新型β-D-N-羟基胞苷类似物的合成与抗 SARS-CoV-2、流感病毒和 DENV-2 的生物评价。
Synthesis and biological evaluation of new β-D-N-hydroxycytidine analogs against SARS-CoV-2, influenza viruses and DENV-2.
机构信息
Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan 49315, South Korea.
Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, South Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, South Korea.
出版信息
Bioorg Med Chem Lett. 2023 Mar 1;83:129174. doi: 10.1016/j.bmcl.2023.129174. Epub 2023 Feb 8.
Drug repurposing approach was applied to find a potent antiviral agent against RNA viruses such as SARS-CoV-2, influenza viruses and dengue virus with a concise strategy of small change in parent molecular structure. For this purpose, β-D-N-hydroxycytidine (NHC, 1) with a broad spectrum of antiviral activity was chosen as the parent molecule. Among the prepared NHC analogs (8a-g, and 9) from uridine, β-D-N-O-isobutyrylcytidine (8a) showed potent activity against SARS-CoV-2 (EC 3.50 μM), Flu A (H1N1) (EC 5.80 μM), Flu A (H3N2) (EC 7.30 μM), Flu B (EC 3.40 μM) and DENV-2 (EC 3.95 μM) in vitro. Furthermore, its potency against SARS-CoV-2 was >5-fold, 3.4-fold, and 3-fold compared to that of NHC (1), MK-4482 (2), and remdesivir (RDV) in vitro, respectively. Ultimately, compound 8a was expected to be a potent inhibitor toward RNA viruses as a viral mutagenic agent like MK-4482.
药物重定位方法被应用于寻找一种针对 RNA 病毒（如 SARS-CoV-2、流感病毒和登革热病毒）的有效抗病毒药物，其策略是对母体分子结构进行微小改变。为此，选择具有广谱抗病毒活性的β-D-N-羟基胞苷（NHC，1）作为母体分子。在所制备的尿苷类 NHC 类似物（8a-g 和 9）中，β-D-N-O-异丁酰胞苷（8a）对 SARS-CoV-2（EC 3.50 μM）、Flu A（H1N1）（EC 5.80 μM）、Flu A（H3N2）（EC 7.30 μM）、Flu B（EC 3.40 μM）和 DENV-2（EC 3.95 μM）具有较强的体外活性。此外，其对 SARS-CoV-2 的活性比 NHC（1）、MK-4482（2）和瑞德西韦（RDV）分别高出 5 倍、3.4 倍和 3 倍。最终，化合物 8a 有望成为一种有效的 RNA 病毒抑制剂，作为一种类似 MK-4482 的病毒诱变剂。
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