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Structural Investigation of Cycloheptathiophene-3-carboxamide Derivatives Targeting Influenza Virus Polymerase Assembly

Serena MassariDepartment of Chemistry and Technology of Drugs, University of Perugia, 06123 Perugia, ItalyGiulio NannettiDepartment of Molecular Medicine, University of Padua, 35121 Padua, ItalyLaura GoracciDepartment of Chemistry, Biology, and Biotechnology, University of Perugia, 06123 Perugia, ItalyLuca SancinetoDepartment of Chemistry and Technology of Drugs, University of Perugia, 06123 Perugia, ItalyGiulia MuratoreDepartment of Molecular Medicine, University of Padua, 35121 Padua, ItalyStefano SabatiniDepartment of Chemistry and Technology of Drugs, University of Perugia, 06123 Perugia, ItalyGiuseppe ManfroniDepartment of Chemistry and Technology of Drugs, University of Perugia, 06123 Perugia, ItalyBeatrice MercorelliDepartment of Molecular Medicine, University of Padua, 35121 Padua, ItalyVioletta CecchettiDepartment of Chemistry and Technology of Drugs, University of Perugia, 06123 Perugia, ItalyMarzia FacchiniDepartment of Infectious, Parasitic, and Immunomediated Diseases, WHO National Influenza Centre, Istituto Superiore di Sanità (ISS), Rome, ItalyGiorgio PalùDepartment of Molecular Medicine, University of Padua, 35121 Padua, ItalyGabriele CrucianiDepartment of Chemistry, Biology, and Biotechnology, University of Perugia, 06123 Perugia, ItalyArianna LoregianDepartment of Molecular Medicine, University of Padua, 35121 Padua, ItalyOriana TabarriniDepartment of Chemistry and Technology of Drugs, University of Perugia, 06123 Perugia, Italy

2013en

ABI

Annotatsiya

The limited number of drug classes licensed for treatment of influenza virus (Flu), together with the continuous emergence of viral variants and drug resistant mutants, highlights the urgent need to find antivirals with novel mechanisms of action. In this context, the viral RNA-dependent RNA polymerase (RdRP) subunits assembly has emerged as an attractive target. Starting from a cycloheptathiophene-3-carboxamide derivative recently identified by us for its ability to disrupt the interaction between the PA and PB1 subunits of RdRP, we have designed and synthesized a series of analogues. Their biological evaluation led to the identification of more potent protein-protein interaction inhibitors, endowed with antiviral activity that also encompassed a number of clinical isolates of FluA, including an oseltamivir-resistant strain, and FluB, without showing appreciable toxicity. From this study, the cycloheptathiophene-3-carboxamide scaffold emerged as being particularly suitable to impart anti-Flu activity.

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DOI: 10.1021/jm401560v

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