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Synthesis, docking, in vitro and in vivo antidiabetic activity of pyrazole‐based 2,4‐thiazolidinedione derivatives as PPAR‐γ modulators
Author(s) -
Naim Mohd. Javed,
Alam Ozair,
Alam Md. Jahangir,
Shaquiquzzaman Mohammad,
Alam Md. Mumtaz,
Naidu Vegi Ganga Modi
Publication year - 2018
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201700223
Subject(s) - rosiglitazone , pioglitazone , transactivation , thiazolidinedione , in vivo , chemistry , peroxisome proliferator activated receptor , pharmacology , docking (animal) , receptor , medicine , endocrinology , diabetes mellitus , stereochemistry , type 2 diabetes , biochemistry , biology , transcription factor , gene , microbiology and biotechnology , nursing
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.