Design, synthesis and biological evaluation of novel 5-(imidazolyl-methyl) thiazolidinediones as antidiabetic agents

• Published in: Bioorganic chemistry 2021-10, Vol.115, p.105162, Article 105162
• Main Authors: Shakour, Neda, Sahebkar, Amirhossein, Karimi, Gholamreza, Paseban, Maryam, Tasbandi, Aida, Mosaffa, Fatemeh, Tayarani-Najaran, Zahra, Ghodsi, Razieh, Hadizadeh, Farzin
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Binding Sites; Catalytic Domain; Cell Survival - drug effects; Diabetes; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - drug therapy; Drug Design; Glucose; Glucose - metabolism; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - metabolism; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Liver - drug effects; Liver - metabolism; Male; Mice; Molecular Docking Simulation; Pancreas - drug effects; Pancreas - metabolism; Pioglitazone; Pioglitazone - pharmacology; PPAR gamma - agonists; PPAR gamma - metabolism; Rats; Structure-Activity Relationship; Synthetic analogue; Thiazolidinedione; Thiazolidinediones - chemistry; Thiazolidinediones - metabolism; Thiazolidinediones - pharmacology; Thiazolidinediones - therapeutic use
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105162

[Display omitted] •Some novel TZD derivatives were synthesized and in silico studies were done for them.•Most synthesized TZDs had better anti-hyperglycemic activity versus the standard drug.•No weight gains or severe side effects on the liver and pancreas were observed for 9e.•Glucose consumption assay showed a significant glucose-lowering effect in HepG2 cells.•The qPCR analysis showed similar behavior of pioglitazone and 9e. A newly designed series of imidazolyl-methyl- l-2,4-thiazolidinediones 9 (a-m) were synthesized and In Silico studies were carried out to rationalize their anti-diabetic activity. Generally, all newly synthesized thiazolidinediones had anti-hyperglycemic activity compared with a diabetic-control group, without toxicity in 3T3 cells (viability ≥ 90%). These studies revealed that the compounds 9e and 9b (11∗10-6mol/kg) lowered blood glucose more effectively when compared to pioglitazone at the same dose. Following the administration of compound 9e, no weight gains or any serious side effects on liver and pancreas were observed. Moreover, the glucose consumption assay results showed a significant glucose-lowering effect (p