Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
Antimicrob Agents Chemother. 2012 Mar;56(3):1315-23. doi: 10.1128/AAC.05764-11. Epub 2011 Dec 27.
To identify novel compounds that possess antiviral activity against hepatitis C virus (HCV), we screened a library of small molecules with various amounts of structural diversity using an HCV replicon-expressing cell line and performed additional validations using the HCV-JFH1 infectious-virus cell culture. Of 4,004 chemical compounds, we identified 4 novel compounds that suppressed HCV replication with 50% effective concentrations of ranging from 0.36 to 4.81 μM. N'-(Morpholine-4-carbonyloxy)-2-(naphthalen-1-yl) acetimidamide (MCNA) was the most potent and also produced a small synergistic effect when used in combination with alpha interferon. Structure-activity relationship (SAR) analyses revealed 4 derivative compounds with antiviral activity. Further SAR analyses revealed that the N-(morpholine-4-carbonyloxy) amidine moiety was a key structural element for antiviral activity. Treatment of cells with MCNA activated nuclear factor κB and downstream gene expression. In conclusion, N-(morpholine-4-carbonyloxy) amidine and other related morpholine compounds specifically suppressed HCV replication and may have potential as novel chemotherapeutic agents.
为了鉴定具有抗丙型肝炎病毒（HCV）活性的新型化合物，我们使用表达 HCV 复制子的细胞系筛选了具有不同结构多样性的小分子文库，并使用 HCV-JFH1 感染性病毒细胞培养物进行了额外的验证。在 4004 种化合物中，我们鉴定出了 4 种新型化合物，它们对 HCV 复制的抑制作用在 50%有效浓度范围内从 0.36 到 4.81 μM。N'-(吗啉-4-羰基氧基)-2-(萘-1-基)乙酰胺（MCNA）是最有效的化合物，与α干扰素联合使用时还产生了较小的协同作用。构效关系（SAR）分析显示，有 4 种具有抗病毒活性的衍生化合物。进一步的 SAR 分析表明，N-(吗啉-4-羰基氧基)脒基部分是抗病毒活性的关键结构要素。MCNA 处理细胞会激活核因子 κB 和下游基因表达。总之，N-(吗啉-4-羰基氧基)脒基和其他相关吗啉化合物特异性地抑制 HCV 复制，可能具有作为新型化学治疗剂的潜力。
