Design, Synthesis, and Biological Evaluation of Thiazolidine‐2,4‐dione Conjugates as PPAR‐γ Agonists

Nazreen, Syed; Alam, Mohammad Sarwar; Hamid, Hinna; Yar, Mohammad Shahar; Dhulap, Abhijeet; Alam, Perwez; Pasha, M. A. Qadar; Bano, Sameena; Alam, Mohammad Mahboob; Haider, Saqlain; Kharbanda, Chetna; Ali, Yakub; Pillai, K. K.

doi:10.1002/ardp.201400280

Cited by 19 publications

(14 citation statements)

References 30 publications

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“…2,4-Thiazolidinedione is the basic molecular compound for the chemical synthesis of all thiazolidinedione molecules known to be specific and potent PPAR γ agonists, including rosiglitazone and pioglitazone [70, 71]. Because of this, 2,4-thiazolidinedione was assumed to be a PPAR γ agonist; however, to our knowledge, it has not been proved that 2,4-TZD is a PPAR γ agonist.…”

Section: Discussionmentioning

confidence: 99%

2,4-Thiazolidinedione Treatment Improves the Innate Immune Response in Dairy Goats with Induced Subclinical Mastitis

et al. 2017

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Mastitis is a major disease in dairy cows resulting in significant economic losses. In vitro works suggest that ruminants peroxisome proliferator-activated receptor gamma (PPARγ) can aid in improving the response to mastitis and can control milk fat synthesis. The objectives of the present experiment were to test if treatment with the putative PPARγ agonist 2,4-thiazolidinedione (TZD) improves (1) the response to subclinical mastitis and (2) milk fat production. Lactating goats received daily injections of 8 mg/kg BW of TZD or saline for 3 weeks. After one week of TZD injection, half of the goats in each group received intramammary infusion of Strep. uberis or saline in both halves for a total of 4 groups (n = 6/group). TZD treatment did not affect milk fat but had positive effect on milk somatic cells count, blood nonesterified fatty acids, inflammatory markers, and liver function. TZD significantly increased myeloperoxidase but did not affect leukocytes phagocytosis or insulin. TZD increased adipocytes size and had minor effect on expression of PPARγ target genes in mammary epithelial cells but not in adipose tissue. Overall, TZD ameliorated the response to intramammary infection but the effect on milk fat synthesis and expression of related transcripts was less than expected.

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Section: Discussionmentioning

confidence: 99%

2,4-Thiazolidinedione Treatment Improves the Innate Immune Response in Dairy Goats with Induced Subclinical Mastitis

et al. 2017

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“…The crucial role of PPARγ in lipid metabolism, adipogenesis, glucose homeostasis, and insulin sensitization is well documented . PPARγ agonists, such as thiazolidinediones, including the widely used drug rosiglitazone, have been used in clinical practice to treat diabetes for several years and have been shown to lower blood glucose levels and improve insulin sensitivity …”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Structure–Activity Relationships of Bavachinin Analogues as Peroxisome Proliferator‐Activated Receptor γ Agonists

Zhao

et al. 2016

ChemMedChem

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Peroxisome proliferator‐activated receptor γ (PPARγ) agonists have been used for the treatment of diabetes with the effect of lowering blood glucose levels and improving insulin sensitivity. Natural compounds such as flavones, flavanones, and isoflavones have shown excellent PPARγ agonist activity. In this study, analogues of bavachinin were designed, synthesized, and evaluated by reporter gene assays for PPARγ agonist activity. Preliminary structure–activity relationships for these bavachinin analogues have been summarized, and seven compounds were found to have higher PPARγ agonist activities than the parent flavanone bavachinin.

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“…No significant body weight change was observed in 5o ‐treated normal rats and normal control rats. However, diabetic rats showed significant improvement in weight gain which is shown in Figure …”

Section: Resultsmentioning

confidence: 95%

“…Diabetes has reached an epidemic level by becoming a major health issue round the globe . Peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) agonists have come up with a leading role as an orally effective antidiabetic agent . Diabetes or diabetes mellitus is a multifactorial metabolic disease/polygenic disorder characterized by increased glucose levels/insulin resistance over prolonged periods in liver and peripheral tissues .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, docking, in vitro and in vivo antidiabetic activity of pyrazole‐based 2,4‐thiazolidinedione derivatives as PPAR‐γ modulators

Naim

Alam

et al. 2018

Archiv der Pharmazie

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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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Design, Synthesis, and Biological Evaluation of Thiazolidine‐2,4‐dione Conjugates as PPAR‐γ Agonists

Cited by 19 publications

References 30 publications

2,4-Thiazolidinedione Treatment Improves the Innate Immune Response in Dairy Goats with Induced Subclinical Mastitis

2,4-Thiazolidinedione Treatment Improves the Innate Immune Response in Dairy Goats with Induced Subclinical Mastitis

Design, Synthesis, and Structure–Activity Relationships of Bavachinin Analogues as Peroxisome Proliferator‐Activated Receptor γ Agonists

Synthesis, docking, in vitro and in vivo antidiabetic activity of pyrazole‐based 2,4‐thiazolidinedione derivatives as PPAR‐γ modulators

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