title: Structural investigation of cycloheptathiophene-3-carboxamide derivatives targeting influenza virus polymerase assembly.
abstract: 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.
authors: Department of Chemistry and Technology of Drugs, University of Perugia , 06123 Perugia, Italy.
authors: Serena
authors: S
authors: Massari
authors: Giulio
authors: G
authors: Nannetti
authors: Laura
authors: L
authors: Goracci
authors: Luca
authors: L
authors: Sancineto
authors: Giulia
authors: G
authors: Muratore
authors: Stefano
authors: S
authors: Sabatini
authors: Giuseppe
authors: G
authors: Manfroni
authors: Beatrice
authors: B
authors: Mercorelli
authors: Violetta
authors: V
authors: Cecchetti
authors: Marzia
authors: M
authors: Facchini
authors: Giorgio
authors: G
authors: Palù
authors: Gabriele
authors: G
authors: Cruciani
authors: Arianna
authors: A
authors: Loregian
authors: Oriana
authors: O
authors: Tabarrini
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000201:enzymology*; D012324:RNA-Dependent RNA Polymerase / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D013876:Thiophenes; D012324:RNA-Dependent RNA Polymerase