Synthesis, Characterization, and Preclinical Evaluation of New Thiazolidin-4-ones Substituted with p-Chlorophenoxy Acetic Acid and Clofibric Acid against Insulin Resistance and Metabolic Disorder

Abstract

We synthesized twenty thiazolidin-4-one derivatives, which were then characterized by standard chromatographic and spectroscopic methods. From the in vitro glucose uptake assay, two compounds behaved as insulin sensitizers, where they enhanced glucose uptake in isolated rat diaphragm. In high-carbohydrate diet-induced insulin resistant mice, these two thiazolidin-4-ones attenuated hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and glucose intolerance. They raised the plasma leptin but did not reverse the diabetes-induced hypoadiponectinemia. Additionally, compound 3a reduced adiposity. The test compounds were also able to reverse the disturbed liver antioxidant milieu. To conclude, these two novel thiazolidin-4-ones modulated multiple mechanisms involved in metabolic disorders, reversing insulin resistance and thus preventing the development of type-2 diabetes.

Exercise Ameliorates Insulin Resistance of Type 2 Diabetes through Motivating Short-Chain Fatty Acid-Mediated Skeletal Muscle Cell Autophagy

“…Consistent with a previous report, our study also revealed that exercise upregulated the reduction of total plasma SCFAs in DM mice. Previous evidence has shown that acetic acid improves muscle glucose uptake, reduces hyperglycemia in diabetic mice and its derivatives are confirmed to treat IR and T2DM [54,55]. Of note, the changes we presented in total plasma SCFAs were mainly highlighted in plasma acetic acid.…”

Dose‐related antihyperglycemic and hypolipidemic effects of two novel thiazolidin‐4‐ones in a rodent model of metabolic syndrome

“…In the present study, combined administration of MSG and HSu clearly induced MetS, characterized by increased body weight, hyperglycemia, hypertriglyceridemia, and glucose intolerance, along with significant hypoalphalipoproteinemia. Further, the model used in the present study exhibited early body weight gain compared with previously reported models of MSG or a high‐calorie diet alone. Male rats had greater weight gain (from Week 6 onwards) than female rats (from Week 17 onwards).…”

“…Earlier work in our laboratory demonstrated the antidiabetic and hypolipidemic effects of thiazolidin‐4‐one derivatives (100 mg/kg doses) possessing a nicotinamide (NAT1) or p ‐chlorophenoxyacetamide (PAT1) substitution at the N3 position of the thiazolidinone ring (Fig. ).…”

Efficacy of a Novel Therapeutic, Based on Natural Ingredients and Probiotics, in a Murine Model of Multiple Food Intolerance and Maldigestion

“…In the HCD study, blood was collected from the tail vein of each mouse and subsequently centrifuged for 10 min, at 3000× g , 4 °C; plasma was stored at −20 °C for assay of insulin and glucose levels as previously reported [ 27 , 33 ]. Plasma glucose was measured spectrophotometrically using commercially available colorimetric kits (Aspen Laboratories Pvt.…”