Synthesis and Evaluation of Antidiabetic Activity of Few 5-(4-(5-Substitutedphenyl)-1,3,4-Oxadiazlole-2-Yl) Methoxy)Benzylidene) Thiazolidine 2,4-Dione Derivatives

 

Roshani Bhalerao*, Dinesh Rishipathak, Pavan Udavant, Sanjay Kshirsagar

MET’S Institute of Pharmacy, Bhujbal Knowledge City, Adgaon, Nashik-422003,

Savitribai Phule Pune University, India

 

ABSTRACT:

The aim of study was to synthesize a new series of Thiazolidinedione. Thiazolidinedione or glitziness forms a significant class of drug which exhibit biological activities ranging from antidiabetic, antiinflamatory, antibacterial, antifungal, antiviral, and anti-cancer. In the present study reported a systematic synthesis of thiazolidinedione. A new series of 2,4-thiazolidinedione based derivative have been synthesize by condensation of. The structure of these compounds were establish by IR and 1H NMR. These new compound (C1-C4) were evaluated for their antidiabetic activity on albino rat. Most of compound shows significant antidiabetic activity when compare with standard drug metformin.

 

 

 

INTRODUCTION:

Diabetic Mellitus is a group of metabolic disorder group of metabolic disorder characterized by chronic hyperglycemia (1). Symptoms of Diabetes Mellitus include frequent urination (polyuria), increased thirst (polydipsia), increased hunger (polyphagia), and weight loss. If left untreated Diabetes can cause complication. Long term complications include cardiovascular disease, stork, chronic kidney failure, foot ulcer, and damage to the eyes. Diabetes mellitus is of two types,  1) Insulin dependent diabetes mellitus (IDDM) 2) Non insulin dependent diabetes mellitus or adult onset diabetes mellitus or diabetes mellitus type 2 is characterized by insulin resistance or reduced insulin sensitivity.

Although the frequency of diabetes is increasing only two clases of oral hypoglycemic agent are available sulfonylureas and Biguanide. Biguanide are banned in western countries due its severe side effects mainly lactic acidosis. Sufonylureas therapy has some problems such as primary and secondary failure of efficacy, enhancement of obesity and high incidence of hypoglycemia. A significant advancement has been made with the introduction of new class of compound Thiazolidine, 2-4-diones (TZDs) which act as insulin enhancers.

 

The class of Thiazolidinediones (TZDs also called as “glitazones”) was introduced in late 1990’s as an adjunct therapy for type II diabetes mellitus and related diseases. 2,4- Thiazolidinediones (TZDs) have become a pharmacologically important class of heterocyclic compounds. Several study have been reported that TZDs has acquired much importance because of there adverse pharmaceutical application such as hyperglycemia, bactericidal, pesticidal, fungicidal, insecticiadal, anticonvulsant, tuberculostatic, antiinflamatory etc. The Thiazolidinedione’s are peroxisome proliferator- activated receptor agonist. The PPARY receptor is a member of the nuclear hormone receptor of ligand activated transcription factors that regulate gene expression of several genes involved infatty acid and carbohydrate metabolism and adipocyte differentiation. In addition to hypoglycemic activity, thiazolidinedione reduce insulin levels and improve insulin resistance, markedly reduce plasma free fatty acids, increased the storage of fat and often improve the blood lipid profile.(2,3)

 

MATERIALS AND METHODS (4,5,6):

The melting points were determined using open capillary tubes and are uncorrected. Purity of the all synthesized compounds was checked by thin layer chromatography technique (0.2 mm thikness of silica gelG plates) and iodine was used as visualizing agent. IR spectra were recorded on FT-IR. Furier Transform (Analytical Technique) Infrared spectrophotometer using KBr disk method. 1H NMR spectrawere recorded in dimethyl sulphoxide (DMSO) using tetramethylsilane (TMS) as an internal standard.

 

Synthesis of Thiazoldine-2-4-dione:                                                                                              

In a 250 ml round bottomed flask transfer a 56.5 g of chloracetic acid (0.6 ml) in a 60 ml water and 45.6 g of thiourea (0.6mol) dissolved in a 60 ml of water. The mixture was stirred for 15 minutes to form a white precipitate, accompanied by considerable cooling. To content of the flask, now added slowly 60ml concentrated hydrochloric acid from dropping funnel. The flask was connected with reflux condenser and gentle heat applied to effect complete dissolution, after which the reaction mixture was stirred and reflux for 8-15 hrs. at 100-110⁰C. On cooling the content of the flask solidified to mass of cluster of white needles. The product was filtered and washed with water to remove traces of hydrochloric acid and dried. It was recrystallized from ethanol. Yield 92%

 

Synthesis of 5-Benzylidine-2,4-Thiazolidinedione:

In 250 ml round bottomed flask benzaldehyde (20g, 0.188 mole) and 2,4-thiazolidinedione (22g, 0.188 mole) were together suspended in dry toluene. To this catalytic amount of piperidine (1 ml) was added. The mixture was reflux with stirring. After the complete removal of water and temperature cross 110^oC, the reaction mixture was stirred for a 1hr. On cooling, the product precipitated from tolune. The compound was filtered and washes with cold, dry toluene and dry ethanol.

 

Synthesis of 2,4-thiazolidine-5-yldine phenyl ethyl carbonate:

Product of step II (1mol) were suspended in dry acetone to this anhydrous K₂CO₃  (1mol) were added to this ethyl chlorformate (1mol) were added dropwsie. This was then stirred for 35-40 hrs at room temperature and reaction were monitored by TLC. The product was then filtered and wash with water. It was then purified by recrystallization from ethanol.

 

Synthesis of 4-(Z)-(2,4- dioxothiazolidine 5-yeldine) methyl) phenyl 2-hydrazinylacetate:

The product of step III (1 mol) was suspended in hydrazine hydrate (1mol) and this was then reflux for 1-2 hrs  and reaction was monitored by TLC. The product was then filtered and washed with water. It was purified by recrystallization from ethanol. The yield was 95 % and 81 % respectively. Simillarly compound C1-C2 were prepare by adopting similar procedure by using appropriate

 

General procedure for Anti Diabetic Activity (7,8,9)

Reagent Preparation:

Dilute the glucose stock solution (45%) with saline to 20% by adding 20ml stock to 25ml 0.9% (w/v) sterile saline.

 

Procedure:

Mice are fasted for six hours by removal to a clean cage without food at the end of their dark (feeding) cycle.  Mice are weighed.  After 6h of fasting, a fasting glucose level is obtained from venous blood from a small tail clip. 1 mg/g body glucose is injected intraperitoneally.  Blood glucose values are obtained at 5, 15 30, 60, and 120 min.  If desired, blood may also be obtained for insulin assay (~50 μl) at any time point.

 

RESULT AND DISCUSION:

A series of thiazolidinedione derivatives were synthesized by reacting various substituted benzaldehyde. The structure of these compounds were established by means of IR and 1H NMR shown in table 1. There antidiabetic activity by using Oral Glucose Tolarence Test. Result of these shown in table 3.

 

 

Table 1: Physical data of compound

Sr. No.	Compounds	Therotical Yield (gm)	Practical Yield (gm)	Percentage Yield (%)	TLC (Rf value)
1.	4-H3CO	2.65	1.94	73.20	0.6
2.	4-NO2	2.52	2.1	83.00	0.7
3.	4-Cl	1.32	1.1	83.33	0.8

 

Table 2: Spectral Data of Compund

Compounds	1H- NMR (δ PPM)	IR (KBR) CM-1
4-H3CO	3.8 Singlet 1H -CH 6.9 Doublet 2H -C6H5 7.7 Doublet 2H -C6H5 10 Singlet 1H -NH	O-CH3 (m) sub. Benzene 833 C=O Carboxyl amide 1604.7 C-S-C Thiol 617.22 C=N Imines 1496.76
4-NO2	3.8 Singlet 1H -CH 6.9 Doublet 2H -C6H5 7.7 Doublet 2H -C6H5 10 Singlet 1H -NH	NO2 Aromatic 1504 1311.09 C=O Carboxyl amide 1604.7 C-S-C Thiol 617.22 C=N Imines 1496.76

 

TABLE.3. Hypoglycemic effects of synthesized test compounds

Treatment	Blood Glucose Level (mg/dl)
	30min	60min	120min
Pioglitazone	142±3.44	96.25±6.98	90.25±1.31
MCR-011	136±1.95	113.5±2.21	102±1.58
MCR-012	131±1.68	117.5±1.70	107.75±3.01
Glucose control	150.5±14.26	149±0.70	131±2.17
Saline control	119±2.27	116.5±2.39	114±2.16

Values are expressed as mean ± S.E.M

 

SYNTHETIC SCHEME:

 

 

CONCLUSION:

All the 2, 4- Thiazolidinedione derivatives were screened for there in vitro antidiabetic activity and MCR-011 having significant antidiabetic activities as compare to MCR- 012. The pharmacological activity were exhibited by synthesized novel thiazolidinedione derivatives have confirmed that these compound may serve the purpose of being accept as the novel therapeutic agents. Furthermore these novel thiazolidinediones derivatives may be optimized by there toxicity and SAR studies.

ACKNOWLEDGEMENT:

Authors are thankful to the trustees and management of MET’s Institute of Pharmacy, Bhujbal Knowledge City, Nashik-422003 for providing necessary chemical and facilities.

 

REFERNCES:

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6.       Shashikant R. Pattana, Prajact Kekareb, Ashwini Patilc, Ana Nikaljec, BS Kitturd the Synthesis of Novel 2,4-ThiazolidinedioneDerivatives with Antidiabetic Activity Kitturd Iranian Journal of Pharmaceutical Sciences Autumn 2009: 5(4): 225-230

7.       Daniel J. Toft a, Miles Fuller a, Matthew Schipma b, Feng Chena, Vincent L. Cryns c αB-crystallin and HspB2 deficiency is protective from diet-induced glucose intolerance: www.elsevier.com

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Received on 30.06.2017       Accepted on 14.07.2017     

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