Discovery of Aryl Benzoyl Hydrazide Derivatives as Novel Potent Broad-Spectrum Inhibitors of Influenza A Virus RNA-Dependent RNA Polymerase (RdRp)

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 mu M. 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.

Automated summary

Influenza A viruses have a high antigenic shift and there are limited approved anti-influenza drugs available. Therefore, developing novel anti-influenza drugs is crucial for clinical treatment and prevention of influenza outbreaks. This study reports a series of novel aryl benzoyl hydrazide analogs that exhibit potent inhibitory activity against influenza A viruses. Compound 11q shows strong inhibitory activity against avian H5N1 flu strain, H1N1 virus, and Flu B virus, and possesses good oral bioavailability and inhibitory activity against influenza A virus in a mouse model.