Chemoselective Hydrogenation of 6-alkynyl-3-fluoro-2-pyridinaldoxime: Access to first-in-class 6-alkyl-3-Fluoro-2-pyridinaldoxime as Reactivator of Sarin-Inhibited AChE with increased BBB Permeability.

Novel 6-alkyl- and 6-alkenyl-3-fluoro-2-pyridinaldoximes have been synthesized using a mild and efficient chemoselective hydrogenation of 6-alkynyl-3-fluoro-2-pyridinaldoxime scaffolds, without altering the reducible unprotected sensitive oxime functionality, and the C-F bond. These novel 6-alkyl-3-fluoro-2-pyridinaldoximes may find medicinal application as antidotes for organophosphates poisoning. Indeed, low molecular weight compound 12d exhibited increased affinity for sarin inhibited acetylcholinesterase ( h -AChE), and greater reactivation efficiency or resurrection for sarin-inhibited h -AChE, compared to 2-pyridinaldoxime (2-PAM) and HI-6, two pyridinium salts currently used as antidote by several countries. In addition, the uncharged 3-fluorinated bifunctional hybrid 12d showed increased in vitro BBB permeability as compared to 2-PAM, HI-6 and obidoxime. These promising features of novel low molecular weight alkylfluoropyridinaldoxime  open a new era for the design, synthesis and discovery of central non-quaternary broad spectrum reactivators for OP-inhibited cholinesterases.