Abstract：
The present study aims to discover novel derivatives as antiapoptotic agents and their protective effects against renal ischemia/reperfusion. Therefore, a series of new thiadiazole analogues 2a-g was designed and synthesized through cyclization of the corresponding opened hydrazinecarbothioamides 1a-g, followed by confirmation of the structure via spectroscopic tools (NMR, IR and mass spectra) and elemental analyses. The antiapoptotic activity showed alongside decreasing of tissue damage induced by I/R in the kidneys of rats using N-acetylcysteine (NAC) as an antiapoptotic reference. Most of the cyclized thiadiazoles are better antiapoptotic agents than their corresponding opened precursors. Particularly, compounds 2c and 2g were the most active antiapoptotic compounds with significant biomarkers. A preliminary mechanistic study was performed through caspase-3 inhibition. Compound 2c was selected along with its corresponding opened precursor 1c. An assay of cytochrome C revealed that there is an attenuation of cytochrome C level of about 5.5-fold, which was better than 1c with a level of 4.1-fold. In caspases-3, 8 and 9 assays, compound 2c showed more potency and selectivity toward caspase-3 and 9 compared with 1c. The renal histopathological investigation indicated normal renal tissue for most of the compounds, especially 2c and 2g, relative to the control. Finally, a molecular docking study was conducted at the caspase-3 active site to suggest possible binding modes.
摘要：
本研究旨在发现作为抗凋亡剂的新型衍生物及其对肾脏缺血/再灌注的保护作用。因此,设计并合成了一系列新的噻二唑类似物2a-g,然后通过光谱工具确认结构(NMR，IR和质谱）和元素分析。使用N-乙酰半胱氨酸（NAC）作为抗凋亡参考，抗凋亡活性显示出大鼠肾脏中I/R诱导的组织损伤的减少。大多数环化噻二唑是比其相应的开放前体更好的抗凋亡剂。特别是,化合物2c和2g是最具活性的抗凋亡化合物,具有显著的生物标志物。通过caspase-3抑制进行了初步的机理研究。选择化合物2c及其相应的打开的前体1c。细胞色素C的测定显示细胞色素C水平衰减约5.5倍，优于1c，水平为4.1倍。在caspases-3、8和9测定中，与1c相比，化合物2c对caspase-3和9显示出更高的效力和选择性。肾组织病理学检查表明大多数化合物的肾组织正常，尤其是2c和2g，相对于控制。最后,在caspase-3活性位点进行了分子对接研究,以提示可能的结合模式.
