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 cholinesterázy * 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 cholinesterázy * MeSH
• sarin * MeSH
• VX MeSH Prohlížeč

Antidotes against organophosphates often possess physicochemical properties that mitigate their passage across the blood-brain barrier. Cucurbit[7]urils may be successfully used as a drug delivery system for bisquaternary oximes and improve central nervous system targeting. The main aim of these studies was to elucidate the relationship between cucurbit[7]uril, oxime K027, atropine, and paraoxon to define potential risks or advantages of this delivery system in a complex in vivo system. For this reason, in silico (molecular docking combined with umbrella sampling simulation) and in vivo (UHPLC-pharmacokinetics, toxicokinetics; acetylcholinesterase reactivation and functional observatory battery) methods were used. Based on our results, cucurbit[7]urils affect multiple factors in organophosphates poisoning and its therapy by (i) scavenging paraoxon and preventing free fraction of this toxin from entering the brain, (ii) enhancing the availability of atropine in the central nervous system and by (iii) increasing oxime passage into the brain. In conclusion, using cucurbit[7]urils with oximes might positively impact the overall treatment effectiveness and the benefits can outweigh the potential risks.

• Klíčová slova
• CB7, K027, acetylcholinesterase, antidote, cucurbit[7]uril, cucurbiturils, in vivo, mouse, paraoxon, pesticide,
• MeSH
• atropin chemie   MeSH
• hematoencefalická bariéra MeSH
• imidazoly chemie   MeSH
• myši MeSH
• oximy chemie   MeSH
• paraoxon chemie   toxicita   MeSH
• počítačová simulace MeSH
• přemostěné cyklické sloučeniny chemie   MeSH
• pyridinové sloučeniny chemie   MeSH
• reaktivátory cholinesterázy chemie   toxicita   MeSH
• simulace molekulového dockingu MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide MeSH Prohlížeč
• atropin MeSH
• cucurbit(7)uril MeSH Prohlížeč
• imidazoly MeSH
• oximy MeSH
• paraoxon MeSH
• přemostěné cyklické sloučeniny MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterázy MeSH