School of Life Sciences and Centre for Protein Science and Crystallography, Faculty of Science, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China.
Key Laboratory of Structure-based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang, 110016, China.
Eur J Med Chem. 2023 Nov 15;260:115775. doi: 10.1016/j.ejmech.2023.115775. Epub 2023 Aug 28.
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 IC 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 IC of the best performers are within low micromolar range and thus have good potential for further development.
安曲法林最初是为抗炎用途设计的药物。在这项工作中，我们合成了它的结构类似物库，并测试了它们的抗流感活性。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的一组。确定了表现最佳的化合物，即 12、34、41，它们对 A/WSN/33(H1N1)的 IC 分别为 5.53、3.21 和 6.73 μM。这些化合物对 A/PR/8/34(H1N1)、A/HK/1/68(H3N2)和 B/Florida/04/2006 病毒也有效。加药时间研究和小基因荧光素酶报告基因检测均支持这些化合物作用于核糖核蛋白（RNP）组分。以 34 和 41 为代表化合物，我们通过微量热泳动法确定，该化合物组结合 PA C 端结构域和核蛋白（NP），NP 是 RNP 中最丰富的亚基。总之，我们已经确定了一类具有双重分子靶标的新型抗流感化合物，具有进一步开发的良好潜力。重要性：流感病毒，尤其是甲型和乙型流感病毒，每年导致许多人死亡。病毒的高突变率使得现有治疗方法的效果随时间降低。在这项工作中，我们确定了一类新型化合物，它们的结构与抗炎药物安曲法林相似，对甲型流感株具有良好的活性。表现最佳的化合物的 IC 处于低微摩尔范围内，因此具有进一步开发的良好潜力。
