Pyridinium Oximes withOrtho-Positioned Chlorine Moiety Exhibit Improved Physicochemical Properties and Efficient Reactivation of Human Acetylcholinesterase Inhibited by Several Nerve Agents

Abstract

Six chlorinated bispyridinium mono-oximes, analogous to potent charged reactivators K027, K048, and K203, were synthesized with the aim of improving lipophilicity and reducing the pK a value of the oxime group, thus resulting in a higher oximate concentration at pH 7.4 compared to nonchlorinated analogues. The nucleophilicity was examined and the pK a was found to be lower than that of analogous nonchlorinated oximes. All the new compounds efficiently reactivated human AChE inhibited by nerve agents cyclosarin, sarin, and VX. The most potent was the dichlorinated analogue of oxime K027 with significantly improved ability to reactivate the conjugated enzyme due to improved binding affinity and molecular recognition. Its overall reactivation of sarin-, VX-, and cyclosarin-inhibited AChE was, respectively, 3-, 7-, and 8-fold higher than by K027. Its universality, PAMPA permeability, favorable acid dissociation constant coupled with its negligible cytotoxic effect, and successful ex vivo scavenging of nerve agents in whole human blood warrant further analysis of this compound as an antidote for organophosphorus poisoning.

Synthesis,in vitroscreening and molecular docking of isoquinolinium-5-carbaldoximes as acetylcholinesterase and butyrylcholinesterase reactivators

“…The obidoxime was found to have some reactivation ability for sarin and VX, but markedly lower for paraoxon. Apparently, some novel compounds (17)(18) showed markedly improved reactivation than obidoxime for sarin (17), VX (17)(18) and paraoxon (17) when tested at 100 mM. This finding seems to be important since obidoxime formerly resulted as the best reactivator of hBChE inhibited by tabun 23 , although its reactivation was found not appropriate for constructing a pseudo-catalytic scavenger.…”

“…Compared to AChE, this discrepancy is obviously ascribed to different structural aspects between cholinesterases 21 . Interestingly, three of them were found in the subgroup containing pyridinium amide (30-32) that were also similarly ranked as weak inhibitors of hAChE 18 .…”

“…The peripheral binding ligands differ and include, for instance, bulky scaffolds like 5-carbaldoximequinolinium moiety attached via linker or medium size scaffolds like pyridinium amide attached via linker in order to define possible differences in further interactions with the AChE or BChE binding sites. Notably, pyridinium amides were formerly highlighted for binding within AChE peripheral site 18 .…”

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

“…[11a] These data support the fact and demonstrate that non-quaternary hybrid reactivators based on 3-hydroxy-2-pyridinaldoxime are promising candidates for the optimisationo fn ew antidotes for OPNAp oisoning, for the future. [10,11] Notably,t remendous efforts have been devotedr ecently to the development of synthetic approaches toward the synthesis of novel reactivators, including the use of PSL ligand-oxime conjugates and Ugi multi-component reactions, [12] the use of chloropyridinium oximes [13] andt he development of non-oxime-based reactivators. [14] Nevertheless,t he narrow therapeutic window of some of these reactivators limits their use in vivo because of the lack of comprehensive biological profiling, which is largely hamperedb ys ynthetic accessibility.D espite the recently reporteds trategies, efforts toward the development of more efficient synthetic routes to create centrally active reactivators have been scarce.…”

Pharmacokinetics of Two Chlorine-Substituted Bis-Pyridinium Mono-Aldoximes with Regenerating Effect on Butyrylcholinesterase

“…Both K-867 and K-870 are also pyridinium aldoximes, chlorine-substituted derivatives of K203, as shown in Figure 1. Zorbaz et al [25] determined the BChE reactivating concentrations of various chloride-substituted pyridinium aldoximes. Both K-867 and K-870 showed an adequate regenerating effect in a certain concentration on sarine-poisoned BuChE in vitro.…”