Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250103, China.
Bioorg Chem. 2023 Jun;135:106527. doi: 10.1016/j.bioorg.2023.106527. Epub 2023 Apr 6.
β-D-N-hydroxycytidine (NHC, EIDD-1931) is a nucleoside analogue that exhibits broad spectrum antiviral activity against a variety of RNA viruses. Herein, we report the synthesis of a series of lipid prodrugs of NHC and a novel 3'-fluoro modified NHC analogue, and evaluation of their antiviral activity against five variants of SARS-CoV-2. All lipid prodrugs showed potent antiviral activity against the tested SARS-CoV-2 variants with EC values in the range of 0.31-3.51 μM, which were comparable to those of NHC or higher than those of remdesivir and molnupiravir. An increase in the cytostatic activity of the lipid prodrugs was found, but prodrug 2d proved equally selective as molnupinavir. The 3'-F analogue of NHC (6) only displayed minor antiviral activity against the SARS-CoV-2 Omicron variant (EC = 29.91 μM), while no activity was found for other variants at the highest concentration tested. The promising antiviral data of the lipid prodrugs of NHC suggest that they deserve further investigation as new anti-SARS-CoV-2 drugs.
β-D-N-羟基胞苷（NHC，EIDD-1931）是一种核苷类似物，对多种 RNA 病毒表现出广谱抗病毒活性。在此，我们报告了一系列 NHC 的脂质前药和一种新型 3'-氟修饰的 NHC 类似物的合成，并评估了它们对五种 SARS-CoV-2 变体的抗病毒活性。所有脂质前药对测试的 SARS-CoV-2 变体均表现出很强的抗病毒活性，EC 值在 0.31-3.51 μM 范围内，与 NHC 相当或高于瑞德西韦和莫努匹韦。发现脂质前药的细胞毒性活性增加，但前药 2d 与莫努匹韦一样具有同等的选择性。NHC 的 3'-F 类似物（6）仅对 SARS-CoV-2 奥密克戎变体表现出轻微的抗病毒活性（EC = 29.91 μM），而在最高测试浓度下，其他变体均未显示活性。NHC 脂质前药有希望的抗病毒数据表明，它们值得作为新型抗 SARS-CoV-2 药物进一步研究。
