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.

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A novel series of heteroaromatic-based benzenesulfonamide derivatives were identified as potent inhibitors of H5N1 influenza A virus.

In this study, we reported the synthesis and biological characterization of a novel series of furancarboxamide derivatives that were potent inhibitors of the influenza A H5N1 virus. The systematic structure-activity relationship (SAR) studies demonstrated that the 2,5-dimethyl-substituted heterocyclic moiety (furan or thiophene) had significant influence on the anti-influenza activity. In particular, 2,5dimethyl-N-(2-((4-nitrobenzyl)thio)ethyl)-furan-3-carboxamide 1a showed the best activity against the H5N1 virus with an EC 50 value of 1.25 mM. For the first time, the simple scaffold furan-carboxamide derivatives were identified as novel inhibitors of lethal H5N1 influenza A virus. † Electronic supplementary information (ESI) available: NMR spectra of nal compounds 1a-1v. See

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