A New Symmetrical Thiazolidinedione Derivative: In Silico Design, Synthesis, and In Vivo Evaluation on a Streptozotocin-Induced Rat Model of Diabetes

Abstract

By activating PPAR-γ, thiazolidinediones normalize glucose levels in animal models of type 2 diabetes and in patients with this pathology. The aim of the present study was to analyze 219 new derivatives in silico and select the best for synthesis, to be evaluated for acute oral toxicity in female rats and for control of diabetes-related parameters in a rat model of streptozotocin-induced diabetes. The best compound was chosen based on pharmacokinetic, pharmacodynamic, and toxicological parameters obtained in silico and binding orientation observed by docking simulations on PPAR-γ. Compound 1G was synthesized by a quick and easy Knoevenagel condensation. Acute oral toxicity was found at a dose greater than 2000 mg/Kg. Compound 1G apparently produces therapeutic effects similar to those of pioglitazone, decreasing glycaemia and triglyceride levels in diabetic animals, without liver damage. Moreover, it did not cause a significant weight gain and tended to reduce polydipsia and polyphagia, while diminishing systemic inflammation related to TNF-α and IL-6. It lowered the level of endogenous antioxidant molecules such as reduced glutathione and glutathione reductase. In conclusion, 1G may be a candidate for further testing as an euglycemic agent capable of preventing the complications of diabetes.

Anti-Diabetic Activity of Glycyrrhetinic Acid Derivatives FC-114 and FC-122: Scale-Up, In Silico, In Vitro, and In Vivo Studies

“…It has been observed that STZ can produce a rat model with severe weight loss [ 32 ], signs, and symptoms [ 13 , 73 , 74 , 75 , 76 , 77 ] similar to those of diabetic patients. The extent of weight loss is proportional to the dosage [ 73 , 74 , 75 , 76 ].…”

“…The same trend was observed for the other treatments (including FC-114 and FC-122), except for glibenclamide treatment. It has been observed that STZ can produce a rat model with severe weight loss [32], signs, and symptoms [13,[73][74][75][76][77] similar to those of diabetic patients. The extent of weight loss is proportional to the dosage [73][74][75][76].…”

“…We decided to start administering treatments at this point to compare their effectiveness. All treatments were given at the same equimolar dose of PIO, as previous research showed that 30 mg/kg of this drug could lower blood glucose and TAG l levels, as well as the area under the curve (AUC) during the oral glucose tolerance test (OGTT) after 14 days of administration [13]. After conducting in vivo tests and statistics analysis using ANOVA and Bonferroni multiple comparison test, it was found that 30 mg/kg of PIO significantly improved glucose blood levels in OGTT after 14 days of administration (Figure 10D) compared to untreated animals (p < 0.0001).…”

“…This is mainly due to an altered insulin signaling pathway, resulting in the decreased activity of glucose transporters (GLUT), mainly GLUT1 and GLUT4 [ 11 , 12 ]. Consequently, glucose cannot cross the plasma membrane on muscle, liver, and adipose tissue [ 13 , 14 ]. This phenomenon is also known as insulin resistance due to the body’s inability to use insulin effectively [ 10 ].…”

Development of novel thiazolidine-2,4-dione derivatives as PPAR-γ agonists through design, synthesis, computational docking, MD simulation, and comprehensive in vitro and in vivo evaluation

“…Insulin resistance in peripheral tissues such as adipose tissue, skeletal muscle, and the liver causes an inability to suppress hepatic glucose production, leading to an uptick in liver glucose release. 5 Chronic hyperglycemia occurs when glucose cannot cross the membrane due to decreased insulin secretion by β-pancreatic cells. 6 Pathogenic effects on the insulin signaling pathway lead to a decrease in the activity of phosphatidylinositol-3-kinase (PI3K) and protein kinase B (PKB), altering transmembrane glucose transport.…”