In:
Chemistry – A European Journal, Wiley, Vol. 26, No. 65 ( 2020-11-20), p. 15035-15044
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.
Type of Medium:
Online Resource
ISSN:
0947-6539
,
1521-3765
DOI:
10.1002/chem.202002012
Language:
English
Publisher:
Wiley
Publication Date:
2020
detail.hit.zdb_id:
1478547-X
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