Marcella 2020. Rational modifications, synthesis and biological evaluation of new potential antivirals for RSV designed to target the M2-1 protein. Highlights• Rational modifications on a zinc-ejecting anti-RSV scaffold.• Synthesis of novel analogues to explore antiviral SARs.• New inhibitors of RSV replication identified.• Molecular dynamics and molecular docking studies on the RSV M2-1 protein. AbstractRespiratory syncytial virus (RSV) is the main cause of lower respiratory tract diseases in infants and young children, with potentially serious and fatal consequences associated with severe infections. Despite extensive research efforts invested in the identification of therapeutic measures, no vaccine is currently available, while treatment options are limited to ribavirin and palivizumab, which both present significant limitations. While clinical and pre-clinical candidates mainly target the viral fusion protein, the nucleocapsid protein or the viral polymerase, our focus has been the identification of new antiviral compounds targeting the viral M2-1 protein, thanks to the presence of a zinc-ejecting group in their chemical structure.Starting from an anti-RSV hit we had previously identified with an in silico structure-based approach, we have designed, synthesised and evaluated a new series of dithiocarbamate analogues, with which we have explored the antiviral activity of this scaffold. The findings presented in this work may provide the basis for the identification of a new antiviral lead to treat RSV infections.