Synthesis and characterization of 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamide-based compounds targeting the PA-PB1 interface of influenza A virus polymerase
| Autor: | Leonardo Tensi, Laura Goracci, Giulio Nannetti, Chiara Bertagnin, Serena Massari, Stefano Di Bona, Maria Chiara Pismataro, Giuseppe Manfroni, Tommaso Felicetti, María Isabel Loza, Arianna Loregian, Anna Donnadio, José Brea, Stefano Sabatini, Violetta Cecchetti, Oriana Tabarrini, Maria Giulia Nizi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Pyrimidine
Stereochemistry medicine.drug_class RNA-dependent RNA polymerase Carboxamide PA-PB1 heterodimerization medicine.disease_cause Antiviral Agents 01 natural sciences Article 03 medical and health sciences chemistry.chemical_compound Protein-protein interaction RNA polymerase Drug Discovery medicine Influenza A virus Humans Moiety Polymerase RNA-Dependent RNA polymerase 030304 developmental biology Pharmacology Influenza virus 0303 health sciences biology 010405 organic chemistry Organic Chemistry General Medicine Triazoles 0104 chemical sciences Molecular Docking Simulation Pyrimidines chemistry Viral replication biology.protein Protein Binding |
| Zdroj: | European Journal of Medicinal Chemistry |
| ISSN: | 0223-5234 |
| Popis: | Influenza viruses (Flu) are responsible for seasonal epidemics causing high rates of morbidity, which can dramatically increase during severe pandemic outbreaks. Antiviral drugs are an indispensable weapon to treat infected people and reduce the impact on human health, nevertheless anti-Flu armamentarium still remains inadequate. In search for new anti-Flu drugs, our group has focused on viral RNA-dependent RNA polymerase (RdRP) developing disruptors of PA-PB1 subunits interface with the best compounds characterized by cycloheptathiophene-3-carboxamide and 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamide scaffolds. By merging these moieties, two very interesting hybrid compounds were recently identified, starting from which, in this paper, a series of analogues were designed and synthesized. In particular, a thorough exploration of the cycloheptathiophene-3-carboxamide moiety led to acquire important SAR insight and identify new active compounds showing both the ability to inhibit PA-PB1 interaction and viral replication in the micromolar range and at non-toxic concentrations. For few compounds, the ability to efficiently inhibit PA-PB1 subunits interaction did not translate into anti-Flu activity. Chemical/physical properties were investigated for a couple of compounds suggesting that the low solubility of compound 14, due to a strong crystal lattice, may have impaired its antiviral activity. Finally, computational studies performed on compound 23, in which the phenyl ring suitably replaced the cycloheptathiophene, suggested that, in addition to hydrophobic interactions, H-bonds enhanced its binding within the PAC cavity. Graphical abstract Image 1 Highlights • New hybrid 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamides showed anti-flu activity by disrupting RdRP PA-PB1 interaction. • A simple phenyl ring can replace the cycloheptathiophene, with advantages in the synthesis and solubility of the compound. • Molecular docking study has rationalized the binding mode of the compounds within the PAC. |
| Databáze: | OpenAIRE |
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