In diabetes, hyperglycemia is the defining characteristic. Type 1 diabetes, in which pancreatic beta cells are destroyed, results in an absolute deficiency of insulin; and type 2 diabetes, in which insulin resistance can lead to hyperglycemia 1. Diabetes type 2 is associated with obesity and is on the rise 2. As well as obesity, research has revealed that a form of diabetes mellitus known as "lean diabetes mellitus" results from fundamental defects in insulin secretion, that is primarily triggered by a dysfunctional pancreas 3. It is a major public health problem to have type-2 diabetes mellitus (T2DM). By 2045, 629 million people are predicted to have diabetes, up from 425 million in 2017 4. The presence of T2DM also puts the individual at risk for cardiovascular diseases, which are among the leading causes of death and disability worldwide and fatalities in the world today 5. In addition, the economic burden of T2DM contributes to approximately 12% of global health expenditures related to diabetic treatment and complications 4. Clinical and epidemiologic research performed within the last two decades has led to the recognition that heart failure contributes significantly to cardiovascular morbidity and mortality in diabetes patients, in addition to myocardial infarction and other atherosclerosis-related cardiovascular events. Myocardial dysfunction has been reported in some diabetic patients in the absence of coronary artery disease, valve disease, and the consequences of related cardiovascular risk factors 6.

Hyperglycemia can be effectively controlled with hypoglycemic agents which exert clinical effects via different mechanisms like in the liver biguanides like metformin reduce gluconeogenesis, sulfonylureas stimulate the pancreas to secrete insulin, thialzolidinediones improves sensitivity of peripheral tissues to insulin, and in the form of recombinant insulin, insulin or its analogues can be provided exogenously 7. However, despite the availability of a number of diabetic drugs, other drug monotherapies failed to manage blood glucose levels and other comorbidities satisfactorily and, as a result; therapeutic management is often achieved by pairing drugs with distinct mechanisms of action 8. Yet they are known to cause side effects, such as hypoglycemia and gastrointestinal problems. Therefore, it is crucial to develop alternatives that reduce the complications of diabetes while reducing the side effects. It is therefore imperative to develop substitutes that reduce the complications of diabetes while also causing fewer side effects. Pyridazinones have six members heterocyclic compounds, and their nitrogen atoms are located adjacently. Pyridazine-3-one refers to a pyridazine ring bearing a carbonyl group at the third carbon and has often been highlighted as a privileged scaffold due to its wide range of biological activities. The pyridazine nucleus serves as a foundation for creating new pharmacologically active molecules. Among diazines—a family of nitrogen-containing heterocyclic compounds—pyridazine, pyrimidine, and pyrazine are notable representatives. These compounds are stable, colorless, and possess good water solubility 9, 10. Pyridazinones, in particular, have long been recognized for exhibiting numerous pharmacological effects shown in Figure 1.

Notably, specific pyridazinone derivatives have displayed potent antihyperglycemic effects and have been shown to inhibit aldose reductase in oral glucose tolerance tests conducted in normal rats as well as in enzyme assays 19.

Likewise, benzoxazole derivatives are also highly valued in medicinal chemistry, owing to their broad spectrum of pharmacological activities. The benzoxazole scaffold forms the core structure for various bioactive molecules and can be chemically modified to yield compounds with novel therapeutic properties. Research in this area has identified numerous benzoxazole analogues with significant pharmaceutical potential, functioning as antibacterial and antifungal agents, inhibitors of HIV-1 reverse transcriptase, topoisomerase-I inhibitors, anticancer drugs, and as antidiabetic agents 20, 21, 22, 23, 24, among others. Due to their complementary bioactivities, integrating a benzoxazole moiety with a pyridazinone core may enhance or unveil new antidiabetic capabilities in the resulting hybrid molecules. Therefore, the test compound—identified as novel pyridazinone derivative 1-(5-chloro-1,3-benzoxazol-2-yl)-4-methyl-1,2-dihydropyridazine-3,6-dione—is hypothesized to possess antidiabetic properties. The current study is designed to evaluate the antidiabetic efficacy of this newly synthesized pyridazinone derivative in a rat model of alloxan-induced diabetes.

1-(5-chloro-1,3-benzoxazol-2-yl)-4-methyl-1,2-dihydropyridazine-3,6-dione synthesised according to the standard procedure 25.

Table 1  presents data on the initial and final blood glucose levels as well as changes in body weight across the various groups of normal and experimental rats. Diabetic control rats (Group 2) exhibited a marked reduction in mean body weight compared to the normal control group. Treatment of diabetic rats with the novel pyridazinone derivative at both 30 mg/kg and 60 mg/kg doses resulted in an increase in body weight, though this change was not statistically significant relative to the normal controls.

Fasting blood glucose was found to be significantly elevated in diabetic animals (222.35 ± 5.10 mg/dl) compared to the normal control group. Administration of the novel pyridazinone derivative at both tested dosages (30 mg/kg and 60 mg/kg, intraperitoneally) effectively reduced fasting blood glucose levels, bringing them closer to those observed in normal animals.

Table 2  summarizes the results for total haemoglobin, glycosylated haemoglobin, and plasma insulin in the different groups. In diabetic rats, there was a significant decrease in total haemoglobin and plasma insulin, while glycosylated haemoglobin levels were markedly increased when compared to the normal controls. Treatment with the pyridazinone derivative at 30 mg/kg and 60 mg/kg doses restored the levels of total haemoglobin, glycosylated haemoglobin, and plasma insulin towards normal values in diabetic rats.

Diabetes mellitus, encompassing a group of metabolic disorders, is primarily distinguished by chronic hyperglycemia resulting from inadequate insulin secretion or impaired insulin function. Clinically, diabetes is categorized into two main types: type 1 and type 2. The alloxan-induced diabetic rat model utilized in this study replicates characteristics of type 1 diabetes, including an autoimmune-like destruction of pancreatic β-cells. This progressive β-cell loss mirrors the gradual decline in early-phase insulin secretion, ultimately culminating in reduced insulin availability and elevated blood glucose levels 30.

In this research, male albino Wistar rats, each weighing between 180 and 220 grams, were employed. Diabetes was established via a single intraperitoneal injection of freshly prepared alloxan at a dose of 150 mg/kg body weight, which effectively induced significant hyperglycemia. Post-induction, diabetic animals received intraperitoneal administrations of the novel pyridazinone derivative at varying dosages for 28 consecutive days. At the start and conclusion of the treatment period, key parameters including blood glucose, body weight, total haemoglobin, glycosylated haemoglobin, and plasma insulin were recorded and evaluated in both control and experimental groups.

Alloxan is known to cause extensive destruction of pancreatic β-cells within the islets of Langerhans, leading to a substantial reduction in insulin secretion 31, 32. In this study, treatment of alloxan-induced diabetic rats with the pyridazinone derivative at both 30 mg/kg and 60 mg/kg doses resulted in a notable elevation in plasma insulin levels. This effect may be attributed to an enhancement of insulin secretion from residual β-cells or the facilitation of insulin release from existing stores.

In uncontrolled diabetes, an increase in glycation of various proteins, including haemoglobin and α-crystallin in the lens, has been documented 33. Glycosylated haemoglobin (HbA1c) is frequently elevated in diabetic individuals, sometimes reaching values close to 16% 34, and this rise is closely linked to current fasting blood glucose levels 35. During diabetes, the surplus glucose in the bloodstream reacts with haemoglobin, leading to reduced levels of total haemoglobin in alloxan-treated rats 36.

Administration of the test pyridazinone derivative at 30 mg/kg and 60 mg/kg over 28 days effectively prevented a significant increase in glycosylated haemoglobin and supported the restoration of total haemoglobin levels. This suggests that the compound contributed to improved glycemic regulation.

Additionally, a decline in body weight was observed in rats following induction of diabetes with alloxan. Treatment with the novel pyridazinone derivative at both administered doses attenuated the loss of body weight seen in diabetic rats. The ability of the compound to mitigate substantial weight reduction is likely related to its pronounced antihyperglycemic action, contributing to an improved metabolic state.

In summary, evaluation of the novel pyridazinone derivative in an alloxan-induced diabetic model using male Wistar rats demonstrated that administration of the compound at doses of 30 mg/kg and 60 mg/kg led to a modest, non-significant improvement in body weight compared to healthy controls. Diabetic rats showed a marked elevation in fasting blood glucose levels (222.35 ± 5.10 mg/dl) relative to non-diabetic animals. Furthermore, significant reductions in total haemoglobin and plasma insulin were observed, alongside a notable increase in glycosylated haemoglobin when compared to normal controls.