Huprine Derivatives as Sub‐Nanomolar Human Acetylcholinesterase Inhibitors: From Rational Design to Validation by X‐ray Crystallography

This complete study—from rational design to validation by X-ray crystallography—allowed us to discover two sub-nanomolar hAChE inhibitors (430 and 530 pM) grafted with an easily derivatized linker directed toward the AChE peripheral site. The crystal structure of mouse AChE in complex with compound 4 was solved and confirms the favorable position of the triazole in the active site gorge, paving the way for a new class of bifunctional ligands.