Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University , 44, West Culture Road, Jinan, Shandong 250012, P. R. China.
J Med Chem. 2014 Oct 23;57(20):8445-58. doi: 10.1021/jm500892k. Epub 2014 Oct 8.
To discover group-1-specific neuraminidase (NA) inhibitors that are especially involved in combating the H5N1 virus, two series of oseltamivir derivatives were designed and synthesized by targeting the 150-cavity. Among these, compound 20l was the most potent N1-selective inhibitor, with IC50 values of 0.0019, 0.0038, and 0.0067 μM against NAs from three H5N1 viruses. These values are better than those of oseltamivir carboxylate. Compound 32 was another potent N1-selective inhibitor that exhibited a 12-fold increase in activity against the H274Y mutant relative to oseltamivir carboxylate. Molecular docking studies revealed that the 150-cavity was an auxiliary binding site that may contribute to the high selectivity of these compounds. The present work is a significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors, which may be further investigated for the treatment of infection by the H5N1 virus.
为了发现特别针对 H5N1 病毒的具有群组 1 特异性的神经氨酸酶 (NA) 抑制剂，我们通过靶向 150 腔设计并合成了两个系列的奥司他韦衍生物。在这些化合物中，化合物 20l 是最有效的 N1 选择性抑制剂，对来自三种 H5N1 病毒的 NAs 的 IC50 值分别为 0.0019、0.0038 和 0.0067 μM，优于奥司他韦羧酸酯。化合物 32 是另一种强效的 N1 选择性抑制剂，其对 H274Y 突变体的活性相对于奥司他韦羧酸酯提高了 12 倍。分子对接研究表明，150 腔是一个辅助结合位点，可能有助于这些化合物的高选择性。本工作在发现强效的群组 1 特异性神经氨酸酶抑制剂方面取得了重大突破，可能会进一步研究用于治疗 H5N1 病毒感染。
