Discovery of Aryl Benzoyl Hydrazide Derivatives as Novel Potent Broad-Spectrum Inhibitors of Influenza A Virus RNA-Dependent RNA Polymerase (RdRp).
Liu X, Liang J, Yu Y, Han X, Yu L, Chen F, Xu Z, Chen Q, Jin M, Dong C, Zhou HB, Lan K, Wu S.
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 <b>10b</b>, <b>10c</b>, <b>10g</b>, <b>11p</b>, and <b>11q</b> exhibited potent inhibitory activity against the avian H5N1 flu strain with EC<sub>50</sub> values ranging from 0.009 to 0.034 μM. Moreover, compound <b>11q</b> 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 <b>11q</b> has the potential to become a potent clinical candidate to combat seasonal influenza and influenza pandemics.