Anti-influenza virus activities and mechanism of antrafenine analogs,European Journal of Medicinal Chemistry

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Anti-influenza virus activities and mechanism of antrafenine analogs
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2023-08-28 , DOI: 10.1016/j.ejmech.2023.115775
Yun-Sang Tang ₁ , Chao Zhang ₂ , Chun-Yeung Lo ₁ , Zhe Jin ₂ , Bobby Lim-Ho Kong ₁ , Meng-Jie Xiao ₁ , Er-Fang Huang ₂ , Chun Hu ₂ , Pang-Chui Shaw ₃

Affiliation

Antrafenine is a drug initially designed for anti-inflammation uses. In this work we have synthesized a library of its structural analogs and tested the anti-influenza activities. These analogs belong to a group of 2-(quinolin-4-yl)amino benzamides or 2-(quinolin-4-yl)amino benzoate derivatives. Best performers were identified, namely 12, 34, 41, with IC₅₀ against A/WSN/33 (H1N1) of 5.53, 3.21 and 6.73 μM respectively. These chemicals were also effective against A/PR/8/34 (H1N1), A/HK/1/68 (H3N2) and B/Florida/04/2006 viruses. Time-of-addition study and minigenome luciferase reporter assay both supported that the compounds act on the ribonucleoprotein (RNP) components. Using 34 and 41 as representative compounds, we determined by microscale thermophoresis that this group of compounds bind to both PA C-terminal domain and the nucleoprotein (NP) which is the most abundant subunit of the RNP. Taken together, we have identified a new class of anti-influenza compounds with dual molecular targets and good potential to be further developed.

Importance

The influenza viruses, especially influenza A and B subtypes, cause many deaths each year. The high mutation rate of the virus renders available therapeutics less effective with time. In this work we identify a new class of compounds, structurally similar to the anti-inflammation drug antrafenine, with good potency against influenza A strains. The IC₅₀ of the best performers are within low micromolar range and thus have good potential for further development.

中文翻译：

安曲芬宁类似物的抗流感病毒活性及机制

安曲芬宁是一种最初设计用于抗炎用途的药物。在这项工作中，我们合成了其结构类似物的库并测试了抗流感活性。这些类似物属于2-(喹啉-4-基)氨基苯甲酰胺或2-(喹啉-4-基)氨基苯甲酸酯衍生物。确定了最佳表现者，即12、34、41，针对 A/WSN/33 (H1N1) 的 IC ₅₀分别为 5.53、3.21 和 6.73 μM。这些化学物质对 A/PR/8/34 (H1N1)、A/HK/1/68 (H3N2) 和 B/Florida/04/2006 病毒也有效。添加时间研究和小基因组荧光素酶报告基因测定均支持该化合物作用于核糖核蛋白 (RNP) 成分。使用34和41作为代表性化合物，我们通过微尺度热泳确定这组化合物既结合PA C末端结构域又结合核蛋白(NP)，核蛋白是RNP最丰富的亚基。综上所述，我们已经确定了一类具有双分子靶点且具有进一步开发潜力的新型抗流感化合物。