(1) Background: Human exposure to organophosphorus compounds employed as pesticides or as chemical warfare agents induces deleterious effects due to cholinesterase inhibition. One therapeutic approach is the reactivation of inhibited acetylcholinesterase by oximes. While currently available oximes are unable to reach the central nervous system to reactivate cholinesterases or to display a wide spectrum of action against the variety of organophosphorus compounds, we aim to identify new reactivators without such drawbacks. (2) Methods: This study gathers an exhaustive work to assess in vitro and in vivo efficacy, and toxicity of a hybrid tetrahydroacridine pyridinaldoxime reactivator, KM297, compared to pralidoxime. (3) Results: Blood–brain barrier crossing assay carried out on a human in vitro model established that KM297 has an endothelial permeability coefficient twice that of pralidoxime. It also presents higher cytotoxicity, particularly on bone marrow-derived cells. Its strong cholinesterase inhibition potency seems to be correlated to its low protective efficacy in mice exposed to paraoxon. Ventilatory monitoring of KM297-treated mice by double-chamber plethysmography shows toxic effects at the selected therapeutic dose. This breathing assessment could help define the No Observed Adverse Effect Level (NOAEL) dose of new oximes which would have a maximum therapeutic effect without any toxic side effects.

Novel 6-alkyl-and 6-alkenyl-3-fluoro-2-pyridinaldoximes have been synthesisedb yu sing amild and efficient chemoselective hydrogenation of 6-alkynyl-3-fluoro-2pyridinaldoximes caffolds, withouta lteringt he reducible, unprotected, sensitive oxime functionality and the CÀFb ond. These novel 6-alkyl-3-fluoro-2-pyridinaldoximesmay 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-pyridin-aldoxime (2-PAM) and 1-({[4-(aminocarbonyl)pyridinio]meth-oxy}methyl)-2-[(hydroxyimino)methyl]pyridiniumchloride (HI-6), two pyridiniums alts currently used as antidote by several countries. In addition, the uncharged 3-fluorinated bifunctional hybrid showedi ncreased in vitro blood-brain barrier permeability compared with those of 2-PAM, HI-6 and obidoxime. These promisingf eatures of novel low-molecular-weight alkylfluoropyridinaldoxime open up an ew era for the design, synthesis and discovery of central non-quaternary broad spectrumr eactivators for organophosphate-inhibitedc holinesterases.

We disclose a general two‐step procedure to access hitherto unknown and under explored 5‐ and 6‐alkynyl‐3‐fluoro‐2‐pyridinamidoximes from 5‐ and 6‐bromo‐3‐fluoro‐2‐cyanopyridines and a wide range of easily available and bench‐stable terminal alkynes, using Sonogashira cross‐coupling, as the first step. The generation of the polar amidoxime group is realized at a late stage upon treatment of the alkynylfluorocyanopyridine by hydroxylamine. This mild and operationally simple two‐step room temperature process is compatible with enantiopure chiral substrates and various functionality including free alcohols, unprotected and CBz‐protected amines, acetonides, benzyl ethers, amide, imide, di‐substituted alkynes and strained saturated heterocycles.