A new symmetrical thiazolidinedione derivative: In silico design, synthesis, and in vivo evaluation on a streptozotocin-induced rat model of diabetes

Samuel Álvarez-Almazán, Gabriel Navarrete-Vázquez, Itzia Irene Padilla-Martínez, José Correa-Basurto, Diana Alemán-González-duhart, Feliciano Tamay-Cach, Jessica Elena Mendieta-Wejebe

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish
Article number1294
JournalProcesses
Volume9
Issue number8
DOIs
StatePublished - Aug 2021

Keywords

  • Acute oral toxicity
  • Diabetes model
  • In silico study
  • Knoevenagel condensation
  • Pioglitazone
  • Streptozotocin
  • Thiazolidinedione

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