Thaizolidinedione: Oral Insulin Sensitizing Agent

 

Sushil D. Patil

Department of Pharmaceutical Chemistry, MET Institute of Pharmacy Bhujabal Knowledge City, Adagaon, Nashik-422003

*Corresponding Author E-mail: sushilpharma@rediffmail.com

Thaizolidinediones molecule has basic pharmacophore which shows wide range of Pharmacological Activity like Antidiabetic, Anticancer, Antimicrobial, and Anti-inflammatory.

 

Introduction of new classes of pharmacologic agents 2 sulfonylurea’s, glinides, biguanides, glitazones (thiazolidinediones) and α-glucosidase inhibitors. In this most of the drugs can cause non-compliance, hypoglycemia and obesity. 2, 4-thiazolidinediones are associated with diverse biocidal activities probably by virtue of a toxophoric –N=C-S- grouping. There are evidences of chemical structures of 2, 4-thiazolidinedione when compared to Rosiglitazone which is considered as oral hypoglycemic agents. The thiazolidinediones represent a novel class of hypoglycemic agents for treatment of NIDDM. Thiazolidinediones (TZDs), which are known to sensitize tissues to insulin, have been developed and clinically used as antidiabetic agents. They have been shown to reduce plasma glucose, lipid, and insulin levels, and used for the treatment of type 2 diabetes. Thiazolidinediones substituted with a phenyloxazolyl group,pyridines and purine containing group improve potency and safety. Substituted at the N-activity deminishes the antidiabetic activity. Molecule has wide range of activity future cytotoxic activity research may be give potent molecule.

 

 

 

INTRODUCTION:

The earlier sources of drugs were from plant, animal and mineral sources, but due to the lack of potential action and definitive cure and sometimes more toxicity, the discovery of new drugs that are more potential and less toxic is essential.  The synthesis of derivatives has been an important part and is aimed at modifying the action of drugs, particularly to reduce the side effects and to potentiate the drug action.  Today more than 60% drugs used in practice are synthesized derivatives, and day-by-day the scope of synthetic medicinal chemistry is broadening. Now in days, medicinal chemists are at the forefront of innovation, blending synthetic chemistry, molecular modeling, computational biology, structural genomics and pharmacology to discovery and design new drugs and investigate their interaction at the cellular level. Many efforts are being made in the design and development of novel drugs from synthetic origin. Thus there is growing interest in the pharmacological potential.

 

The tools of medicinal chemistry have changed dramatically over the past few decades, and continue to change today. Most medicinal chemists learn how to use these tools by trial and error once they enter the pharmaceutical industry, a process that can take many years. Medicinal chemists continue to redefine their role in the drug discovery process, as the industry struggles to find a successful paradigm to fulfill the high expectations for delivering new drugs. But it is clear that however this new paradigm works out, synthetic and medicinal chemistry will continue to play a crucial role.

 

Diabetes mellitus is one of life threatening disorder found in most of the countries in the world which is due to impaired carbohydrate, fat and protein metabolism. [1] A defective or deficient insulin secretion, which translates into impaired carbohydrate (glucose) use, is a characteristic feature of diabetes mellitus results in hyperglycemia in the blood.[2] Recent survey showed that it is fourth leading cause of death in developed countries and worry more than 5% of world’s population; suffer from diabetes. There are more than 125 million persons with diabetes in the world today and by 2010, this number is expected to approach 220 million. [3]

 

 

Table no-1. Thiazolidinediones structure and Pharmacological Activity:

Sr.N	Name of Compound	Structure	Pharmacological  Activity and Remark
1.	Clofibrate		Oral insulin sensitizing agents that improve insulin resistance, are agonists of peroxisome proliferators activated receptor-γ (PPAR-γ), a receptor subtype selectively expressed in adipocytes and shown to induce adipocyte differentiation.[5-7].
2.	Ciglitazone		Hypolipidemic agent was first such compound found to improve insulin resistance. [8 -12]
3.	Troglitazone		Hypolipidemic agents have been clinically examined.  Under TZDs, a class. [13-15] Hepatotoxicity[23-25]
4.	Englitazone		Hypolipidemic agent [16]
5.	Pioglitazone		Hypolipidemic agent [17] weight gain is reported as side effect [18].
6.	Rosiglitazone		Hypolipidemic agent[19]
7.	KRP-297		Hypolipidemic agent. Under TZDs, a class. Has been discontinued following instances of carcinogenicity. [20, 21]
8.	Netoglitazone		Have been reported with PPAR- α/γ dual agonistic activity. [22]
9.	5-[[7-(4-trifluoromethyl- benzyloxy)-3-quinolyl]methyl]thiazolidine-2,4-dione		Several quinolinyl TZDs have been reported [26] to lower blood sugar level (56% of control).
10.	5-[4-{2-([{1-(6-Methoxypyridin-3-yl)ethylidene} amino] oxy) ethoxy} benzyl]thiazoli-dine-2,4-dione		Several oximes containing TZDs are reported [27] useful for treating or preventing hyperlipidemia, hyperglycemia, obesity, impaired glucose tolerance, insulin resistance, diabetic complications and gestational diabetes mellitus. orally in hyperglycemic mice reduced blood glucose (49.3%) after 3 h.[28]
11.	5-[4-[2-(4-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)methoxy]phenyl] methyl thiazolidine-2,4-dione		Blood glucose reduction (65.8%) TZD ring residue [29] linked to either of 2-, 3-, 4-, 5- and 6-positions on the indole rings have been shown to exhibit excellent effects of reducing blood sugar level and reducing the lipid concentrations in blood.
12.	5[3-(6-hydroxy-naphthalen-2-yl)-methy-propylidenene] -thiazolidine-2,4-dione		A methoxy naphthyl moiety of nabumetone type compounds were showed better antidiabetic activity and anti-inflammatory properties. both in terms of plasma glucose (PG) and triglycerides (TG) reduction[30]
13.	5[-1-(6-Methoxy-naphthalen-2-yl)-ethylidenene] -thiazolidine-2,4-dione		Methyl group at the α-position showed better PG reduction[31]
14.	5[-1-(6-Methoxy-naphthalen-2-yl)-3-oxo-butylidenene]- thiazolidine-2,4-dione		methyl group at the α-position showed better less PG reduction as compare Compound sr.no.13[31]
15.	5[-3-(6-Methoxy-naphthalen-2-yl)-3-oxo-propylidenene]- thiazolidine-2,4-dione		Demethylated compound had completely abolished anti-inflammatory activity, but retained the blood glucose lowering activity. [31]
16.	5-[3-(7-(6-Hydroxy-2,5,7,8-tetramethyl-chromen-2-ylmethoxy)-naphthalen-1-yl-methyl-propylidenene)- thiazolidine-2,4-dione		Naphthyl spacer group in this compound had no antidiabetic activity when compared to troglitazone, which had a phenyl spacer. [31]
17.	Series-1  5-(3-aryl-2-propynyl)-5-(arylsulfonyl) thiazolidine-2,4-diones		This compound effective at lowering glucose and insulin in the obese insulin. With Ar = phenyl and Ar′ = 4-chlorophenyl [32]
18.	Series-2   5-(3-aryl-2-propynyl)-5-(arylsulfanyl)thiazolidine-2,4-diones		This compound not significantly improved the glucose tolerance of obese insulin as compare with series 1 [32]
19.	5[4-{2-(1H-indol-1-yl)ethoxy}benzyl]thiazoli-dine-2,4-dione		The indole analogue DRF-2189 very potent insulin sensitizer comparable to BRL-49653 also possessed better lipid profile including reduction in total cholesterol, VLDL, LDL and an increase in beneficial HDL cholesterol activities.[33,34]
20.	5-[4-{(1-pyridin-2-ylpyrrolidin-2-yl)methoxy}benzylidene]thiazolidine-2,4-dione		Substituted pyridyl- and quinolinyl-containing 2, 4-thiazolidinediones having interesting cyclic amines was found very potent euglycemic and hypolipidemic compound.  [35]
21.	5-[4-[N-[6-benzyloxy-2,5,7,8-tetramethylchroman-3-ylmethyl]pyrrolidine-2-methoxy]phenylmethylene]thiazolidine-2,4-dione		Analogues having an amino alkyl group as a linker between the chroman ring leads to a decrease in metabolism, thereby resulting in superior pharmacological profile. [36]
22.	[a].5-(4(2-(1-Biphenyl-4-yl-ethylideneaminooxy)-ethoxy)-benzyl)-thizolidione-2,4-dione [b].5-(6(Phenylpyridin-3-yl ethylideneaminooxy)-ethoxy)-benzyl)-thizolidione-2,4-dione		More potent PPARγ agonistic activity than rosiglitazone along with strong blood glucose lowering activity. [37]
23.	2-(4-[3-(5-Methyl-2-Phenyl-Oxazol-4-yl)-propyl]-benzylidene)-4-(octahydro-isoindol-2-yl-4-oxo-butryric acid		With a phenyloxazolyl group stimulated insulin secretion significantly, potency was almost the same as that of nateglinide. The compound also exhibited a similar triglyceride accumulation profile to pioglitazone in 3T3-L1 cells. [38]
24.	5-[4-(5- methoxy-3-methyl-3H-imidazo[4,5-b]pyridin-2-ylme-thoxy)benzyl]thiazolidine-2,4-dione		A series of imidazopyridine thiazolidine-2,4-dioneswas evaluated for its effect on insulin induced 3T3-L1 adipocytes differentiation in vitro and its hypoglycemic activity in the genetically diabetic KK mouse in vivo.[39]
25.	5-[4-{2-(4-methyl-1-oxophthalazin-2(1H)-yl)ethoxy} benzyl] thiazolidine-2,4-dione		Vitro PPARγ transactivation potential than troglitazone and pioglitazone. In insulin PHT46 showed better plasma glucose and triglyceride lowering activity than standard drugs. Pharmacokinetic.[40]
26.	Two compounds (A = 4-pyridyl and R = 2-pyridyl) ofsubstitutedbenzylthiazolidine-2,4-dione		Substituted benzylthiazolidine-2,4-dione derivatives enhanced transcriptional activity of human PPARγ in CHO cells.  [41]
27.	5-[4-{(3-methyl-4-oxo-1,2,3,4-tetrahydroquinazolin-2-yl)methoxy} benzyl]thiazo-lidine-2,4-dione		Showed reduction in blood glucose level (55%) and triglyceride (35%) lowering activity. [42]
28.	5-[4-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)benzylidene] thiazolidine-2,4-dione		Benzylidene-TZDs and analogs, are reported as antidiabetics [43]
29.	PMT13, 5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]-ethoxy]phenylmethyl]thiazolidine-2,4-dione		Exhibited better plasma glucose, triglyceride and insulin lowering activity and better PPARγ transactivation than rosiglitazone and pioglitazone [44].
30.	5-{4-[2-(1-benzyl-3,4-bis-benzyloxypyrrolidin-2-yl)ethoxy]benzylidene}thiazolidine-2,4-dione		Antihyperglycemic activity of erythrose, ribose and substituted pyrrolidine containing TZD derivatives have been reported[45].
31.	6-(2-methoxyethoxymethoxy)-N-[4-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylme-thyl]-N-methylnaphthalene-2-carboxamide		1,1-biphenyl derivatives in vitro activated PPARα (22.4%) and PPARγ (93.3%) receptors expressed in Hela cells.[46]
32.	4-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl derivatives		The compound showed Kd of 250.0nM against PPARγ receptor binding [47].
33.	5-arylidene-3-(4-methylbenzyl)thiazolidine-2,4-dione		Novel pyrimidine derivatives glucose and lipid lowering activity found more potent than pioglitazone and rosiglitazone, respectively. [48,49]
34.	5-[4-(2-(4-oxo-2H-1,3-benzoxazin-3(4H)yl)ethoxy)benzyl]thiazolidine-2,4-dione		1, 3-benzoxazinone was identified as potent dual PPAR-α and -γ activator. It showed significant plasma glucose, insulin and lipid lowering activity. [50]

 

A standard treatment regimen has considered the use of Insulin and number of other chemical classes of drugs which may increase the production of Insulin. Type 2 diabetes that is non-insulin dependent diabetes mellitus (NIDDM), which is characterized by insulin resistance and hyperglycemia [4]. Sulfonylureas, glinides, biguanides, glitazones (thiazolidinediones) and α-glucosidase inhibitors. In this most of the drugs can cause non-compliance, hypoglycemia and obesity.

 

Sulfonylureas, glinides, biguanides, glitazones (thiazolidinediones) and α-glucosidase inhibitors. In this most of the drugs can cause non-compliance, hypoglycemia and obesity. 2, 4-thiazolidinediones are associated with diverse biocidal activities probably by virtue of a toxophoric –N=C-S- grouping. Thiazolidinediones substituted with a phenyloxazolyl group,pyridines and purine containing group improve potency and safety.

 

Table no-2 Thiazolidinediones with different Pharmacological Activity:

Sr.no	Authors	Structure	Pharmacological activity
1	C. Prabhakar et al; 1998	R1 R   CH3       CH3   CH3	Ant diabetic and anti-inflammatory Activity[51]
2	Meral Tunc bilek et al. 1999		Antimicrobial Activity[52]
3	Rahmiye Ertan et al;2003		Insulinotropic activity [53]
4	I.R. Pitta et al. 2005		Antihyperglycemic activity. [54]
5	Pattan S.R. et al.2007		Anti-inflammatory Activity[55]
6	Nandini R.P. et al.2007		Antihyperglycemic activity. [56]
7	Pattan  S.R. et al;2008		Antidiabetic Activity[57]
8	Amal M. Youssef et al;2010		Anti-Inflammatory and neuroprotective activity. [58]
9	Manjunath Ghate   et al., (2011)		Oral Hypoglycemic Activity[59]
10	Oya Bozdag etal		Synthesis and some physico-chemical properties of flavonyl thiazolidinedione derivatives.[60]
11	Oya Bozdag  etal		Aldose reductase (AR) and Insulin tropic  activity[61]

 

 

Table no-3 Effects of thiazolidinediones on components of the insulin resistance syndrome: [62]

Sr.No.	Component	Thiazolidinedione effect
1.	Hyperglycemia	Decrease fasting plasma glucose Decrease HbA1c
2.	Hyperinsulinemia	Decrease plasma insulin levels
3.	Hypertension	Decrease blood pressure
4.	Dyslipidemia	Decrease total/HDL-cholesterol ratio Decrease triglycerides Increase size and decrease density of LDL cholesterol particles
5.	Microalbuminuria	Decrease Urinary albumin excretion
6.	Endothelial dysfunction	Increase vascular reactivity Decrease ROS (Reactive Oxygen Species)
7.	Vascular inflammation	Decrease CRP (C-Reactive Protein) Decrease MCP-1 Decrease production of proinflammatory factors Decrease macrophage activation
8.	Plaque destabilisation	Decrease MMP-9 (Matrix Metallo Proteinase) Decrease MMP-13
9.	Decreased fibrinolytic activity	Decrease PAI-1

 

 

 

CONCLUSION:

Present review fruitful for researches for synthesis of different substituent on thiazolidinediones which may be highly effective in sensitizing agent for hypoglycemia, potent dual PPAR-α and -γ activator. Thiazolidinediones showed significant plasma glucose, insulin and lipid lowering activity. When it substituted with a phenyloxazolyl group stimulated insulin secretion significantly and Substitutedbenzylthiazolidine-2, 4-dione derivatives enhanced transcriptional activity of human PPARγ in CHO cells.

 

A series of substituted pyridines and purine containing 2, 4 thiazolidinediones improve potency and safety. In future, more thiazolidinedione derivatives with such substituted can be utilized as potent antidiabetic agents. Thiazolidinediones has wide range of activity future cytotoxic activity research may be give potent molecule.

 

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Received on 14.10.2013         Modified on 28.10.2013

Accepted on 04.11.2013         © AJRC All right reserved