tetano
Editor, Senior Moderator
ChemMedChem
. 2026 Aug 14;21(15):e70434.
doi: 10.1002/cmdc.70434.
Synthesis of 1,3,5-Triazine-Indole Conjugates as Broad-Spectrum Coronavirus Entry Inhibitors
Shazia Asghar[SUP] 1 [/SUP], Leentje Persoons[SUP] 2 [/SUP], Yanicka Smolders[SUP] 2 [/SUP], Niels Willems[SUP] 2 [/SUP], Dirk Daelemans[SUP] 2 [/SUP], Steven De Jonghe[SUP] 2 [/SUP], Najim A Al-Masoudi[SUP] 3 [/SUP], Shahid Hameed[SUP] 1 [/SUP]
Affiliations
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[SUB]50[/SUB] > 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[SUB]50[/SUB] 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.
Keywords: 1,3,5‐triazines; SARS‐CoV‐2; coronavirus entry inhibitors; indole‐2‐carbohydrazides.
. 2026 Aug 14;21(15):e70434.
doi: 10.1002/cmdc.70434.
Synthesis of 1,3,5-Triazine-Indole Conjugates as Broad-Spectrum Coronavirus Entry Inhibitors
Shazia Asghar[SUP] 1 [/SUP], Leentje Persoons[SUP] 2 [/SUP], Yanicka Smolders[SUP] 2 [/SUP], Niels Willems[SUP] 2 [/SUP], Dirk Daelemans[SUP] 2 [/SUP], Steven De Jonghe[SUP] 2 [/SUP], Najim A Al-Masoudi[SUP] 3 [/SUP], Shahid Hameed[SUP] 1 [/SUP]
Affiliations
- PMID: 42587342
- PMCID: PMC13469574
- DOI: 10.1002/cmdc.70434
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[SUB]50[/SUB] > 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[SUB]50[/SUB] 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.
Keywords: 1,3,5‐triazines; SARS‐CoV‐2; coronavirus entry inhibitors; indole‐2‐carbohydrazides.