.),628.8 (C-S-str.) --3094.6 (Ar-CH-str.), 1694.5 (C=O-str.), 1286.4 B3 (C-N-str.), 1639.4 (C= C str.),628.8 (C-S-str.) 3095.4 (Ar-CH-str.),1694.5 (C=O-str.), 1298.0 7.42-7.75(4H,Ar-CH ) 6.13(1H, NH) 7.41(1H, B4 (C-N-str.),3394.6 (N -H str.), 612.7 (C-S-str.) tetrazole) 3.46(1H-Benzylidine ) 3069.5 (Ar-CH-str.),1693.4 (C=O-str.), 1299.4 7.34-7.7 (4H,Ar-CH ) 5.16(1H, NH) 3.4B5 (C-N-str.), 3408.2 (N -H str.), 612.8 (C-S-str.) 3.6(10H,Piperidine) 2.9(1H-Benzylidine) 3084.5(Ar-CH-str.),1695.2 (C=O-str.), 1299.6 7.34-7.6(4H,Ar-CH ) 5.15(1H, NH) 3.06B6 (C-N-str.), 3408.2 (N -H str.), 617.4 (C-S-str.) 3.08(8H,Morpholine.) 3.8(1H-Benzylidine) --3041.5 (Ar-CH-str.), 1698.2 (C=O-str.), 1301.3 B7 (C-N-str.), 3408.2 (N -H str.), 619.8 (C-S-str.) 3041.5 (Ar-CH-str.), 1696.2 (C=O-str.), 1300.8 --B8 (C-N-str.), 3406.4 (N -H str.), 619.8 (C-S-str.) 3041.5 (Ar-CH-str.), 1698.4 (C=O-str.), 1300.8 --B9 (C-N-str.), 3409.2 (N -H str.), 619.8 (C-S-str.)

EXPERIMENTAL:

Melting Points were determined in open capillary method and are uncorrected. IR spectra were recorded on Thermo Nicolet IR 200 spectrophotometer using KBr disc method. The 1H-NMR spectra were recorded on sophisticated multinuclear FT-NMR Spectrometer model Avance-II (Bruker), using dimethylsulfoxide-d6

as solvent and tetramethylsilane as internal standard. The reactions were carried in microwave oven. Synthesis of 2, 4-thiazolidinedione: (I) In a 250 mL three necked round-bottomed flask was place, solution containing (56.4 gm, 0.6 mol) of chloracetic acid in 60 mL of water and (45.6 gm, 0.6 mol) of thiourea dissolved in 60 mL of water.

124

Asian J. Research Chem. 2(2): April.-June, 2009

Scheme

COOH C-Cl H 2

H2N

S C

N H2

C o n c. H Cl r e fl u x f o r 1 0h r.

O S I

H N O

CHO

O S II O NH

C hlor o s ulp h o nic a cid O R S O O S O NH R-H + Cl O O S O III

R B1
H2N N S N N H

S O

NH

R B4

N N

N N

N H
N

B7

N H Cl
N

N S N H

B2

B5

O2N
H C H C N N S N H

B8

N H

B3

B6

N
B9

N S

N H

The mixture was stirred for 15 min to form a white precipitate, accompanied by considerable cooling. To the contents of the flask was then added slowly 60 mL of concentrated hydrochloric acid from a dropping funnel, the flask was then connected with a reflux condenser and gentle heat applied to effect complete solution, after which the reaction mixture was stirred and refluxed for 8-10 hrs at 100-110C. On cooling the contents of the flask solidified to a cluster of white needles. The product was filtered and washed with water to remove traces of hydrochloric acid and dried. It was purified by recrystallization from ethyl alcohol. Yield 85%, m.p.123-125 C. Synthesis of 5-benzylidine 2,4-thiazolidinedione: (II) In a 250 mL three necked round-bottomed flask provided with a Dean-Stark apparatus, benzaldehyde (20 gm, 0.188 mol) and 2,4-thiazolidinedione (22 gm, 0.188 mol) were together suspended in ethanol. To

this a catalytic amount of piperidine (1mL) was added. The mixture was stirred and refluxed. After the complete removal of water and when the temperature reached above 110C the reaction mixture was stirred for a further 1 hr. On cooling the product precipitated out from ethanol. The compound was filtered and washed with cold dry toluene and dry ethanol. Yield 93%, m.p. 240-242 C. Synthesis of 4'-chlorosulphonyl-benzylidene 2, 4thiazolidinedione: (III) Benzylidine-2, 4-thiazolidinedione (8 gm, 0.0388 mol) was placed in a 100mL round-bottomed flask equipped with a condenser and a dropping-funnel. Chlorosulphonic acid (18.08 gm, 0.155 mol) was added at room temperature using the dropping funnel. The reaction was found to be exothermic. After addition of Chlorosulphonic acid was over the reaction mass was refluxed for 1 hr on a water bath. The reaction was

125

Asian J. Research Chem. 2(2): April.-June, 2009

cooled and poured in a thin stream with stirring into crushed ice contained in a one litre beaker. The product was filtered and dried6,7. The product was purified by recrystallization from ethanol. Yield 68%, m.p. 180-181C. Synthesis of (Z)-N-(5-(4-aminophenyl)-1,3,4thiadiazole-4-((2,4-dioxothiazolidin-5-ylidene) benzenesulfonamide. (B1): A mixture of 5-(4-Chlorosulfonyl benzylidene)-2,4thiazolidenedione (0.01 mole) and 5-(4-aminophenyl)N-ethyl-1,3,4-thiadiazole-2mine were taken in a beaker and made a homogenous paste. The paste was exposed to microwave irradiation for 1-2 min, at intervals of 30 seconds. After the completion of reaction, ice-cold water was added to the reaction mixture and precipitated solid was separated by filtration, dried and recrystallized from ethanol to get (Z)-N-(5-(4-aminophenyl)-1,3,4-thiadiazole-4-((2,4dioxothiazolidin-5 ylidene) benzenesulfonamide (B1).Yield68%, m.p. 174-176C. The compounds B2B9 were synthesized following a similar procedure. The physical data of the synthesized compounds are shown in Table 2.

REFERENCES:
1. 2. 3. 4. 5. 6.

7.

Gurram R M, Chakrabarti R, Reeba K V, Bioorganic and Medicinal Chemistry, 2002; 10: 2671. Turner N C, Drug discovery today, 1996, 109. Lebovitz H E, Clinicians manual on insulin resistance, London Science Press ltd, 2002;162. Fujita and Sugiyama Y, Diabetes, 1983; 32: 804. Saltile A.R and Olefsky J.M, Diabetes, 1996; 45: 1661. Pattan S.R., Khade A.B., Pawar P.D., Tarnalli A.D., Kittur B.S.and Borkar S.D, Synthesis of 2-amino [5-(4sulphonyl benzylidene)-2,4-thiazolidinedione]-6-fluro benzothiazoles as antiinflammatory agents. Indian Journal of Heterocyclic Chemistry, 2007; 16: 299-300. Pattan S. R., Suresh Ch., Pujar V D, Reddy VVK, Rasal V P and B C Koti, Synthesis and antidiabetic activity of 2amino [5(4-sulphonylbenzylidine)-2,4-thiazolidinedione] -7-chloro-6-fluorobenzothiazole. Indian Journal of Chemistry, 2005; 44B: 2404-2408.

RESULT AND DISCUSSION:

A series of thiazolidinedione derivatives were synthesized. The structures of these compounds were established by means of IR, 1H-NMR and elemental analysis. Infra Red/ 1H-NMR spectral study of the synthesised compounds are shown in Table 3. The title compounds were screened for their antidiabetic activity by Alloxan induced tail tipping method. The Albino rats of either sex weighing between 150-200 g were selected. The blood glucose level was induced and the study was carried out in six difference groups. Out of Nine compounds synthesized (B1-B9). The compounds B1, B2, B4, B7, B8, and B9 have shown significant antidiabetic activity. B3, B5 and B6 have shown moderate antidiabetic activity on oral administration. The results were calculated by measuring the mean SE and p value with the suitable molecular manipulations of the synthesized compounds, and the attracting significance of thiazolidinediones can be better explored in future as a potent candidate for diabetus mellitus. It is also note worthy that the toxicity studies have been carried out for these compounds and least toxicity is being found in all these compounds.

ACKNOWLEDGEMENT:

Authors wish to thank Honorable Shri.Radhakrishna Vikhe Patil, Minister for Education, Law and Justice govt. of maharashtra for his constant encouragement and support. Sincere thanks to Mr. Sanjay Bhawar for his help in carrying out antidiabetic activity.

126