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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
Author(s) -
Yerri Jagadeesh,
Dias José,
Nimmakayala Mallikajurna Reddy,
Razafindrainibe Franck,
Courageux Charlotte,
Gastellier AnneJulie,
Jegoux Johanne,
Coisne Caroline,
Landry Christophe,
Gosselet Fabien,
Hachani Johan,
Goossens JeanFrançois,
Dehouck MariePierre,
Nachon Florian,
Baati Rachid
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202002012
Subject(s) - chemistry , sarin , pyridinium , oxime , acetylcholinesterase , organophosphate , bifunctional , alkyl , medicinal chemistry , antidote , stereochemistry , organic chemistry , enzyme , toxicity , pesticide , agronomy , biology , catalysis
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.