Targeted Synthesis and Development of Neotype Antiviral Agents with a Radical-Mediated Deoxyphosphoamination Strategy

The persistent threat of emerging and re-emerging viral infections underscores the urgent need for the continuous development of next-generation antiviral agents. The deoxygenative functionalization of oxygen-containing compounds offers a powerful route to address this challenge. Herein, we report a radical-mediated deoxyphosphoamination of ketones to synthesize a new class of antiviral compounds, including N-(2-(diphenylphosphoryl)-1H-inden-3-yl)-P,P-diphenylphosphinic amide (IDPA) and its homologues. This transformation proceeds under simple, mild, and easily operable reaction conditions, exhibiting a broad substrate scope and excellent functional group tolerance. Mechanistic investigations, including control and radical inhibition experiments, high-resolution mass spectrometry detection of key intermediates, and density functional theory calculations, reveal a concerted pathway involving nitrogen, oxygen, and phosphorus radicals that facilitate N-O bond cleavage and the formation of C═C, C-P, and N-P bonds. Biological evaluations demonstrate that these scaffolds possess potent broad-spectrum antiviral activity with low cytotoxicity. Proteomic analysis, molecular docking, and Western blotting further elucidate the mechanism by which IDPA inhibits porcine reproductive and respiratory syndrome virus (PRRSV) replication through its interactions with receptor protein CD163 and host protein HSP70. These findings establish a versatile strategy for developing radical-based antiviral agents and provide promising candidates for therapeutic intervention.