基于 2,4-噻唑烷二酮的酰胺衍生物的合成、分子对接和抗糖尿病评价。
Synthesis, molecular docking and anti-diabetic evaluation of 2,4-thiazolidinedione based amide derivatives.
机构信息
Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hyderabad 500037, India.
出版信息
Bioorg Chem. 2017 Aug;73:24-36. doi: 10.1016/j.bioorg.2017.05.007. Epub 2017 May 6.
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.
设计、合成并对接了一系列噻唑烷二酮基酰胺衍生物，以 PPARγ 受体为靶点。根据链脲佐菌素诱导的糖尿病大鼠模型，从该系列中选择了具有良好滑行分数的 11 种化合物进行体内抗糖尿病研究。结果表明，与罗格列酮和吡格列酮作为参比药物相比，有 4 种化合物（6c、6e、6m 和 6n）表现出显著的抗糖尿病活性。化合物 6c 是降低血糖水平最有效的衍生物，与 SER 342、ILE 281 具有良好的相互作用，与 ARG 288 存在 π-π 相互作用，与 LYS 367 存在卤键相互作用。此外，还进行了化合物 6c 的 PPARγ 转录激活和基因表达研究，以通过 PPARγ 调节来研究其可能的作用机制。化合物 6c 表现出 53.65%的转录激活作用，并将 PPARγ 基因表达水平提高了 2.1 倍。生化参数（AST、ALT 和 ALP 水平）均在正常范围内，对肝脏无明显损害。
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