tetano
Editor, Senior Moderator
J Med Chem
. 2021 Dec 14.
doi: 10.1021/acs.jmedchem.1c01527. Online ahead of print.
Lead Optimization of Influenza Virus RNA Polymerase Inhibitors Targeting PA-PB1 Interaction
Satoshi Mizuta[SUP] 1 [/SUP], Hiroki Otaki[SUP] 1 [/SUP], Takeshi Ishikawa[SUP] 2 [/SUP], Juliann Nzembi Makau[SUP] 3 [/SUP], Tomoko Yamaguchi[SUP] 1 [/SUP], Takuya Fujimoto[SUP] 4 [/SUP], Nobuyuki Takakura[SUP] 4 [/SUP], Nobuki Sakauchi[SUP] 4 [/SUP], Shuji Kitamura[SUP] 4 [/SUP], Hikaru Nono[SUP] 5 [/SUP], Ryota Nishi[SUP] 5 [/SUP], Yoshimasa Tanaka[SUP] 6 [/SUP], Kohsuke Takeda[SUP] 7 [/SUP], Noriyuki Nishida[SUP] 8 [/SUP], Ken Watanabe[SUP] 9 [/SUP]
Affiliations
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 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 (EC[SUB]50[/SUB]) = 0.061-0.226 μM with low toxicity (50% cytotoxic concentration (CC[SUB]50[/SUB]) >10 μM).
. 2021 Dec 14.
doi: 10.1021/acs.jmedchem.1c01527. Online ahead of print.
Lead Optimization of Influenza Virus RNA Polymerase Inhibitors Targeting PA-PB1 Interaction
Satoshi Mizuta[SUP] 1 [/SUP], Hiroki Otaki[SUP] 1 [/SUP], Takeshi Ishikawa[SUP] 2 [/SUP], Juliann Nzembi Makau[SUP] 3 [/SUP], Tomoko Yamaguchi[SUP] 1 [/SUP], Takuya Fujimoto[SUP] 4 [/SUP], Nobuyuki Takakura[SUP] 4 [/SUP], Nobuki Sakauchi[SUP] 4 [/SUP], Shuji Kitamura[SUP] 4 [/SUP], Hikaru Nono[SUP] 5 [/SUP], Ryota Nishi[SUP] 5 [/SUP], Yoshimasa Tanaka[SUP] 6 [/SUP], Kohsuke Takeda[SUP] 7 [/SUP], Noriyuki Nishida[SUP] 8 [/SUP], Ken Watanabe[SUP] 9 [/SUP]
Affiliations
- PMID: 34905383
- DOI: 10.1021/acs.jmedchem.1c01527
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 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 (EC[SUB]50[/SUB]) = 0.061-0.226 μM with low toxicity (50% cytotoxic concentration (CC[SUB]50[/SUB]) >10 μM).