Cycloheptathiophene-3-carboxamide derivatives as influenza A virus polymerase inhibitors

The currently available anti-influenza (Flu) drugs, i.e. M2 blockers and neuraminidase inhibitors are still inadequate to treat Flu virus,(1) an important pathogen responsible for both yearly seasonal epidemics and more extensive global pandemics. Clearly, next-generation antivirals are needed to efficiently combat flu, preferably with an innovative mechanism of action. The viral RNA-dependent RNA polymerase (RdRP), a heterotrimer formed by the PB1, PB2, and PA subunits, provides an attractive target,(2) being essential for viral replication and involved in virus pathogenicity.(3) Moreover, it is highly conserved among flu A, B, and C while no homologue has been found in mammalian cells. With the aim to disrupt the RdRP correct assembly through protein-protein interaction inhibitors, an in silico screening of small molecule libraries using the crystal structure of a truncated form of PA bound to a PB1-derived peptide,(4) has been recently performed. Some interesting compounds showing the ability to specifically interfere with the PA-PB1 interaction, which translated in the capacity to block virus growth in cell cultures at non-cytotoxic concentrations, have been identified.(5,6) In this work, one of these hits, a cycloheptathiophene-3-carboxamide derivative, has been structurally investigated in order to increase the anti-PA/PB1 activity and achieve potent anti-flu activity, also encompassing clinical isolates and drug-resistant strains. The design and synthesis of a large series of derivatives that led to identify improved anti-flu compounds along with preliminary SAR information, will be presented.