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Published on: June 28, 2013
Lead Optimization of Influenza Virus RNA Polymerase Inhibitors Targeting PA-PB1 Interaction
Satoshi Mizuta1, Hiroki Otaki1, Takeshi Ishikawa2
1Center for Bioinformatics and Molecular Medicine, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo, Nagasaki 852-8521, Japan.
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 (EC50) = 0.061-0.226 μM with low toxicity (50% cytotoxic concentration (CC50) >10 μM).
Insights
New quinolinone derivatives show potent anti-influenza virus activity by inhibiting viral RNA polymerase. Compounds 100 and 118 effectively suppressed influenza A and B replication with low toxicity.
Area of Science:
- Virology
- Medicinal Chemistry
- Drug Discovery
Background:
- Influenza viruses cause significant global health burdens through seasonal epidemics and pandemics.
- The influenza virus RNA-dependent RNA polymerase (RdRp) is a validated target for antiviral therapies.
- Previous work identified PA-49, a quinolinone derivative, as an inhibitor of influenza virus replication by disrupting PA-PB1 interaction.
Purpose of the Study:
- To optimize the structure of PA-49 to develop more potent anti-influenza virus agents.
- To identify novel quinolinone and related heterocyclic compounds with improved efficacy against influenza viruses.
Main Methods:
- Structure-activity relationship (SAR) studies were performed on PA-49.
- Hit compound 89 was identified through optimization.
- Scaffold hopping was employed, leading to compounds 100 (quinolinone) and 118 (1,8-naphthyridinone).
- Antiviral activity was assessed by measuring 50% effective concentration (EC50) against influenza viruses.
- Cytotoxicity was evaluated by determining 50% cytotoxic concentration (CC50).
Main Results:
- Structure optimization of PA-49 yielded more potent derivatives, including compound 89.
- Further optimization and scaffold hopping led to highly potent compounds 100 and 118.
- Compounds 100 and 118 demonstrated significant anti-influenza virus activity against both influenza A and B.
- The EC50 values for compounds 100 and 118 ranged from 0.061 to 0.226 μM.
- These compounds exhibited low cytotoxicity, with CC50 values greater than 10 μM.
Conclusions:
- Compounds 100 and 118 represent promising novel anti-influenza virus agents.
- The identified compounds effectively suppress influenza virus replication.
- The optimized quinolinone and 1,8-naphthyridinone scaffolds offer potential for developing new influenza therapeutics.
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