485337-98-2Relevant articles and documents
Lead Optimization of Influenza Virus RNA Polymerase Inhibitors Targeting PA-PB1 Interaction
Mizuta, Satoshi,Otaki, Hiroki,Ishikawa, Takeshi,Makau, Juliann Nzembi,Yamaguchi, Tomoko,Fujimoto, Takuya,Takakura, Nobuyuki,Sakauchi, Nobuki,Kitamura, Shuji,Nono, Hikaru,Nishi, Ryota,Tanaka, Yoshimasa,Takeda, Kohsuke,Nishida, Noriyuki,Watanabe, Ken
supporting information, p. 369 - 385 (2021/12/27)
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 RNA-dependent 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 (EC50) = 0.061-0.226 μM with low toxicity (50% cytotoxic concentration (CC50) >10 μM).
