Lead Optimization of Influenza Virus RNA Polymerase Inhibitors Targeting PA-PB1 Interaction.
Mizuta S, Otaki H, Ishikawa T, Makau JN, Yamaguchi T, Fujimoto T, Takakura N, Sakauchi N, Kitamura S, Nono H, Nishi R, Tanaka Y, Takeda K, Nishida N, Watanabe K.
Influenza viruses are responsible for contagious respiratory illnesses in humans and cause seasonal epidemics and occasional pandemics worldwide. Previously, we identified a quinolinone derivative <b>PA-49</b>, which inhibited the influenza virus RNA-dependent RNA polymerase (RdRp) by targeting PA-PB1 interaction. This paper reports the structure optimization of <b>PA-49</b>, which resulted in the identification of 3-((dibenzylamino)methyl)quinolinone derivatives with more potent anti-influenza virus activity. During the optimization, the hit compound <b>89</b>, which was more active than <b>PA-49</b>, was identified. Further optimization and scaffold hopping of <b>89</b> led to the most potent compounds <b>100</b> and a 1,8-naphthyridinone derivative <b>118</b>, respectively. We conclusively determined that compounds <b>100</b> and <b>118</b> 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<sub>50</sub>) = 0.061-0.226 μM with low toxicity (50% cytotoxic concentration (CC<sub>50</sub>) >10 μM).