Synthesis, docking,in vitroandin vivoantidiabetic activity of pyrazole‐based 2,4‐thiazolidinedione derivatives as PPAR‐γ modulators

Feb 6, 2018Archiv der Pharmazie

Design and testing of new compounds that may help control diabetes by targeting a key fat and sugar metabolism regulator

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Abstract

Eight 2,4-thiazolidinedione derivatives exhibited PPAR-γ transactivation ranging from 40.36% to 52.06%, compared to rosiglitazone's 85.30%.

Compounds 5o, 5n, and 5a demonstrated significant blood glucose lowering effects in a diabetic rat model.
The most effective compound 5o showed a 2.35-fold increase in PPAR-γ gene expression.
Compounds 5o, 5n, and 5a lowered AST, ALT, and ALP levels without causing liver damage.
Molecular docking studies indicated that the eight derivatives interacted similarly with key amino acids in PPAR-γ.
The Glide XP scores of the eight derivatives were all greater than -8, suggesting promising potential as PPAR-γ modulators.

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The design, synthesis, structure-activity relationship, and biological activity of 2,4-thiazolidinedione derivatives as peroxisome proliferator-activated receptor-γ (PPAR-γ) modulators for antidiabetic activity are reported. Fifteen 2,4-thiazolidinedione derivatives clubbed with pyrazole moiety were docked into the ligand binding domain of PPAR-γ by the Glide XP module of Schrodinger. Eight derivatives (5a, 5b, 5d, 5f, 5i, 5l, 5n, 5o) having Glide XP scores > -8 as compared to the standard drug, rosiglitazone (Glide XP score = -9.165), showed almost similar interaction with the amino acids such as HIS 449, TYR 473, TYR 327, HIS 323, and SER 289 in the molecular docking studies. These eight derivatives were further screened for PPAR-γ transactivation and in vivo blood glucose lowering activity in the streptozotocin-induced diabetic rat model. Compounds 5o, 5n, 5a, 5i, and 5b showed 52.06, 51.30, 48.65, 43.13, and 40.36% PPAR-γ transactivation as compared to the reference drugs rosiglitazone and pioglitazone with 85.30 and 65.22% transactivation, respectively. The data analysis showed significant blood glucose lowering effects (hypoglycemia) of compounds 5o, 5n, and 5a (140.1 ± 4.36, 141.4 ± 6.15, and 150.7 ± 4.15, respectively), along with reference drugs pioglitazone (135.2 ± 4.91) and rosiglitazone (141.1 ± 5.88) as compared to the diabetic control. Furthermore, the most potent compound 5o also elevated the PPAR-γ gene expression by 2.35-fold as compared to rosiglitazone (1.27-fold) and pioglitazone (1.6-fold). It also significantly lowered the AST, ALT, and ALP levels and caused no damage to the liver.

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Synthesis, docking,in vitroandin vivoantidiabetic activity of pyrazole‐based 2,4‐thiazolidinedione derivatives as PPAR‐γ modulators

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