Synthesis, molecular docking and anti-diabetic evaluation of 2,4-thiazolidinedione based amide derivatives

• Published in: Bioorganic chemistry Vol. 73; pp. 24 - 36
• Main Authors: Naim, Mohd. Javed, Alam, Md. Jahangir, Nawaz, Farah, Naidu, V.G.M., Aaghaz, Shams, Sahu, Meeta, Siddiqui, Nadeem, Alam, Ozair
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.08.2017; Elsevier
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Animals; Antidiabetic; Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; Diabetes Mellitus, Experimental - drug therapy; Disease Models, Animal; Female; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Life Sciences & Biomedicine; Male; Molecular docking; Molecular Docking Simulation; Physical Sciences; PPARγ; Rats; Rats, Wistar; Science & Technology; Thiazolidinedione; Thiazolidinediones - chemical synthesis; Thiazolidinediones - chemistry; Thiazolidinediones - pharmacology; Antidiabetic; PPARγ; Thiazolidinedione; Molecular docking; ACID-DERIVATIVES; IN-VITRO; POTENT; DESIGN; SILICO; GAMMA PPAR-GAMMA; ALPHA; PPAR gamma; AGONISTS
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2017.05.007

[Display omitted] •Thiazolidinedione based amide derivatives were evaluated for antidiabetic activity.•Compound 6c appeared as the most potential antidiabetic agent.•Compound 6c alleviated the expression of PPARγ gene by 2.1 folds. A series of thiazolidinedione based amide derivatives were designed, synthesized and docked against the PPARγ receptor target. 11 compounds from the series with good glide scores were selected for in vivo antidiabetic study based on streptozotocin induced diabetic rat model. It was observed that 4 compounds (6c, 6e, 6m &6n) showed significantly good antidiabetic activity in comparison to rosiglitazone and pioglitazone as reference drugs. Compound 6c appeared as the most potent derivative in lowering blood glucose level and showed excellent interaction with SER 342, ILE 281, pi-pi interaction with ARG 288 and halogen bond interaction with LYS 367. Further, PPARγ transactivation and gene expression studies of compound 6c were carried out to investigate the possible mechanism of action through PPARγ modulation. Compound 6c exhibited 53.65% transactivation and elevated PPARγ gene expression by 2.1 folds. The biochemical parameters (AST, ALT and ALP levels) were found within the range with no noteworthy damage to liver.