Non-chelating p-phenylidene-linked bis-imidazoline analogs of known influenza virus endonuclease inhibitors: Synthesis and anti-influenza activity.

A novel chemotype topologically similar to known influenza virus PA endonuclease inhibitors has been designed. It was aimed to reproduce the extended topology of the known metal-chelating ligands with a p-phenylidene-linked bis-imidazoline scaffold. It was envisioned that aromatic groups introduced to this scaffolds via metal-catalyzed N-arylation (Buchwald-Hartwig or Chan-Evans-Lam) would contribute to lipophilic binding to the target and one of the imidazoline nitrogen atoms would ensure non-chelating coordination to the prosthetic divalent metal ion. The compounds displayed appreciable anti-influenza activity in vitro and substantial concentration window from the general cytotoxicity range. Docking analysis of low-energy poses of the most active compound (as well as their comparison to the binding of an inactive compound) revealed that these compounds reproduced similar binding components to a known PA endonuclease inhibitor and displayed similar binding pose and desired monodentate metal coordination, as was initially envisioned. These findings warrant further investigation of the mechanism of action of the newly discovered series.