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. Issue 65 (20th October 2020)

• Record Type: Journal Article
• Authors: Yerri, Jagadeesh; Dias, José; Nimmakayala, Mallikajurna Reddy; Razafindrainibe, Franck; Courageux, Charlotte; Gastellier, Anne‐Julie; Jegoux, Johanne; Coisne, Caroline; Landry, Christophe; Gosselet, Fabien; Hachani, Johan; Goossens, Jean‐François; Dehouck, Marie‐Pierre; Nachon, Florian; Baati, Rachid
• Is Part Of: Chemistry. Volume 26:Issue 65(2020)
• Page Start: 15035
• Page End: 15044
• Publication Date: 2020-10-20
• Subjects: 3-fluoro-2-pyridinaldoximes -- blood–brain barrier permeability -- chemical warfare agents -- chemoselective hydrogenation -- synthesis design; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202002012
• Languages: English
• ISSNs: 0947-6539

Abstract

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. Abstract : Permeable antidotes : The chemoselective hydrogenation of 6‐alkynyl‐3‐fluoro‐2‐pyridinaldoximes to afford 6‐alkyl‐3‐fluoro‐2‐pyridinaldoximes under mild hydrogenation conditions, without altering the C−F and oxime functionalities, is described. One of the resulting products acts as a low‐molecular‐weight non‐quaternary fluorinated hybrid reactivator of sarin‐inhibited human‐acetylcholinesterase, with unprecedented blood–brain barrier permeability efficacy.