Synthesis of 1,3,5-Triazine-Indole Conjugates as Broad-Spectrum Coronavirus Entry Inhibitors.

A series of hybrid molecules containing indole and 1,3,5-triazine scaffolds was synthesized and evaluated for their antiviral activity against several human RNA and DNA viruses. The conjugates displayed overall low cytotoxicity (CC50 > 50 µM) and potent antiviral activity across a coronavirus panel, with the most promising analogs (compounds 5d, 5g and 5o) showing sub- to low-micromolar EC50 values against HCoV-OC43, HCoV-229E, and SARS-CoV-2. Structure-activity relationship studies highlighted that the substitution pattern on the anilino moiety allowed to modulate antiviral activity. Time-of-drug addition, adsorption, and fusion assays indicated inhibition of viral replication at an early viral entry step, consistent with inhibition of spike-mediated membrane fusion. Overall, these data suggest that 1,3,5-triazine-indole conjugates are a promising scaffold to develop broad-spectrum coronavirus entry inhibitors. ADMET profiling of lead compounds (5d, 5g, and 5o) revealed favorable pharmacokinetic properties, including high oral absorption, limited CNS penetration, and non-mutagenic safety profiles.