Discovery and Structure–Activity Relationship Studies of Thienopyrroles as Group 2 Influenza A Entry Inhibitors

The influenza A virus has been detrimental to public health for centuries and continues to take the lives of tens of thousands of people annually. Although current therapeutics have been effective in the past, the emergence of drug-resistant strains underscores the need for agents with new mechanisms of action. Here, we report thieno[3,2-b]pyrroles as novel group 2 influenza A virus entry inhibitors. In this study, we used a HA-based surrogate entry assay to perform the structure–activity relationship (SAR) studies to optimize the lead compounds. Docking studies in the predicted hemagglutinin binding site provided insight into potential binding interactions. Mutagenesis studies supported the proposed binding site. We validated the lead compounds that were potent in pseudovirus against infectious H3N2 strains including an oseltamivir-resistant strain. Lead compounds were counter-screened against other pseudoviruses and found to be selective. Together, these findings establish thieno[3,2-b]pyrroles as a promising new scaffold for combating group 2 influenza A viruses.