Synthesis, Optimization, and Structure–Activity Relationships of Imidazo[1,2‑a]pyrimidines as Inhibitors of Group 2 Influenza A Viruses

• Published in: Journal of medicinal chemistry 2022-10, Vol.65 (20), p.14104-14120
• Main Authors: Alqarni, Saad, Cooper, Laura, Galvan Achi, Jazmin, Bott, Ryan, Sali, Veeresh Kumar, Brown, Andrew, Santarsiero, Bernard D., Krunic, Aleksej, Manicassamy, Balaji, Peet, Norton P., Zhang, Pin, Thatcher, Gregory R. J., Gaisina, Irina N., Rong, Lijun, Moore, Terry W.
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01329

The influenza A virus (IAV) is a highly contagious virus that causes pandemics and seasonal epidemics, which are major public health issues. Current anti-influenza therapeutics are limited partly due to the continuous emergence of drug-resistant IAV strains; 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 IAV 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 IAVs. These small molecules target hemagglutinin (HA), which mediates the viral entry process. Mapping a known small-molecule-binding cavity of the HA structure with resistant mutants suggests that these molecules bind to that cavity and block HA-mediated membrane fusion.