The Second Hospital of Shandong University, No. 247 Beiyuan Avenue, 250033, Jinan, Shandong, PR China.
Department of Pharmacy, Faculty of Health Science, American University of Madaba, P.O Box 2882, Amman, 11821, Jordan.
Eur J Med Chem. 2020 Apr 1;191:112147. doi: 10.1016/j.ejmech.2020.112147. Epub 2020 Feb 15.
From our research group, it was noticed that oseltamivir derivatives targeting 150-cavity of neuraminidase enzyme (NA) could significantly increase antiviral activity. Thus, we further enriched the C5-NH position of oseltamivir structure to obtain more potent oseltamivir derivatives. In this article a series of oseltamivir derivatives were synthesized by modifying C5-NH position of oseltamivir. All the compounds were evaluated for in vitro antiviral activity against H5N1 and H5N8. Encouragingly, compounds 9a and 11e were exhibited prominent activity, which is similar to oseltamivir carboxylate (OSC) and in NAs inhibitory assay, 11e showed remarkable potency against N1 (H5N1), N2 (H5N2), N6 (H5N6) and N8 (H5N8). In addition, 11e demonstrated low cytotoxicity and no obvious toxicity at the dose of 1500 mg/kg in mice. Molecular docking studies of 9a and 11e provided a plausible rationale for the high potency against group-1 NAs. This work provided new insights to design further neuraminidase inhibitors, which can help to investigate new potent inhibitors for group-1 and group-2 shortly.
从我们的研究小组中注意到，针对神经氨酸酶（NA）150 腔的奥司他韦衍生物可以显著提高抗病毒活性。因此，我们进一步丰富了奥司他韦结构的 C5-NH 位置，以获得更有效的奥司他韦衍生物。在本文中，通过修饰奥司他韦的 C5-NH 位置合成了一系列奥司他韦衍生物。所有化合物均针对 H5N1 和 H5N8 进行了体外抗病毒活性评估。令人鼓舞的是，化合物 9a 和 11e 表现出突出的活性，与奥司他韦羧酸盐（OSC）相似，在 NA 抑制试验中，11e 对 N1（H5N1）、N2（H5N2）、N6（H5N6）和 N8（H5N8）显示出显著的效力。此外，在 1500mg/kg 剂量下，11e 在小鼠中表现出低细胞毒性和无明显毒性。9a 和 11e 的分子对接研究为其对 1 组 NAs 的高效力提供了合理的依据。这项工作为设计进一步的神经氨酸酶抑制剂提供了新的思路，这有助于短期内研究针对 1 组和 2 组的新型有效抑制剂。
