SARs of Imidazo[1,2-a]pyrimidines as Inhibitors and Target Degraders of Group 2 Influenza A Viruses

Influenza A virus is a highly contagious virus that causes pandemics and seasonal epidemics, which are major public health issues. Current anti-influenza therapeutics are limited by the resistant strains of Influenza A viruses that are constantly emerging; thus, there is an unmet need to develop novel anti-influenza therapies. Here, we present a novel imidazo[1,2-a]pyrimidine scaffold that targets group 2 Influenza A virus entry. We have explored three different regions of the lead compound, and we have developed a series of small molecules that have nanomolar activity against oseltamivir-sensitive and -resistant forms of group 2 Influenza A virus. These small molecules likely target hemagglutinin, a key component of the viral entry process. The interaction with HA is supported by site-directed mutagenesis. To evaluate an alternative approach to target influenza, imidazo[1,2-a]pyrimidine scaffold was modified to make small molecule degraders that can inhibit the infectivity of the virus. These modified molecules maintained the entry inhibition effect in a pseudotyped viral assay. Further testing and evaluation of these molecules’ activity will assess the effectiveness of the degradation approach.