Assessment of anti-hyperglycemic and anti-hyperlipidemic effects of thiazolidine-2,4-dione derivatives in HFD-STZ diabetic animal model.

Type 2 diabetes mellitus (T2DM) is a chronic endocrine/metabolic disorder characterized by elevated postprandial and fasting glycemic levels that result in disturbances in primary metabolism. In this study, we evaluated the metabolic effects of thiazolidine-2,4-dione derivatives in Wistar rats and Swiss mice that were fed a high-fat diet (HFD) for 4 weeks and received 90 mg/kg of streptozotocin (STZ) intraperitoneally as a T2DM model. The HFD consisted of 17% carbohydrate, 58% fat, and 25% protein, as a percentage of total kcal. The thiazolidine-2,4-dione derivatives treatments reduced fasting blood glucose (FBG) levels by an average of 23.98%-50.84%, which were also improved during the oral starch tolerance test (OSTT). Treatment with thiazolidine-2,4-dione derivatives also improved triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), and total cholesterol levels (P < 0.05). The treatment intake has also shown a significant effect to modulate the altered hepatic and renal biomarkers. Further treatment with thiazolidine-2,4-dione derivatives for 28 days significantly ameliorated changes in appearance and metabolic risk factors, including favorable changes in histopathology of the liver, kidney, and pancreas compared with the HFD/STZ-treated group, suggesting its potential role in the management of diabetes. Thiazolidine-2,4-dione derivatives are a class of drugs that act as insulin sensitizers by activating peroxisome proliferator-activated receptor-gamma (PPAR-γ), a nuclear receptor that regulates glucose and lipid metabolism. The results of this study suggest that thiazolidine-2,4-dione derivatives may be a promising treatment option for T2DM by improving glycemic control, lipid metabolism, and renal and hepatic function.

Biological, toxicological and molecular docking evaluations of isoxazoline-thiazolidine-2,4-dione analogues as new class of anti-hyperglycemic agents.

In this work, three isoxazoline-thiazolidine-2,4-dione derivatives were synthesized and characterized by FT-IR, 1H-NMR, 13C-NMR and ESI-MS spectrometry. All compounds have been investigated for their α-amylase and α-glucosidase inhibitory activities. In vitro enzymatic evaluation revealed that all compounds were inhibitory potent against α-glucosidase with IC50 values varied from 40.67 ± 1.81 to 92.54 ± 0.43 µM, and α-amylase with IC50 in the range of 07.01 ± 0.02 to 75.10 ± 1.06 µM. One of the tested compounds were found to be more potent inhibitor compared to other compounds and standard drug Acarbose (IC50 glucosidase= 97.12 ± 0.35 µM and IC50 amylase= 2.97 ± 0.01 µM). All compounds were then evaluated for their acute toxicity in vivo and shown their safety at a high dose with LD > 2000mg/kg BW. A cell-based toxicity evaluation was performed to determine the safety of compounds on liver cells, using the MTT assay against HepG2 cells, and the results shown that all compounds have non-toxic impact against cell viability and proliferation compared to reference drug (Pioglitazone). Furthermore, the molecular homology analysis, SAR and the molecular binding properties of compound with the active site of α-amylase and α-glucosidase were confirmed through computational analysis. This study has identified the inhibitory potential of a new class of synthesized isoxazoline-thiazolidine-2,4-dione derivatives in controlling both hyperglycemia and type 2 diabetes mellitus without any hepatic toxicity.Communicated by Ramaswamy H. Sarma.

Synthesis, α-glucosidase and α-amylase inhibitory activities, acute toxicity and molecular docking studies of thiazolidine-2,4-diones derivatives.

In the present study, a series of thiazolidine-2,4-diones derivatives (3a-3e) and (4a-4e) were synthesized and characterized by 1H NMR, 13C NMR and ESI-MS spectrometry. All compounds were screened for their α-glucosidase and α-amylase inhibitory activities. In vitro biological investigations revealed that most of compounds were active against α-glucosidase with IC50 values in the range of 43.85 ± 1.06 to 380.10 ± 1.02 µM, and α-amylase with IC50 in the range of 18.19 ± 0.11 to 208.10 ± 1.80 µM. Some of the tested compounds were found to be more potent inhibitors than the clinical drug Acarbose (IC50glucosidase = 97.12 ± 0.35 µM and IC50amylase = 2.97 ± 0.004 µM). The lead compounds were evaluated for their acute toxicity on Swiss mice and found to be completely non-toxic with LD > 2000 mg/kg BW. Furthermore, the Structure-activity relationship (SAR) and the binding interactions of all compounds with the active site of α-glucosidase and α-amylase were confirmed through molecular docking and stabilizing energy calculations. This study has identified the inhibitory potential a new class of synthesized thiazolidine-2,4-diones in controlling both hyperglycemia and type 2 diabetes mellitus. Furthermore, the theoretical binding mode of the target molecules was evaluated by molecular docking studies against the 3D Crystal Structure of human pancreatic α-amylase (PDB ID: 1B2Y) and α-glucosidase (PDB ID: 3W37)Communicated by Ramaswamy H. Sarma.

Ultrasound-assisted one-pot green synthesis of new N- substituted-5-arylidene-thiazolidine-2,4-dione-isoxazoline derivatives using NaCl/Oxone/Na3PO4 in aqueous media.

A rapid and green method for the synthesis of novel N-thiazolidine-2,4-dione isoxazoline derivatives 5 from N-allyl-5-arylidenethiazolidine-2,4-diones 3 as dipolarophiles with arylnitrile oxides via 1,3-dipolar cycloaddition reaction. The corresponding N-allyl substituted dipolarophiles were prepared by one-pot method from thiazolidine-2,4-dione with aldehydes using Knoevenagel condensation followed by N-allylation of thiazolidine-2,4-dione in NaOH aqueous solution under sonication. In addition, the isoxazoline derivatives 5 were synthesized by regioselective and chemoselective 1,3-dipolar cycloaddition using inexpensive and mild NaCl/Oxone/Na3PO4 as a Cl source, oxidant and/or catalyst under ultrasonic irradiation in EtOH/H2O (v/v, 2:1) as green solvent. All synthesized products are furnished in good yields in the short reaction time, and then their structures were confirmed by NMR, mass spectrometry and X-ray crystallography analysis.