Chemoselective Hydrogenation of 6-Alkynyl-3-fluoro-2-pyridinaldoximes: Access to First-in-Class 6-Alkyl-3-Fluoro-2-pyridinaldoxime Scaffolds as New Reactivators of Sarin-Inhibited Human Acetylcholinesterase with Increased Blood-Brain Barrier Permeability

Chemistry. 2020 Nov 20;26(65):15035-15044. doi: 10.1002/chem.202002012. Epub 2020 Oct 20.

Abstract

Novel 6-alkyl- and 6-alkenyl-3-fluoro-2-pyridinaldoximes have been synthesised by 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 to organophosphate poisoning. Indeed, one low-molecular-weight compound exhibited increased affinity for sarin-inhibited acetylcholinesterase (hAChE) and greater reactivation efficiency or resurrection for sarin-inhibited hAChE, compared with those of 2-pyridinaldoxime (2-PAM) and 1-({[4-(aminocarbonyl)pyridinio]methoxy}methyl)-2-[(hydroxyimino)methyl]pyridinium chloride (HI-6), two pyridinium salts currently used as antidote by several countries. In addition, the uncharged 3-fluorinated bifunctional hybrid showed increased in vitro blood-brain barrier permeability compared with those of 2-PAM, HI-6 and obidoxime. These promising features of novel low-molecular-weight alkylfluoropyridinaldoxime open up a new era for the design, synthesis and discovery of central non-quaternary broad spectrum reactivators for organophosphate-inhibited cholinesterases.

Keywords: 3-fluoro-2-pyridinaldoximes; blood-brain barrier permeability; chemical warfare agents; chemoselective hydrogenation; synthesis design.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Blood-Brain Barrier* / metabolism
  • Cholinesterase Inhibitors
  • Cholinesterase Reactivators
  • Humans
  • Hydrogenation
  • Oximes
  • Permeability
  • Pyridinium Compounds
  • Sarin

Substances

  • Cholinesterase Inhibitors
  • Cholinesterase Reactivators
  • Oximes
  • Pyridinium Compounds
  • pyridine-2-aldoxime
  • Sarin
  • Acetylcholinesterase