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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 (<jats:italic>Z<\/jats:italic>)-5-benzylidene-3-((2-chloroquinolin-3-yl)methyl)thiazolidine-2,4-dione (compound <jats:bold>7<\/jats:bold>), a novel TZD derivative that functions as a potential PPAR\u03b3 modulator. Compound <jats:bold>7<\/jats:bold> 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 PPAR\u03b3 expression to 75% of the activation level induced by Pioglitazone (PIO). Further characterization of its safety profile reveals that compound <jats:bold>7<\/jats:bold> is safer on the liver compared to PIO, as alanine transaminase (ALT) and aspartate transaminase (AST) levels remained significantly lower (147.4\u2009\u00b1\u20094.2 IU\/L and 229.9\u2009\u00b1\u20092.7 IU\/L, respectively). Moreover, compound <jats:bold>7<\/jats:bold> exerts a protective effect on hepatic and pancreatic tissues. Computational metabolic studies predict that compound <jats:bold>7<\/jats:bold> does not produce toxic metabolites or undergo hydrolysis of the TZD ring, contributing to its improved safety. The docking of Compound <jats:bold>7<\/jats:bold> into the PPAR\u03b3 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 <jats:bold>7<\/jats:bold> as a selective PPAR\u03b3 modulator to dissociate insulin-sensitizing effects from adverse side effects, offering a safer alternative to current TZD-based therapies.<\/jats:p>","DOI":"10.1038\/s41598-025-03387-9","type":"journal-article","created":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T10:02:33Z","timestamp":1748772153000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Design and synthesis of a novel quinoline thiazolidinedione hybrid as a potential antidiabetic PPAR\u03b3 modulator"],"prefix":"10.1038","volume":"15","author":[{"given":"Ayman M.","family":"Ibrahim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai E.","family":"Shoman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radwa Taher Mohie","family":"el-dien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Entesar Ali","family":"Saber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Abdelnaser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherif A.","family":"Maher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa M.","family":"Hayallah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud Abdul-Aziz","family":"El-Rehany","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gamal El-Din A.","family":"Abuo-Rahma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,1]]},"reference":[{"key":"3387_CR1","doi-asserted-by":"publisher","first-page":"15019","DOI":"10.1038\/nrdp.2015.19","volume":"1","author":"RA DeFronzo","year":"2015","unstructured":"DeFronzo, R. 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