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

Abstract

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.

In silico characterization of aryl benzoyl hydrazide derivatives as potential inhibitors of RdRp enzyme of H5N1 influenza virus

“…Significantly, these results of 3D-QSAR validate the developed structure-based pharmacophore which in turn justifies the interactions obtained from molecular docking. Therefore, it may be inferred that these aryl benzoyl hydrazide derivatives may actually bind to the binding site proposed earlier by Liu et al (Liu et al, 2022) and the derived structure-based pharmacophore model may indeed be used to screen and predict the anti-viral activity of these compounds. Even though structure-based pharmacophore successfully aligned the conformations of the ligands to generate predictive 3D-QSAR models, we also resorted to an atom-based alignment (or rigid body molecular alignment) of the structures to check if any better 3D-QSAR model may exist or not.…”

“…Bank (https://www.rcsb.org/) (Berman et al, 2003). The B-chain of this crystal structure that represents the PB1 domain of the protein (Liu et al, 2022) was selected from the docking analysis with AutoDock Vina (version 1.1.2., The Scripps Research Institute, La Jolla, CA, United States) (Trott and Olson, 2010).…”

“…Therefore, new RdRp inhibitors acting on subunits other than PA, such as PB1, should be studied thoroughly to obtain novel lead molecules against influenza A. In a recent study, Liu et al reported a series of aryl benzoyl hydrazide derivatives as RNA-dependent RNA polymerase inhibitors of influenza A ( Liu et al, 2022 ). Furthermore, preliminary mechanistic studies conducted by the same authors suggested that these compounds may exhibit anti-influenza virus activity by binding to the PB1 subunit of RdRp ( Liu et al, 2022 ).…”

“…In a recent study, Liu et al reported a series of aryl benzoyl hydrazide derivatives as RNA-dependent RNA polymerase inhibitors of influenza A ( Liu et al, 2022 ). Furthermore, preliminary mechanistic studies conducted by the same authors suggested that these compounds may exhibit anti-influenza virus activity by binding to the PB1 subunit of RdRp ( Liu et al, 2022 ). Besides, recent works showed that RdRp inhibitors are promising potent anti-RNA virus drugs that may ultimately be used for the treatment of the coronavirus disease 2019 (COVID-19) ( Pachetti et al, 2020 ; Picarazzi et al, 2020 ; Dejmek et al, 2021 ; Tian et al, 2021 ).…”

“…Ligand- and structure-based in silico modelling strategies have been successfully employed in the past to design and develop novel therapeutic agents ( Sabe et al, 2021 ). In the present work, we report cheminformatic modeling approaches such as 2D and 3D-quantitative structure-activity relationships (2D-QSAR and 3D-QSAR) to characterize the structural requirements of the aryl benzoyl hydrazide derivatives reported by Liu et al ( Liu et al, 2022 ) for owning higher potency against influenza A. In the later study, the synthesized compounds were primarily assayed against avian H5N1 flu strain with 50% effective concentration (EC 50 ) values ranging from 9.3 nM to 86 μM.…”