Organophosphorus compounds are highly toxic irreversible inhibitors of cholinesterases, causing the disruption of cholinergic functions. Treatment of poisoning includes causal antidotes (oximes) used as reactivators of inhibited cholinesterases, such as pralidoxime. In this work, new halogenated oxime reactivators derived from pralidoxime were developed. The oximes were designed with a halogen substituent that lowers the pK a and enhances oximate formation. Their synthesis, stability, physicochemical properties, inhibition of native cholinesterases, and in vitro reactivation of organophosphate-inhibited cholinesterases were investigated. A series of C4 and C6 halogenated oximes showed instability and their degradation products were identified, while C3 and C5 oximes exhibited sufficient stability for the evaluation. C3 oximes displayed overall low inhibition of cholinesterases and high reactivation ability of organophosphate-inhibited cholinesterases compared to pralidoxime, indicating the significant impact of halogen substitution on reactivation ability.

• Publication type
• Journal Article MeSH

A-series agent A-234 belongs to a new generation of nerve agents. The poisoning of a former Russian spy Sergei Skripal and his daughter in Salisbury, England, in March 2018 led to the inclusion of A-234 and other A-series agents into the Chemical Weapons Convention. Even though five years have already passed, there is still very little information on its chemical properties, biological activities, and treatment options with established antidotes. In this article, we first assessed A-234 stability in neutral pH for subsequent experiments. Then, we determined its inhibitory potential towards human recombinant acetylcholinesterase (HssAChE; EC 3.1.1.7) and butyrylcholinesterase (HssBChE; EC 3.1.1.8), the ability of HI-6, obidoxime, pralidoxime, methoxime, and trimedoxime to reactivate inhibited cholinesterases (ChEs), its toxicity in rats and therapeutic effects of different antidotal approaches. Finally, we utilized molecular dynamics to explain our findings. The results of spontaneous A-234 hydrolysis showed a slow process with a reaction rate displaying a triphasic course during the first 72 h (the residual concentration 86.2%). A-234 was found to be a potent inhibitor of both human ChEs (HssAChE IC50 = 0.101 ± 0.003 µM and HssBChE IC50 = 0.036 ± 0.002 µM), whereas the five marketed oximes have negligible reactivation ability toward A-234-inhibited HssAChE and HssBChE. The acute toxicity of A-234 is comparable to that of VX and in the context of therapy, atropine and diazepam effectively mitigate A-234 lethality. Even though oxime administration may induce minor improvements, selected oximes (HI-6 and methoxime) do not reactivate ChEs in vivo. Molecular dynamics implies that all marketed oximes are weak nucleophiles, which may explain the failure to reactivate the A-234 phosphorus-serine oxygen bond characterized by low partial charge, in particular, HI-6 and trimedoxime oxime oxygen may not be able to effectively approach the A-234 phosphorus, while pralidoxime displayed low interaction energy. This study is the first to provide essential experimental preclinical data on the A-234 compound.

• Keywords
• Acute toxicity, Hydrolysis, Nerve agent A-234, Reactivation, Therapy,
• MeSH
• Acetylcholinesterase MeSH
• Antidotes pharmacology   MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors toxicity   MeSH
• Phosphorus MeSH
• Rats MeSH
• Oxygen MeSH
• Humans MeSH
• Oximes pharmacology   MeSH
• Pralidoxime Compounds * MeSH
• Pyridinium Compounds pharmacology   MeSH
• Cholinesterase Reactivators * pharmacology   MeSH
• Taurine analogs & derivatives   MeSH
• Trimedoxime pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 2-(N-cyclohexylamino)ethanesulfonic acid MeSH Browser
• Acetylcholinesterase MeSH
• Antidotes MeSH
• asoxime chloride MeSH Browser
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Phosphorus MeSH
• Oxygen MeSH
• N,N'-monomethylenebis(pyridiniumaldoxime) MeSH Browser
• Oximes MeSH
• pralidoxime MeSH Browser
• Pralidoxime Compounds * MeSH
• Pyridinium Compounds MeSH
• Cholinesterase Reactivators * MeSH
• Taurine MeSH
• Trimedoxime MeSH

Oxime reactivators of acetylcholinesterase are commonly used to treat highly toxic organophosphate poisoning. They are effective nucleophiles that can restore the catalytic activity of acetylcholinesterase; however, their main limitation is the difficulty in crossing the blood-brain barrier (BBB) because of their strongly hydrophilic nature. Various approaches to overcome this limitation and enhance the bioavailability of oxime reactivators in the CNS have been evaluated; these include structural modifications, conjugation with molecules that have transporters in the BBB, bypassing the BBB through intranasal delivery, and inhibition of BBB efflux transporters. A promising approach is the use of nanoparticles (NPs) as the delivery systems. Studies using mesoporous silica nanomaterials, poly (L-lysine)-graft-poly(ethylene oxide) NPs, metallic organic frameworks, poly(lactic-co-glycolic acid) NPs, human serum albumin NPs, liposomes, solid lipid NPs, and cucurbiturils, have shown promising results. Some NPs are considered as nanoreactors for organophosphate detoxification; these combine bioscavengers with encapsulated oximes. This study provides an overview and critical discussion of the strategies used to enhance the bioavailability of oxime reactivators in the central nervous system.

• Keywords
• Acetylcholinesterase, Blood–brain barrier, Delivery system, Nanoparticle, Oxime, Reactivator,
• MeSH
• Acetylcholinesterase * MeSH
• Biological Availability MeSH
• Biological Transport MeSH
• Central Nervous System * MeSH
• Blood-Brain Barrier MeSH
• Humans MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Acetylcholinesterase * MeSH