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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

Massari, Serena, Bertagnin, Chiara, Pismataro, Maria Chiara, Donnadio, Anna, Nannetti, Giulio, Felicetti, Tommaso, Di Bona, Stefano, Nizi, Maria Giulia, Tensi, Leonardo, Manfroni, Giuseppe, Loza, Maria Isabel, Sabatini, Stefano, Cecchetti, Violetta, Brea, Jose, Goracci, Laura, Loregian, Arianna and Tabarrini, Oriana 2021. 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. European Journal of Medicinal Chemistry 209 , 112944. 10.1016/j.ejmech.2020.112944
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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Elsevier
ISSN: 0223-5234
Date of First Compliant Deposit: 26 November 2020
Date of Acceptance: 13 October 2020
Last Modified: 20 Jan 2021 12:23

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