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

Abstract

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.

Sonogashira Cross‐Coupling Reaction of Bromocyanofluoro Pyridine Compounds: Access to 5‐ and 6‐Alkynylfluoropyridinamidoximes Scaffolds

“…We also demonstrated that these oxime‐containing scaffolds showed promise as reactivators of VX‐inhibited h AChE in vitro [20] . More recently, further developments in that field led us, to discover and highlight the benefit of 6‐alkynyl‐3‐fluoro‐2‐pyridinaldoximes 3 (Figure 1), as precursor of 6‐alkanylfluoropyridinaldoximes, used for the efficient reactivation and resurrection of sarin‐inhibited human acetylcholinesterase [21] . We then hypothesized that unknown alkynylfluoropyridinamidoximes such as 4 could find novel applications as precursors of innovative reactivators of OP‐inhibited h AChE.…”

“…In addition, the value of alkynylfluoropyridinamidoximes as synthetic intermediates towards alkyl‐linked hybrid reactivators was demonstrated by the one‐pot selective hydrogenation/hydrogenolysis of the internal alkyne and CBz group present in 4 h . Exposure of 4 h to hydrogen (1 atm) over a Pd/C catalyst smoothly delivered the alkanylfluoropyridinamidoxime 14 in excellent 92 % yield, without disturbing the potentially reducible amidoxime functionality, or the C−F bond [21] …”

Straightforward Synthesis of Halopyridine Aldehydes via Diaminomethylation

“…Fluoropyridines are versatile components in pharmaceuticals, serving as both pharmacophore cores and modifying groups. Their presence allows for the design and optimization of pharmaceutical compounds with desired therapeutic effects and improved drug properties [1–3] . Fluoro‐substituted pyridine structures can be found in approved drugs such as enoxacin, tosufloxacin, and other fluoroquinolone antibiotics [4] .…”

“…Their presence allows for the design and optimization of pharmaceutical compounds with desired therapeutic effects and improved drug properties. [1][2][3] Fluorosubstituted pyridine structures can be found in approved drugs such as enoxacin, tosufloxacin, and other fluoroquinolone antibiotics. [4] Fluorine atoms alter biological activity and provide distinctive physicochemical properties.…”