TY - JOUR
T1 - A new symmetrical thiazolidinedione derivative
T2 - In silico design, synthesis, and in vivo evaluation on a streptozotocin-induced rat model of diabetes
AU - Álvarez-Almazán, Samuel
AU - Navarrete-Vázquez, Gabriel
AU - Padilla-Martínez, Itzia Irene
AU - Correa-Basurto, José
AU - Alemán-González-duhart, Diana
AU - Tamay-Cach, Feliciano
AU - Mendieta-Wejebe, Jessica Elena
N1 - Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
KW - Acute oral toxicity
KW - Diabetes model
KW - In silico study
KW - Knoevenagel condensation
KW - Pioglitazone
KW - Streptozotocin
KW - Thiazolidinedione
UR - http://www.scopus.com/inward/record.url?scp=85111623596&partnerID=8YFLogxK
U2 - 10.3390/pr9081294
DO - 10.3390/pr9081294
M3 - Artículo
AN - SCOPUS:85111623596
SN - 2227-9717
VL - 9
JO - Processes
JF - Processes
IS - 8
M1 - 1294
ER -