Title: Review on Synthesis of Novel Thiazolidinedione Derivatives for Antidiabetic Activity

Diabetes mellitus (DM) is an endocrine disease that is usually caused by a deficiency of insulin or less commonly, by a decrease in insulin resistance ^[1]. Medical interventions for hyperglycemia can shorten life expectancy and improve overall quality of life ^[2]. Given its impact on human suffering, diabetes is considered the seventh most common disease worldwide, measured in disability-adjusted life years. ^[3]. Hyperglycaemia occurs due to insufficient insulin and glucagon secreted by the β and alfa cells of the pancreas ^[4,5]. Alpha cells control the blood sugar by secreting glucagon, and insulin transports glucose to the liver, muscle, and fat tissue, lowering blood sugar by producing glycogen ^[6]. It is characterised by Dehydration, Polyurea, Tiredness, Polyphagia, and Polydipsia ^[7]. consequently, it is far essential to keep normal blood glucose levels, mainly in the course of the early stages of diabetes. Various types of oral hypoglycaemic agents are utilized either alone or in combination to manage diabetes mellitus. It consists of Biguanides, Meglitinides, Sulphonyl-urea, and Alpha-glucosidase inhibitors. similarly to, sesquiterpenoids have also been said to be Hypoglycemic retailers because Of their distinctive feature of shielding Beta cells of the pancreas and Enhance insulin Production ^[8]. The Management of Type-2 diabetes mellitus has improved with the introduction of Thiazolidine-2,4-diones elegance of molecules that lowers the elevated blood glucose to regular ^[9]. Thiazolidinedione is a mighty heterocyclic ring because of its numerous organic activities. TZD is under investigation for the layout and synthesis of newer compounds. Thiazolidine is the tetrahydro by-product of thiazole and oxo by-product of its miles referred to as thiazolidinedione. A substitution is viable on the Second, Third, and fifth positions which cause a change in the residences of the compound. To create new derivatives, it is possible to change the substituents that are bonded to the nitrogen and methylene carbon atoms. The carbonyl organization of four-thiazolidinone is especially non-reactive ^[10]. Thiazolidine 2,4-dione is extensively utilized for designing novel anti-diabetic capsules. This scaffold exhibits some of the sports which include anti-diabetic, anti-cancer, anti-arthritic, anti-microbial, anti-melanoma, and many others. ^[11] all of those, anti-diabetic activities have been widely done and a good-sized quantity of medication is already to be had within the market together with rosiglitazone, pioglitazone, lobeglitazone, troglitazone, and so forth. these capsules act as hypoglycaemic retailers by performing upon peroxisome proliferator hobby receptor γ (PPARγ) ^[12]. TZD has a fully saturated five-membered thiazolidine with a sulfur atom at position 1 and a nitrogen atom at position 3 as shown in Fig. 1 ^[13]. modification can occur only 3^rd and 5^th positions of the Thiazolidinedione Scaffold making it more functional ^[14].

Figure-1 Thiazolidine-2,4-dione

Mechanism of Action

Thiazolidine produces a biological response by increasing the Peroxisome proliferator-activated γ receptors (antihyperglycemic activity) and cytoplasmic Mur ligase enzyme (anti-inflammatory activity), and scavenging ROS (antioxidant activity)

PPAR family

PPAR is a family of transduction proteins that act as a transcription factor and are also included in the nuclear superfamily of Retinoic acid/Thyroid Hormone Receptor/Steroid Receptor. involved in different Processes and also helps regulate and express many genes important for glucose and lipid metabolism.^[15.16]
Thiazolidinedione influences their Hypoglycaemic activity by activation of  Peroxisome proliferated- activated Gamma Receptor. It is a nuclear receptor. Thiazolidinedione-produced activation of Peroxisome proliferated -activated receptor that changes in expression of many genes involved in Energy balance, Lipid and Glucose metabolism (figure-2), These include those that encode the GLUT4 glucose transporter, fatty acid Transporter protein, adipocyte fatty acid binding protein, fatty acyl-CoA synthase, malic enzyme, glucokinase and lipoprotein lipase.  Thiazolidinedione is reduces insulin resistance in Muscle, Liver, and Adipose tissue.  However, Peroxisome Proliferated-Acivated Gamma Receptor is predominantly expressed in Adipose tissue. The effect of Thiazolidinedione on insulin resistance in Liver and Muscle may be promoted by endocrine signaling from adipocytes^[17,18].

Thiazolidinedione are commonly used as hypoglycaemic agent  in the treatment of diabetes for the last fourty years. Ciglitazone is one of the example of thiazolidinedione class of drugs. Ciglitazone developed by Takeda Pharmaceuticals in Japan was first introduced in the market during the early 1980s, ^[19]. Despite its potential as a therapeutic agent, its effectiveness in treating certain conditions has not been fully realized. The hepatotoxic properties of this substance have been realized. In 1988 , the Daiichi Sankyo a global Pharmaceutical Company of Japan developed the Thiazolidinedione analogue Troglitazone to treat various medical conditions. As a treatment for diabetes, this medication can be used to regulate blood sugar levels. However, its toxicity to the liver led to its discontinuation. In the year 2000, a ban was implemented, prohibiting the use of the product. ^[13]. In 1999, Takeda and Pfizer was  developed two drugs called Pioglitazone and emglitazone.However , emglitazone was banned due to side effects on the Liver. In contrast, Pioglitazone was declared safe for the treatment of liver disease. Meanwhile, rosiglitazone and daglitazone are manufactured by SmithKline and Pfizer. They were shown to cause heart failure due to fluid retention and heart failure. The Pioglitazone drug was removed from Food and Drug Administration restriction because it failed to prevent heart attacks. ^[14,20]_. Development of a new partial PPAR-γ agonist balaglitazone as an Antihyperglycemic agent, Dr. Reddy's laboratory iscurrently conducting phase 3 clinical trials in the US and Europe^.[14]. In 2013, Chong Kun Dang (Korea) successfully developed a new pharmaceutical compound, namely lobeglitazone. The drug has been approved by the Ministry of Food and Drug Safety. ^[21]. Fig. 3 displays the structure of various clinically reported thiazolidinedione drugs.^[13,22]

Figure-3 Clinically and experimentally investigated compounds of TZD and their current status

Recent advances of TZD in antidiabetic activity

Diabetes mellitus is a metabolic syndrome that is characterized by high blood sugar levels. It affects many people, both male and female, Across the planet. The life years of diabetic patients are decreased due to damage to the Body organs like the Eyes, Kidneys, Heart, Blood vessels, And nerves.^[23] Around 200 million people are suffering. The many people with diabetes will be increased to 350 million by the year 2025. By the year 2030, there will be more than 300 million.^[24] The derivatives of TZD, the antidiabetic agents troglitazone, rosiglitazone, and many more were approved. They were withdrawn from the market due to their toxicity.^[25] In the search for new antidiabetic agents, Naim et al. (2018) synthesized and evaluated fifteen pyrazole-based 2,4-thiazolidinedione (TZD) derivatives as PPAR-γ modulators for anti-diabetic activity. Docking studies identified eight promising compounds with strong PPAR-γ binding. In vivo tests on diabetic rats showed that compound 5o effectively lowered blood glucose and increased PPAR-γ gene expression more than standard drugs, while exhibiting minimal hepatotoxicity. This study highlights the therapeutic potential of modified TZD derivatives for safer, effective diabetes management.^[26]

Mendes et al. (2021) has Developed a series of hybrid compounds combining functional aspects of glibenclamide, a sulfonylurea, and pioglitazone, a thiazolidinedione, for the treatment of type 2 diabetes mellitus (DM2). The hybridization approach aimed to consolidate the insulin secretagogue effects of glibenclamide with the insulin-sensitizing properties of pioglitazone, potentially minimizing the adverse effects of both. The study found that the compound 4-[2-(2-phenyl-4-oxo-1,3-thiazolidin-3-yl) ethyl] benzene-1-sulfonamide (PTEBS) was particularly effective, exhibiting improved glycaemic control, enhancing insulin secretion, and promoting glycogen accumulation in hepatic and muscular tissues. Moreover, PTEBS increased glucose uptake in skeletal muscle by activating GLUT4 translocation and synthesis, indicating a potential for enhanced insulin sensitivity without adverse hypoglycaemic effects ^?[27].

Mandal et al. (2022) has synthesized and evaluated phenyl glycine-based glitazones as potent PPAR-γ agonists for type 2 diabetes management. The compounds, designed to maintain core glitazone characteristics while incorporating bioisosteric modifications, demonstrated enhanced glucose uptake and insulin sensitivity in cellular assays. Compound 6a, in particular, showed promising results in both in vitro and in vivo models, with improved pharmacokinetic properties and reduced adverse effects compared to pioglitazone. These findings highlight the potential of phenyl glycine-modified glitazones as novel agents for safer and more effective diabetes management? ^[28].

Gowdru et al. (2023) reported novel thiazolidine-2,4-dione derivatives (3h–3j) to enhance PPAR-γ agonistic activity for antidiabetic therapy. These compounds demonstrated improved binding affinity and stability in molecular docking and dynamics simulations, showing high binding scores compared to standard drugs. In vivo studies in a diabetic rat model showed that these derivatives significantly lowered blood glucose levels without liver toxicity, outperforming pioglitazone. The study’s integration of ADMET profiling and cytotoxicity assays further supported the therapeutic potential of these compounds as safer alternatives for diabetes management? ^[29].

Liu et al. (2019) synthesized trihybrids combining rosiglitazone, ferulic acid, and a nitric oxide (NO) donor to enhance glucose tolerance and address cardiovascular risks associated with rosiglitazone. The hybrid compound 21 showed superior glucose-lowering effects in diabetic models, attributed to its NO production, antioxidant properties, and reduced fluid retention compared to rosiglitazone alone. Moreover, compound 21 displayed stability in simulated gastrointestinal environments and selectively released rosiglitazone in plasma, which improved its safety profile, marking it as a promising candidate for diabetes management^{? [30]}.

Tanis et al. (2018) developed thiazolidinedione analogs designed to reduce direct activation of PPARγ, focusing instead on the mitochondrial pyruvate carrier (MPC) as an alternative insulin-sensitizing target. Compounds 6 and 7 demonstrated minimal binding to PPARγ but showed significant antihyperglycemic activity in diabetic mouse models, suggesting that MPC modulation may achieve insulin sensitization with fewer PPARγ-related side effects, such as weight gain and fluid retention. This approach opens new avenues for developing safer, more effective diabetes therapies by targeting mitochondrial pathways. ^[31].

Zou et al. (2019) synthesized a novel class of 2,4-thiazolidinedione derivatives using rosiglitazone as a lead compound to improve insulin sensitivity for type 2 diabetes. These compounds, optimized for enhanced binding to PPARγ, demonstrated strong in vitro activity with compound 6e showing an EC50 of 0.03 µM. In vivo studies confirmed significant glucose-lowering effects and low toxicity, positioning these derivatives as promising candidates for safer, more effective antidiabetic therapy? [32].

Chhajed et al. (2017) synthesized and evaluated a series of substituted benzylideneamino-benzylidene-thiazolidine-2,4-diones as potential PPAR-γ agonists for type 2 diabetes management. Compounds TZD-1, TZD-4, TZD-16, and TZD-34 demonstrated significant glucose uptake in 3T3-L1 cell assays, showing 1.6-2.1-fold increases over control, comparable to rosiglitazone. Docking studies confirmed strong interactions with PPAR-γ, with para-substituted analogs displaying the highest binding affinity. These findings highlight the potential of structural modifications to thiazolidinedione for enhanced antidiabetic efficacy and reduced adverse effects ^[33].

Nazreen et al. (2021) had generated a library of chromone-2,4- thiazolidinedione conjugates by way of the use of hydrogen  gas and lead/ carbon  as catalysts through  knoevenagel condensation. In terms of lowering blood glucose level, compounds S-39 and S-40  have been as effective. In the molecular docking evaluation, all the compounds had an excessive go with the flow rating when as compared to the Peroxisome Proliferated-Activated Gamma receptor target, and S-39, S-40, and Pioglitazone all exhibited nearly identical docking results, sharing one hydrogen bond (with HIS449) and one cation bond (with ARG288). Each of the three compounds has one hydrogen bond and one cation bond. Compound S-40 significantly increased the expression of the PPAR-γ gene by 2.56 times when compared to the gold standard medication pioglitazone. Compounds S-39 and S-forty are non-toxic, which suggests that they could be helpful in the hunt for a new antidiabetic medication ^[34].