Synthesis of 1,3,5-Triazine-Indole Conjugates as Broad-Spectrum Coronavirus Entry Inhibitors
Shazia Asghar1, Leentje Persoons2, Yanicka Smolders2
1Department of Chemistry, Quaid-I-Azam University, Islamabad, Pakistan.
Chemmedchem
|August 13, 2026
Summary
New hybrid molecules combining indole and 1,3,5-triazine show potent antiviral activity against coronaviruses, including SARS-CoV-2. These compounds inhibit viral entry, offering a promising new scaffold for broad-spectrum coronavirus inhibitors with favorable safety profiles.
Area of Science:
- Medicinal Chemistry
- Virology
- Drug Discovery
Background:
- Coronaviruses pose a significant global health threat, necessitating the development of novel antiviral agents.
- Existing antiviral therapies have limitations, driving research into new therapeutic scaffolds.
Purpose of the Study:
- To synthesize and evaluate novel indole-1,3,5-triazine hybrid molecules for antiviral activity.
- To identify potent inhibitors targeting key steps in the viral replication cycle, specifically viral entry.
Main Methods:
- Synthesis of indole-1,3,5-triazine conjugates.
- Antiviral screening against a panel of human RNA and DNA viruses, including coronaviruses (HCoV-OC43, HCoV-229E, SARS-CoV-2).
- Cytotoxicity assays (CC50), antiviral efficacy assays (EC50), structure-activity relationship (SAR) studies, time-of-drug addition, adsorption, and fusion assays, and ADMET profiling.
Main Results:
- Synthesized conjugates exhibited low cytotoxicity (CC50 > 50 µM).
- Compounds 5d, 5g, and 5o demonstrated potent antiviral activity (sub- to low-micromolar EC50) against HCoV-OC43, HCoV-229E, and SARS-CoV-2.
- Mechanism of action studies indicated inhibition of viral entry, specifically spike-mediated membrane fusion.
- Lead compounds showed favorable pharmacokinetic properties, including high oral absorption, limited CNS penetration, and a non-mutagenic safety profile.
Conclusions:
- Indole-1,3,5-triazine conjugates represent a promising scaffold for developing broad-spectrum coronavirus entry inhibitors.
- The substitution pattern on the anilino moiety is crucial for modulating antiviral activity.
- The identified lead compounds possess favorable drug-like properties, supporting further development as potential antiviral therapeutics.
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