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Synthesis of novel norsufentanil analogs via a four‐component Ugi reaction and in vivo, docking, and QSAR studies of their analgesic activity
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2018-01-23 , DOI: 10.1111/cbdd.13157
Majid Nami 1 , Peyman Salehi 2 , Minoo Dabiri 1 , Morteza Bararjanian 2 , Sajjad Gharaghani 3 , Mona Khoramjouy 4 , Ahmed Al-Harrasi 5 , Mehrdad Faizi 4
Affiliation  

Novel substituted amino acid tethered norsufentanil derivatives were synthesized by the four‐component Ugi reaction. Norsufentanil was reacted with succinic anhydride to produce the corresponding carboxylic acid. The resulting carboxylic acid has undergone a multicomponent reaction with different aldehydes, amines, and isocyanides to produce a library of the desired compounds. In all cases, amide bond rotation was observed in the NMR spectra. In vivo analgesic activity of the synthesized compounds was evaluated by a tail flick test. Very encouraging results were obtained for a number of the synthesized products. Some of the synthesized compounds such as 5a, 5b, 5h, 5j, and 5r were found to be more potent than sufentanil, sufentanil citrate, and norsufentanil. Binding modes between the compounds and mu and delta‐opioid receptors were studied by molecular docking method. The relationship between the molecular structural features and the analgesic activity was investigated by a quantitative structure–activity relationship model. The results of the molecular modeling studies and the in vivo analgesic activity suggested that the majority of the synthesized compounds were more potent than sufentanil and norsufentanil.

中文翻译:

通过四组分Ugi反应以及其镇痛活性的体内,对接和QSAR研究合成新型诺舒芬太尼类似物

通过四组分Ugi反应合成了新型取代的氨基酸束缚的去甲芬太尼衍生物。使去甲芬太尼与琥珀酸酐反应以产生相应的羧酸。所得的羧酸已与不同的醛,胺和异氰酸酯进行了多组分反应,以生成所需化合物的文库。在所有情况下,在NMR光谱中观察到酰胺键旋转。通过甩尾试验评估合成的化合物的体内止痛活性。许多合成产物获得了非常令人鼓舞的结果。一些合成的化合物,例如5a5b5h5j5r被发现比舒芬太尼,柠檬酸舒芬太尼和去甲芬太尼更有效。通过分子对接方法研究了化合物与mu和δ阿片受体之间的结合方式。通过定量结构-活性关系模型研究了分子结构特征与镇痛活性之间的关系。分子模型研究和体内止痛活性的结果表明,大多数合成的化合物比舒芬太尼和去甲芬太尼更有效。
更新日期:2018-01-23
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