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

Jagadeesh Yerri (1) , José Dias (2) , Mallikajurna Reddy Nimmakayala (1) , Franck Razafindrainibe (1) , Charlotte Courageux (2) , Anne‐julie Gastellier (2) , Johanne Jegoux (2) , Caroline Coisne (3) , Christophe Landry (3) , Fabien Gosselet (3) , Johan Hachani (3) , Jean‐françois Goossens (4) , Marie‐Pierre Dehouck (3) , Florian Nachon (2) , Rachid Baati (1)

1 ICPEES - Institut de chimie et procédés pour l'énergie, l'environnement et la santé
2 IRBA - Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge]
3 LBHE - Laboratoire de la Barrière Hémato-Encéphalique
4 GRITA - Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365

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.

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

Domaines: Chimie thérapeutique; Chimie organique

Jagadeesh Yerri, José Dias, Mallikajurna Reddy Nimmakayala, Franck Razafindrainibe, Charlotte Courageux, et al.. 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 - A European Journal, 2020, 26 (65), pp.15035-15044. ⟨10.1002/chem.202002012⟩. ⟨hal-03127205⟩