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.

• Publikační typ
• časopisecké články MeSH

Six novel brominated bis-pyridinium oximes were designed and synthesized to increase their nucleophilicity and reactivation ability of phosphorylated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Their pKa was valuably found lower to parent non-halogenated oximes. Stability tests showed that novel brominated oximes were stable in water, but the stability of di-brominated oximes was decreased in buffer solution and their degradation products were prepared and characterized. The reactivation screening of brominated oximes was tested on AChE and BChE inhibited by organophosphorus surrogates. Two mono-brominated oximes reactivated AChE comparably to non-halogenated analogues, which was further confirmed by reactivation kinetics. The acute toxicity of two selected brominated oximes was similar to commercially available oxime reactivators and the most promising brominated oxime was tested in vivo on sarin- and VX-poisoned rats. This brominated oxime showed interesting CNS distribution and significant reactivation effectiveness in blood. The same oxime resulted with the best protective index for VX-poisoned rats.

• Klíčová slova
• Cholinesterase, Nerve agent, Nucleophile, Organophosphate, Oxime, Reactivation,
• MeSH
• acetylcholinesterasa * metabolismus   účinky léků   MeSH
• butyrylcholinesterasa * metabolismus   MeSH
• chemické bojové látky toxicita   MeSH
• cholinesterasové inhibitory * toxicita   farmakologie   MeSH
• halogenace MeSH
• krysa rodu Rattus MeSH
• nervová bojová látka * toxicita   MeSH
• organothiofosforové sloučeniny * toxicita   MeSH
• oximy * farmakologie   chemie   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny farmakologie   MeSH
• reaktivátory cholinesterasy * farmakologie   chemie   MeSH
• sarin * toxicita   MeSH
• stabilita léku MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa * MeSH
• butyrylcholinesterasa * MeSH
• chemické bojové látky MeSH
• cholinesterasové inhibitory * MeSH
• nervová bojová látka * MeSH
• organothiofosforové sloučeniny * MeSH
• oximy * MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterasy * MeSH
• sarin * MeSH
• VX MeSH Prohlížeč

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.

• Klíčová slova
• Acetylcholinesterase, Blood–brain barrier, Delivery system, Nanoparticle, Oxime, Reactivator,
• MeSH
• acetylcholinesterasa * MeSH
• biologická dostupnost MeSH
• biologický transport MeSH
• centrální nervový systém * MeSH
• hematoencefalická bariéra MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• acetylcholinesterasa * MeSH