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 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.