On the basis of our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Among the synthesized compounds, 15b and 15c were exceptionally active against both group-1 and -2 NAs. Especially for 09N1, N2, N6, and N9 subtypes, they showed 6.80–12.47 and 1.20–3.94 times greater activity than oseltamivir carboxylate (OSC). They also showed greater inhibitory activity than OSC toward H274Y and E119V variant. In cellular assays, they exhibited greater potency than OSC toward H5N1, H5N2, H5N6, and H5N8 viruses. 15b demonstrated high metabolic stability, low cytotoxicity in vitro, and low acute toxicity in mice. Computational modeling and molecular dynamics studies provided insights into the role of R group of 15b in improving potency toward group-1 and -2 NAs. We believe the successful exploitation of the 150-cavity of NAs represents an important breakthrough in the development of more potent anti-influenza agents.

中文翻译：

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优化N-取代的Oseltamivir衍生物作为第1组和-2型A型流感病毒神经氨酸酶的有效抑制剂，包括抗药性变异株

根据我们较早发现的N1选择性抑制剂，可以进一步利用150腔流感病毒神经氨酸酶（NAs）来产生更有效的oseltamivir衍生物。在合成的化合物中，15b和15c对第1组和-2 NA均具有异常活性。特别是对于09N1，N2，N6和N9亚型，它们的活性是奥司他韦羧酸盐（OSC）的6.80–12.47和1.20–3.94倍。他们还显示出比OSC对H274Y和E119V变体更大的抑制活性。在细胞分析中，它们对H5N1，H5N2，H5N6和H5N8病毒显示出比OSC更高的效价。15b小鼠具有较高的代谢稳定性，较低的细胞毒性和较低的急性毒性。计算模型和分子动力学研究为15b R基团在提高对第1组和-2 NAs的效力中的作用提供了见解。我们相信成功利用150孔的NA代表着开发更有效的抗流感药物的重要突破。