Design and synthesis of a novel quinoline thiazolidinedione hybrid as a potential antidiabetic PPARγ modulator
Abstract Peroxisome proliferator-activated receptor γ (PPARγ) remains a critical target for antidiabetic drug development due to its role in glucose and lipid metabolism. However, the adverse effects associated with full agonists of the thiazolidinedione (TZD) class, such as weight gain and hepatoto...
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Nature Portfolio
2025-06-01
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| Online Access: | https://doi.org/10.1038/s41598-025-03387-9 |
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| author | Ayman M. Ibrahim Mai E. Shoman Radwa Taher Mohie el-dien Entesar Ali Saber Mahmoud Abdelnaser Sherif A. Maher Alaa M. Hayallah Mahmoud Abdul-Aziz El-Rehany Gamal El-Din A. Abuo-Rahma |
| author_facet | Ayman M. Ibrahim Mai E. Shoman Radwa Taher Mohie el-dien Entesar Ali Saber Mahmoud Abdelnaser Sherif A. Maher Alaa M. Hayallah Mahmoud Abdul-Aziz El-Rehany Gamal El-Din A. Abuo-Rahma |
| author_sort | Ayman M. Ibrahim |
| collection | DOAJ |
| description | Abstract Peroxisome proliferator-activated receptor γ (PPARγ) remains a critical target for antidiabetic drug development due to its role in glucose and lipid metabolism. However, the adverse effects associated with full agonists of the thiazolidinedione (TZD) class, such as weight gain and hepatotoxicity, limit their clinical utility. Herein, we report the design and synthesis of (Z)-5-benzylidene-3-((2-chloroquinolin-3-yl)methyl)thiazolidine-2,4-dione (compound 7), a novel TZD derivative that functions as a potential PPARγ modulator. Compound 7 reduced blood glucose level (BGL) by 22.33% after 15 days of treatment with a daily single oral dose, demonstrating an antidiabetic effect comparable to TZDs. Additionally, it elevated PPARγ expression to 75% of the activation level induced by Pioglitazone (PIO). Further characterization of its safety profile reveals that compound 7 is safer on the liver compared to PIO, as alanine transaminase (ALT) and aspartate transaminase (AST) levels remained significantly lower (147.4 ± 4.2 IU/L and 229.9 ± 2.7 IU/L, respectively). Moreover, compound 7 exerts a protective effect on hepatic and pancreatic tissues. Computational metabolic studies predict that compound 7 does not produce toxic metabolites or undergo hydrolysis of the TZD ring, contributing to its improved safety. The docking of Compound 7 into the PPARγ ligand-binding domain (LBD) demonstrates a unique binding mode, positioning it centrally within the LBD and interacting with key amino acids critical for selective modulation. These findings emphasize the potential of compound 7 as a selective PPARγ modulator to dissociate insulin-sensitizing effects from adverse side effects, offering a safer alternative to current TZD-based therapies. |
| format | Article |
| id | doaj-art-498ff2ab5b7444f797b50cee5bc4cdb2 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-498ff2ab5b7444f797b50cee5bc4cdb22025-08-20T03:22:08ZengNature PortfolioScientific Reports2045-23222025-06-0115111910.1038/s41598-025-03387-9Design and synthesis of a novel quinoline thiazolidinedione hybrid as a potential antidiabetic PPARγ modulatorAyman M. Ibrahim0Mai E. Shoman1Radwa Taher Mohie el-dien2Entesar Ali Saber3Mahmoud Abdelnaser4Sherif A. Maher5Alaa M. Hayallah6Mahmoud Abdul-Aziz El-Rehany7Gamal El-Din A. Abuo-Rahma8Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya UniversityDepartment of Medicinal Chemistry, Faculty of Pharmacy, Minia UniversityDepartment of Pharmacognosy, Faculty of Pharmacy, New Valley UniversityDepartment of Medical science, Histology and Cell Biology, Faculty of Pharmacy, Deraya UniversityDepartment of Biochemistry, Faculty of Pharmacy, Deraya UniversityDepartment of Biochemistry, Faculty of pharmacy, New Valley UniversityDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut UniversityDepartment of Biochemistry, Faculty of Pharmacy, Deraya UniversityDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya UniversityAbstract Peroxisome proliferator-activated receptor γ (PPARγ) remains a critical target for antidiabetic drug development due to its role in glucose and lipid metabolism. However, the adverse effects associated with full agonists of the thiazolidinedione (TZD) class, such as weight gain and hepatotoxicity, limit their clinical utility. Herein, we report the design and synthesis of (Z)-5-benzylidene-3-((2-chloroquinolin-3-yl)methyl)thiazolidine-2,4-dione (compound 7), a novel TZD derivative that functions as a potential PPARγ modulator. Compound 7 reduced blood glucose level (BGL) by 22.33% after 15 days of treatment with a daily single oral dose, demonstrating an antidiabetic effect comparable to TZDs. Additionally, it elevated PPARγ expression to 75% of the activation level induced by Pioglitazone (PIO). Further characterization of its safety profile reveals that compound 7 is safer on the liver compared to PIO, as alanine transaminase (ALT) and aspartate transaminase (AST) levels remained significantly lower (147.4 ± 4.2 IU/L and 229.9 ± 2.7 IU/L, respectively). Moreover, compound 7 exerts a protective effect on hepatic and pancreatic tissues. Computational metabolic studies predict that compound 7 does not produce toxic metabolites or undergo hydrolysis of the TZD ring, contributing to its improved safety. The docking of Compound 7 into the PPARγ ligand-binding domain (LBD) demonstrates a unique binding mode, positioning it centrally within the LBD and interacting with key amino acids critical for selective modulation. These findings emphasize the potential of compound 7 as a selective PPARγ modulator to dissociate insulin-sensitizing effects from adverse side effects, offering a safer alternative to current TZD-based therapies.https://doi.org/10.1038/s41598-025-03387-9QuinolineThiazolidinedionePPARγAntidiabeticSPPARMs |
| spellingShingle | Ayman M. Ibrahim Mai E. Shoman Radwa Taher Mohie el-dien Entesar Ali Saber Mahmoud Abdelnaser Sherif A. Maher Alaa M. Hayallah Mahmoud Abdul-Aziz El-Rehany Gamal El-Din A. Abuo-Rahma Design and synthesis of a novel quinoline thiazolidinedione hybrid as a potential antidiabetic PPARγ modulator Scientific Reports Quinoline Thiazolidinedione PPARγ Antidiabetic SPPARMs |
| title | Design and synthesis of a novel quinoline thiazolidinedione hybrid as a potential antidiabetic PPARγ modulator |
| title_full | Design and synthesis of a novel quinoline thiazolidinedione hybrid as a potential antidiabetic PPARγ modulator |
| title_fullStr | Design and synthesis of a novel quinoline thiazolidinedione hybrid as a potential antidiabetic PPARγ modulator |
| title_full_unstemmed | Design and synthesis of a novel quinoline thiazolidinedione hybrid as a potential antidiabetic PPARγ modulator |
| title_short | Design and synthesis of a novel quinoline thiazolidinedione hybrid as a potential antidiabetic PPARγ modulator |
| title_sort | design and synthesis of a novel quinoline thiazolidinedione hybrid as a potential antidiabetic pparγ modulator |
| topic | Quinoline Thiazolidinedione PPARγ Antidiabetic SPPARMs |
| url | https://doi.org/10.1038/s41598-025-03387-9 |
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