Pyridobenzothiazolones as anti-flavivirus agents: Impact on Zika virus

Zika virus is considered a major threat to human health since it can cause severe diseases in both adults and newborns and no drugs or vaccines are available against this virus. Moreover, Zika usually cocirculate in endemic regions together with other dangerous flaviviruses; thus there is a pressing need to discover broad antiflavivirus drugs. In this book chapter, we describe the identification and hit explosion of a very promising 1H-pyrido[2,1-b][1,3]benzothiazol-1-one (PBTZ) class endowed with a potent antiviral activity and promising selectivity toward several flaviviruses. Within this class, we identified compounds 1, 3, and 6 as the most potent PBTZs exerting a potent sub-μM antiviral activity against Zika replication in cells coupled with good selectivity indexes. Compounds 1, 3, and 6 also emerged as dual inhibitors of NS5 RNA-dependent RNA polymerase (RdRp) and NS3–NS5 protein-protein interaction (PPI), likely through cavity B binding. We also discuss the potential of PBTZs as promising lead candidates and the impact in Zika infections.