Lead Optimization of Influenza Virus RNA Polymerase Inhibitors Targeting PA–PB1 Interaction

Abstract

Influenza viruses are responsible for contagious respiratory illnesses in humans and cause seasonal epidemics and occasional pandemics worldwide. Previously, we identified a quinolinone derivative PA-49, which inhibited the influenza virus RNAdependent RNA polymerase (RdRp) by targeting PA−PB1 interaction. This paper reports the structure optimization of PA-49, which resulted in the identification of 3-((dibenzylamino)methyl)quinolinone derivatives with more potent anti-influenza virus activity. During the optimization, the hit compound 89, which was more active than PA-49, was identified. Further optimization and scaffold hopping of 89 led to the most potent compounds 100 and a 1,8-naphthyridinone derivative 118, respectively. We conclusively determined that compounds 100 and 118 suppressed the replication of influenza virus and exhibited anti-influenza virus activity against both influenza virus types A and B in the range of 50% effective concentration (EC 50 ) = 0.061−0.226 μM with low toxicity (50% cytotoxic concentration (CC 50 ) >10 μM).

Design, Synthesis, Molecular Docking Analysis and Biological Evaluations of 4-[(Quinolin-4-yl)amino]benzamide Derivatives as Novel Anti-Influenza Virus Agents

“…Residues 618−621, GLU623, VAL636, LEU640, LEU666, GLN670, ARG673, TRP706, and PHE710 of influenza A virus PA protein were several reported residues on the PA−PB1 interface [ 23 , 24 ]. Amino sequence alignment was used to analyze the full sequences of influenza A virus PA protein and influenza B virus PA protein.…”

Identification of N- and C-3-Modified Laudanosoline Derivatives as Novel Influenza PAN Endonuclease Inhibitors

“…However, it is noteworthy that influenza vaccines are remarkably less effective for individuals with compromised immunity or other similar high-risk medical conditions . Besides, antiviral therapies are also important for the prevention and treatment of influenza in clinical use, which could be classified into several categories, mainly including M2 ion-channel inhibitors (amantadine and rimantadine), neuraminidase (NA) inhibitors (oseltamivir, zanamivir, laninamivir octanoate, peramivir), and recently polymerase acidic protein (PA) inhibitors (baloxavir marboxil). − Currently, amantadine and rimantadine are no longer recommended in clinical use due to their unbearable side effects and widespread M2-S31N mutation among circulating IAVs . Among the approved NA inhibitors, only oseltamivir is orally available that has been a first-line therapy since its approval in 1999.…”

Docking-based workflow and ADME prediction of some compounds in Curcuma longa and Andrographis paniculata as polymerase PA-PB1 inhibitors of influenza A/H5N1 virus

“…According to recent research on PA-PB1 inhibitors of influenza A, the 3-((dibenzylamino)methyl)quinolinone derivative has potent efficacy by preventing the replication of the virus at 50% effective concentrations (EC50) = 0.061-0.226 µM and low toxicity (50% cytotoxic concentration (CC50) >10 µM) [24]. Furthermore, the compounds R160792 and R151785 discovered through screening findings based on the in vitro split luciferase complementation-based assay also demonstrated effective suppression of PA-PB1 from the IAV.…”