Wang Boyu, Wang Kuanglei, Meng Peipei, Hu Yaping, Yang Fei, Liu Kemin, Lei Zaiqiang, Chen Binfeng, Tian Yongshou
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Benxi, Liaoning 117004, China.
Wuyi University, Jiangmen, Guangdong 529020, China; International Healthcare Innovation Institute (Jiangmen), Jiangmen, Guangdong 529080, China.
Bioorg Med Chem Lett. 2018 Nov 15;28(21):3477-3482. doi: 10.1016/j.bmcl.2018.09.014. Epub 2018 Sep 12.
In this study, a series of carboxyl-modified oseltamivir analogs with improved lipophilicity were designed and synthesized, and their inhibitory activities against neuraminidase from influenza A virus H5N1 subtype were evaluated. The results demonstrated that compound 5m exhibited potent inhibitory activity (IC = 1.30 ± 0.23 μM), and it targeted the recently discovered 430-cavity. Compound 5m (LogD = -0.12) is more lipophilic than oseltamivir carboxylate (LogD = -1.69) at pH 7.4, which is potentially propitious to improved membrane permeability and oral drug absorption. Meanwhile, 5m showed high stability in human liver microsomes. The findings of this study can be valuable in identifying neuraminidase inhibitors with optimal lipophilicity and in the exploration of 430-cavity.
在本研究中，设计并合成了一系列具有改善亲脂性的羧基修饰的奥司他韦类似物，并评估了它们对甲型流感病毒H5N1亚型神经氨酸酶的抑制活性。结果表明，化合物5m表现出强效抑制活性（IC = 1.30±0.23 μM），并且它靶向最近发现的430腔。在pH 7.4时，化合物5m（LogD = -0.12）比奥司他韦羧酸盐（LogD = -1.69）更具亲脂性，这可能有利于改善膜通透性和口服药物吸收。同时，5m在人肝微粒体中表现出高稳定性。本研究结果对于鉴定具有最佳亲脂性的神经氨酸酶抑制剂以及探索430腔可能具有重要价值。
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