Synthesis and pharmacodynamic evaluation of 2-aminoindole derivatives against influenza A virus in vitro/vivo

Influenza virus is a kind of respiratory pathogen with high morbidity and mortality, which still threatens human health. Existing anti-influenza drugs have various limitations, such as the inability to alleviate body injury and side effects. There remains an urgent need to develop a novel antiviral drug to efficiently inhibit viral infection while avoiding body injury. A series of 2-aminoindole derivatives were synthesized via the TMSOTf-catalyzed reactions of N-arylynamides with sulfilimines and evaluated for their anti-influenza virus activity. The experimental results showed that 2-aminoindole 3h had significant antiviral activity (EC50 = 8.37 ± 0.65 μM) and the lowest cytotoxicity (CC50 = 669.26 ± 11.42 μM) in vitro. 2-Aminoindole 3h could inhibit viral replication by effectively binding to RNA-dependent RNA polymerase (RdRp), and could also directly target host cells to inhibit cytokine storms and apoptosis induced by viral infection, thereby improving host cell survival rate. In addition, viral load and organ injury in the lung tissue of infected mice were effectively reduced by 2-aminoindole 3h with satisfactory biosafety. These findings highlight the potential of a valuable therapeutic option against influenza infection while also laying the foundation for further research and development in this area. [Display omitted] •We synthesized a series of 2-aminoindole derivatives and detected their antiviral activity against Influenza A virus (IAV).•2-Aminoindole 3h can reduce the upregulation of inflammatory factors and apoptosis induced by IAV infection.•2-Aminoindole 3h can significantly alleviate the lung injury caused by IAV infection.