Among the most important influenza virus targets is the RNA-dependent RNA polymerase acidic N-terminal (PA<sub>N</sub>) endonuclease, which is a critical component of the viral replication machinery. To inhibit the activity of this metalloenzyme, small-molecule inhibitors employ metal-binding pharmacophores (MBPs) that coordinate to the dinuclear Mn<sup>2+</sup> active site. In this study, several metal-binding isosteres (MBIs) were examined where the carboxylic acid moiety of a hydroxypyridinone MBP is replaced with other groups to modulate the physicochemical properties of the compound. MBIs were evaluated for their ability to inhibit PA<sub>N</sub> using a FRET-based enzymatic assay, and their mode of binding in PA<sub>N</sub> was determined using X-ray crystallography.