Thiazole Derivatives in Diabetes Management: Recent Progress and Future Perspective

Diabetes mellitus (DM) is a metabolic disorder characterized by elevated blood glucose levels, resulting in hyperglycemia. This condition is associated with complications affecting the eyes, kidneys, and heart (Maulina et al., 2025). The prevalence of DM is increasing globally, and over the past two decades, there has been a rise in the use of synthetic agents for treating chronic diseases, including diabetes DM is broadly categorized into two types: Type II DM is caused by resistance to insulin or a malfunction of insulin hormone, while Type I DM can be brought on by the death of pancreatic beta cells. More than eighty per cent of individuals with diabetes worldwide suffer from type II, or non-insulin-dependent diabetes, which is the most predominant type of the medical condition. Resistance to glucose and reduced production of insulin are characteristics of this complex conditions. Because DM frequently coexists with cardiac and metabolic challenges, it has a substantial influence on public health (Kumaret al., 2013; Siddiqui et al., 2011). This group of metabolic disorders impacts approximately half a billion individuals globally and responsible for almost 5 million deaths every year. An inefficient use of nutritional energy by the body is caused by DM. The WHO estimates that by the year 2025, there will be 422 million instances of diabetes around the world, compared to a total of 108 million cases in the year 1980. Additionally, according to the WHO, there are currently 250 million patients worldwide who have diabetes, and by 2030, it is expected that this figure will rise to nearly 367 million. Anxiety, increased obesity rates, and longer lifespans are all responsible for this explosion. Molecular hybridization—the method for mixing many pharmacophoric moieties of physiologically active chemicals to form new, more efficient hybrid molecules is becoming increasingly accepted in the 5medicinal chemistry arena. In 2016, diabetes was the seventh leading cause of death worldwide. Another WHO report indicated that the number of diabetes cases could rise to 592 million by 2035, largely due to an increase in adult-onset diabetes (Shyam et al., 2016; Khatik et al., 2011).  Substituted 1,3,4-thiadiazole derivatives have garnered significant research interest due to their diverse pharmacological activities. The N−C−S moiety present in these derivatives is believed to play a key role in their biological effects. Researchers suggest that the biological activities of 1,3,4-thiadiazole are attributed to its strong aromatic nature, in vivo stability, and minimal toxicity to higher vertebrates, including humans, making it suitable for cancer treatment. The five-membered aromatic ring of 1,3,4-thiadiazole comprises two nitrogen atoms and one sulfur atom, along with a two-electron donor system and a hydrogen bonding domain (Kumar et al., 2014). These features enable it to function as a carbonic anhydrase inhibitor. 1,3,4-Thiadiazole exhibits a wide array of biological activities, including antimicrobial, antituberculosis, anti-inflammatory, carbonic anhydrase inhibitory, anticonvulsant, antihypertensive, antioxidant, anticancer, and antifungal properties (Kaur &Khatik 2016). Examples of drug molecules incorporating the 1,3,4-thiadiazole group include carbonic anhydrase inhibitors like acetazolamide and methazolamide. Additionally, the thiadiazole group can act as a bioisosteric replacement for the thiazole moiety, enhancing its biological activity through strong aromaticity and structural stability. The significance of thiazole in synthetic and biological chemistry began to gain traction after the pioneering work of several studies. Numerous reviews have since been published, exploring the diverse biological activities of thiazole and its derivatives (Mazalan et al., 2025; Chhabria et al., 2016). This review focuses on the biological significance of thiazole and its derivatives as antidiabetic agents, emphasizing recent advancements in this field. It serves as a complement to earlier reviews by summarizing research on thiazole and thiazolidinedione derivatives as antidiabetic compounds in recent years. Since 1995, there has been a surge in the development of new classes of antidiabetic agents, including insulin and its analogs, sulfonylureas, glinides, biguanides, glitazones, and α-glucosidase inhibitors (Borelli et al., 2008). However, many of these drugs are associated with side effects such as metabolic disorders, poor patient compliance, hypoglycemia, and obesity. As a result, there is a growing need for novel antidiabetic drugs with improved patient compliance and reduced adverse effects. This review discusses recent progress in the study of thiazole compounds, highlighting their potential in the design and development of promising new antidiabetic drug candidates (Agustini et al., 2025; Ichaleet al., 2024).

2. Theoretical Framework

Literature Review

Gupta et al., (2024) in their research primarily focuses on 2,4-thiazolidinedione derivatives, which are nitrogen-containing heterocyclic compounds used in managing type 2 diabetes mellitus. It discusses their synthesis, structure-activity relationships, and various therapeutic potentials, including anticancer and anti-inflammatory activities. However, it does not specifically address thiazole derivatives in diabetes management. The review emphasizes mitigating side effects of marketed TZD derivatives and presents novel TZD derivatives with enhanced therapeutic potentials, warranting further evaluation of their biological activities (Gupta et al., 2024). Ullah et al., (2024) The research investigates eleven novel thiazole derivatives derived from thiophene carbaldehyde for their potential in diabetes management. Seven derivatives exhibited excellent α-glucosidase inhibitory activity, outperforming the standard acarbose, with IC50 values ranging from 10.21 to 18.21 μM. The study also confirmed that these compounds do not exhibit cytotoxic effects. Additionally, molecular docking studies indicated strong binding potential to the α-glucosidase active site, suggesting their promise as therapeutic agents in managing diabetes (Ullah et al., (2024). Maslat et al., (2024) suggested that thiazole derivatives have shown potential in diabetes management, as evidenced by a study investigating their effects on STZ-induced diabetic mice. The synthesized thiazole compound significantly reduced hyperglycemia, restored pancreatic insulin secretion, decreased serum triglyceride levels, and increased pancreatic superoxide dismutase (SOD) activity. These findings suggest that thiazole derivatives possess anti-hyperglycemic and antioxidant properties, indicating their potential as therapeutic agents in the treatment of diabetes. Further research is needed to explore their mechanisms of action (Maslat et al., 2024). Fettach et al., (2024) in their study focuses on thiazolidine-2,4-dione derivatives in diabetes management. These derivatives were evaluated for their anti-hyperglycemic and anti-hyperlipidemic effects in a diabetic animal model. The study found that they significantly reduced fasting blood glucose levels and improved lipid profiles, suggesting their potential role in managing Type 2 diabetes mellitus by enhancing insulin sensitivity through activation of peroxisome proliferator-activated receptor-gamma (PPAR-γ) (Fettach et al., 2024). Singh et al., (2024) concluded in their about thiazolidinediones (TZDs), a class of anti-diabetic agents that reduce insulin resistance and activate PPARγ. The review highlights the medicinal potential, structure-activity relationships, and safety aspects of TZD analogues developed over the last two decades, emphasizing their efficacy and side effects. While thiazole derivatives may be relevant, they are not the primary focus of this research (Singh et al., 2024). Kashyap et al., (2024) in their review suggested that thiazole derivatives exhibit significant anti-diabetic activity, making them valuable in diabetes management. The research highlights their potential to modulate biological pathways associated with glucose metabolism and insulin sensitivity. By optimizing the structural properties of these compounds, researchers aim to enhance their efficacy and reduce toxicity. The exploration of thiazole derivatives in this context paves the way for developing innovative therapeutic agents that can provide alternative treatment options for diabetes, contributing to improved patient outcomes (Kashyap et al., (2024). Rajesh et al., (2023) revived about thiazole derivatives have been recognized for their hypoglycemic properties, contributing significantly to diabetes management. Compounds such as rosiglitazone, pioglitazone, and troglitazone demonstrate effectiveness in controlling elevated blood sugar levels. The unique aromatic properties of thiazole allow for various chemical reactions, enhancing their biological activities, including antidiabetic effects. This review highlights the synthesis of different thiazole derivatives and their potential role in developing effective treatments for diabetes, showcasing their importance in pharmacological advancements (Gupta et al., (2023). Hussain et al., (2023) in their research suggested that thiazole derivatives, specifically the synthesized imidazopyridine-based compounds have shown promising potential as antidiabetic agents by inhibiting the α-glucosidase enzyme. The docking analysis revealed that these  compounds and demonstrated excellent binding interactions with the enzyme's active site, indicating their potential utility in diabetes management through effective carbohydrate absorption inhibition (Hussain et al., 2023). Arineitwe et al., (2023) in their paper focuses on thiazolidinedione (TZD) derivatives, which are a class of compounds related to thiazole, synthesized to evaluate their anti-diabetic properties. Four novel TZD derivatives were tested for their effects on glucose metabolism and enzyme inhibition. The study found that these derivatives exhibited significant inhibition of key enzymes involved in glucose utilization, with TZDD2 showing enhanced glucose uptake in liver cells and notable inhibition in α-amylase, α-glucosidase, and aldose reductase assays, indicating their potential in diabetes management (Arineitwe et al., (2023). Naseem et al., (2022) synthesized xanthene-based thiazole derivatives exhibit significant inhibition of key enzymes related to diabetes management, specifically α-amylase and α-glycosidase. Among them many compounds demonstrated superior inhibitory potential with IC50 values of 56.47 nM and 61.34 nM for α-Gly, and 152.48 nM and 124.84 nM for α-Amy, respectively. These findings suggest that thiazole derivatives could serve as promising candidates for developing effective antidiabetic agents (Naseem et al., (2022).

3. METHODOLOGY

Gupta et al., (2023) in their paper primarily focuses on 2,4-thiazolidinedione derivatives containing heterocyclic rings used in managing type 2 diabetes mellitus. It discusses their synthesis, structure-activity relationships, and various therapeutic potentials, including anticancer and anti-inflammatory activities. However, it does not specifically address thiazole derivatives in diabetes management. The review emphasizes mitigating side effects of marketed TZD derivatives and presents novel TZD derivatives with enhanced therapeutic potentials, warranting further evaluation of their biological activities (Gupta et al., 2023).

Fig.1:3-(4-Methylphenyl)-2-thioxo-1,3-thiazolidin-4-one

Fig. 2: 2-[2-(Diphenylmethyl)-1H-imidazol-1-yl]-N-phenylthiazolidine-4-carboxamide

Ullah et al., (2024) in their research investigates novel thiazole derivatives derived from cholorophenyl for their potential in diabetes management namely 2-[3-(2,4-dichlorophenyl)-1-(4-phenylphenyl)-2-propen-1-ylidene]-4-thiazolidinone. These derivatives exhibited excellent α-glucosidase inhibitory activity, outperforming the standard acarbose, with IC50 values ranging from 10.21 to 18.21 μM. The study also confirmed that these compounds do not exhibit cytotoxic effects. Additionally, molecular docking studies indicated strong binding potential to the α-glucosidase active site, suggesting their promise as therapeutic agents in managing diabetes (Ullah et al.,2024).

Fig. 3: 2-[3-(2,4-dichlorophenyl)-1-(4-phenylphenyl)-2-propen-1-ylidene]-4-thiazolidinone

Maslat et al., (2024) suggested that thiazole derivatives have shown potential in diabetes management, as evidenced by a study investigating their effects on STZ-induced diabetic mice. The synthesized thiazole compound significantly reduced hyperglycemia, restored pancreatic insulin secretion, decreased serum triglyceride levels, and increased pancreatic superoxide dismutase (SOD) activity. These findings suggest that thiazole derivatives possess anti-hyperglycemic and antioxidant properties, indicating their potential as therapeutic agents in the treatment of diabetes. Further research is needed to explore their mechanisms of action (Maslat et al.,2024).

Figure 4: Thiadiazine and thiazole derivatives: (a) N-[5-(4-Bromo-phenyl)-6H-[1,3,4]- thiadiazine-2-yl]-N'-furan-2-ylmethylene-hydrazine, (b) 2-[(4-methoxy-benzylidene)-hydrazono]-4-phenyl-thiazol-3-ylamine.

Fig.5: 2,4-thiazolidinedione

Singh et al., (2024) concluded in their about thiazolidinediones (TZDs), a class of anti-diabetic agents that reduce insulin resistance and activate PPARγ. The review highlights the medicinal potential, structure-activity relationships, and safety aspects of TZD analogues such as Troglitazone, Ciglitazone, and Pioglitazone as shown in figure 6 and 7 developed over the last two decades, emphasizing their efficacy and side effects. While thiazole derivatives may be relevant, they are not the primary focus of this research (Singh et al., 2024).

Fig. 6: Troglitazone (5-[[4-[(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromen-2-yl) methoxy] phenyl]methyl]-1,3-thiazolidine-2,4-dione)

Fig. 6: Ciglitazonei (5-{4-[(1-methylcyclohexyl) methoxy] benzyl}-1,3-thiazolidine-2,4-dione)

Fig. 7: Ethyl 5-((Z)-((Z)-3-(4-fluorophenyl)-2-((4-fluorophenyl) imino)-4-oxothiazolidin-5-ylidene) methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylate.