Influenza A viruses possess a high antigenic shift, and the approved anti-influenza drugs are extremely limited, which makes the development of novel anti-influenza drugs for the clinical treatment and prevention of influenza outbreaks imperative. Herein, we report a series of novel aryl benzoyl hydrazide analogs as potent anti-influenza agents. Particularly, analogs 10b, 10c, 10g, 11p, and 11q exhibited potent inhibitory activity against the avian H5N1 flu strain with EC₅₀ values ranging from 0.009 to 0.034 μM. Moreover, compound 11q exhibited nanomolar antiviral effects against both the H1N1 virus and Flu B virus and possessed good oral bioavailability and inhibitory activity against influenza A virus in a mouse model. Preliminary mechanistic studies suggested that these compounds exert anti-influenza virus effects mainly by interacting with the PB1 subunit of RNA-dependent RNA polymerase (RdRp). These results revealed that 11q has the potential to become a potent clinical candidate to combat seasonal influenza and influenza pandemics.

中文翻译：

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发现芳基苯甲酰肼衍生物作为新型强效广谱 A 型流感病毒 RNA 依赖性 RNA 聚合酶 (RdRp) 抑制剂

甲型流感病毒具有较高的抗原性转变，而获批的抗流感药物极为有限，这使得开发用于临床治疗和预防流感暴发的新型抗流感药物势在必行。在此，我们报告了一系列新型芳基苯甲酰肼类似物作为有效的抗流感药物。特别地，类似物10b、10c、10g、11p和11q表现出对禽H5N1流感病毒株的有效抑制活性，EC ₅₀值范围为0.009至0.034 μM。此外，化合物11q对 H1N1 病毒和乙型流感病毒均表现出纳摩尔级抗病毒作用，并在小鼠模型中具有良好的口服生物利用度和对甲型流感病毒的抑制活性。初步机制研究表明，这些化合物主要通过与 RNA 依赖性 RNA 聚合酶 (RdRp) 的 PB1 亚基相互作用来发挥抗流感病毒作用。这些结果表明，11q有可能成为对抗季节性流感和流感大流行的有效临床候选药物。