Design, synthesis, and anti-influenza A virus evaluation of 2-aminoquinoline derivatives

The rapid emergence of drug-resistant influenza A virus (IAV) strains has severely limited the efficacy of current antiviral therapies, highlighting an urgent need for novel agents with distinct mechanisms of action. In this study, a series of 2-aminoquinoline derivatives were synthesized via a trimethylsilyl trifluoromethanesulfonate (TMSOTf) -catalyzed annulation strategy. Evaluation of their anti-influenza virus activity revealed that derivative 3g exhibited potent antiviral efficacy, low cytotoxicity, and a high selectivity index(SI), making it the most promising candidate in this series. In vitro investigations revealed that 3g primarily acted during the early-to-mid stages of viral replication, significantly suppressing the transcription and translation of viral nucleoprotein (NP) and matrix protein 2 (M2), thereby effectively blocking viral replication and protein synthesis. Furthermore, 3g inhibited virus-induced apoptosis, reduced excessive production of reactive oxygen species (ROS) and nitric oxide (NO) triggered by viral infection, and markedly attenuated cytokine storm responses by suppressing the retinoic acid-inducible gene I (RIG-I)/Toll-like receptor 3 (TLR3)-mediated signaling pathways. In vivo experiments confirmed that 3g significantly reduced viral loads in the lungs of infected mice, alleviated pulmonary histopathological damage, and downregulated inflammatory factor levels, while exhibiting good biosafety. Collectively, these results position derivative 3g as a promising compound for the development of novel anti-influenza therapies.