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 (CC 50 > 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 EC 50 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.