Synthesis of 3-heteroaryl-pyrrolo[2,3-b]pyridines as potent inhibitors of AP-2-associated protein kinase 1 (AAK1) with antiviral activity

Inhibition of AP-2-associated protein kinase 1 (AAK1) has been shown to be a promising avenue for the development of broad-spectrum antiviral agents. On a previously described AAK1 inhibitor based on a pyrrolo[2,3-b]pyridine scaffold, the concept of isosterism was applied, by replacing a carboxamide linker by various five-membered heterocycles. It led to the discovery of a novel series of AAK1 inhibitors with IC50 values in the low nM range, that also displayed antiviral activity against the dengue virus and Venezuelan equine encephalitis virus. [Display omitted] •AAK1 inhibitors are promising broad-spectrum antiviral agents.•Various isosteres of known pyrrolo [2,3-b]pyridines were prepared.•Compounds show potent AAK1 inhibition in the low nM range.•Selected analogues display antiviral activity against DENV-2 and VEEV.