【摘要】 本文合成了6个芳香族、氨基酸甲酯取代的奥司他韦衍生物，以及分离纯化得到奥司他韦降解杂质4个。它们均进行了神经氨酸酶（H1N1,H3N2和耐药株H5N1-H275Y）的体外活性测试。其中，化合物4c对H1N1亚型和H5N1-H275Y突变具有明显的抑制作用(IC₅₀分别为0.31±0.16和1.40±0.93μg·mL^-1)。分子对接结果显示4c的酯基和氨基在430环入口附近与Arg118、Arg371、Tyr406和Thr439形成额外的氢键。本文所述的药物设计方法将有助于神经氨酸酶抑制剂前药的研究，化合物4c可进一步优化，为临床提供候选药物。更多还原

【Abstract】 In this paper,6 aromatic,amino acid methyl ester-substituted oseltamivir derivatives were synthesized,and 4 oseltamivir degraded impurities were isolated and purified.They were all tested for in vitro activity of neuraminidase（ H1N1,H3N2 and H5N1-H275Y mutation）.Compound 4c had a potent inhibitor to H1N1 subtype and H5N1-H275Y mutation( IC₅₀= 0. 31 ± 0. 16 and 1. 40± 0. 93 μg·m L^-1,respectively).Molecular docking revealed that the ester and amino groups of 4c could form additional hydrogen bonds with Arg118,Arg371,Tyr406 and Thr439 near the entrance of the 430-loop.The drug design method described here would be beneficial for research into prodrugs of neuraminidase inhibitors. Compound 4c might be further optimized to provide clinical drug candidates.更多还原