Novel antiviral compounds: Synthesis, biological studies on SARS-CoV-2, and structure-activity relationship analysis.

SARS-CoV-2 has caused a global epidemic, causing grave public health concerns. In this work, we synthesized a library of 28 compounds derived from the fusion of hydroxyethylamine and aniline and evaluated their antiviral activity. During the initial screening, compounds 3d and 3f were identified as hits with greater than 90% inhibition. Furthermore, their IC50 values were determined, and the compound 3f was noted as highly effective against SARS-CoV-2 infection. Compound 3f exhibited remarkable potency with an IC50 of 31 nM (mean, n = 3), coupled with minimal cytotoxicity (CC50 = 13.48 μM; selectivity index >430). In vitro assays confirmed the antiviral activity observed in cell-based assays of viral RNA replication and plaque reduction. However, compound 3f displayed rapid hepatic clearance in microsomal stability assays (t1/2 = 2.8 min), suggesting poor metabolic stability. In vivo evaluation in mice at a single oral dose of 200 mg/kg revealed no significant toxicity based on histopathology and serum biochemistry. Collectively, compound 3f represents a promising scaffold for anti-SARS-CoV-2 development, though optimization to improve metabolic stability and mechanistic studies to confirm its molecular target are warranted.