The genetic recombination and antigenic variation of influenza viruses may decrease the efficacy of antiviral vaccines, highlighting the imperativeness of developing novel anti-influenza agents. Herein, a series of thiophene-based compounds were designed and synthesized as potent anti-influenza agents. Among them, ATV2301 exhibited an excellent anti-influenza activity (EC₅₀, H1N1 = 1.88 nM, H3N2 = 4.77 nM), a higher safety index (SI, H1N1 = 18218, H3N2 = 7180), and a remarkably improved oral bioavailability (F = 71.60%). The prodrug ATV2301A demonstrated strong therapeutic efficacy and protection in H1N1-infected BALB/c mice, with low toxicity and broad tissue distribution. ATV2301 also exhibited high stability in both human and mouse liver microsomes. Mechanistic studies indicated that ATV2301’s anti-influenza activity was due to its effects on polymerase acid protein (PA), nuclear protein (NP), and RNA-dependent RNA polymerase (RdRp). Additionally, ATV2301 showed potent activities against clinical isolates of anti-influenza A virus (IAV) and anti-influenza B virus (IBV), positioning it as a promising cap-dependent endonuclease inhibitor for further clinical research.

中文翻译：

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发现新型基于噻吩的 baloxavir 衍生物作为有效的帽依赖性核酸内切酶抑制剂治疗流感


流感病毒的基因重组和抗原变异可能会降低抗病毒疫苗的功效，凸显了开发新型抗流感药物的必要性。在此，设计并合成了一系列基于噻吩的化合物作为有效的抗流感药物。其中，ATV2301表现出优异的抗流感活性 （EC₅₀， H1N1 = 1.88 nM， H3N2 = 4.77 nM）、较高的安全指数 （SI， H1N1 = 18218， H3N2 = 7180） 和显着提高的口服生物利用度 （F = 71.60%）。前药ATV2301A在 H1N1 感染的 BALB/c 小鼠中表现出很强的治疗效果和保护作用，毒性低，组织分布广。ATV2301 在人和小鼠肝脏微粒体中也表现出高稳定性。机制研究表明，ATV2301 的抗流感活性是由于它对聚合酶酸蛋白 （PA） 、核蛋白 （NP） 和 RNA 依赖性 RNA 聚合酶 （RdRp） 的影响。此外，ATV2301 对抗甲型流感病毒 （IAV） 和抗乙型流感病毒 （IBV） 的临床分离株显示出有效的活性，使其成为一种有前途的帽依赖性核酸内切酶抑制剂，可用于进一步的临床研究。