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

The pyridinium-2-carbaldoximes with quinolinium carboxamide moiety were designed and synthesised as cholinesterase reactivators. The prepared compounds showed intermediate-to-high inhibition of both cholinesterases when compared to standard oximes. Their reactivation ability was evaluated in vitro on human recombinant acetylcholinesterase (hrAChE) and human recombinant butyrylcholinesterase (hrBChE) inhibited by nerve agent surrogates (NIMP, NEMP, and NEDPA) or paraoxon. In the reactivation screening, one compound was able to reactivate hrAChE inhibited by all used organophosphates and two novel compounds were able to reactivate NIMP/NEMP-hrBChE. The reactivation kinetics revealed compound 11 that proved to be excellent reactivator of paraoxon-hrAChE better to obidoxime and showed increased reactivation of NIMP/NEMP-hrBChE, although worse to obidoxime. The molecular interactions of studied reactivators were further identified by in silico calculations. Molecular modelling results revealed the importance of creation of the pre-reactivation complex that could lead to better reactivation of both cholinesterases together with reducing particular interactions for lower intrinsic inhibition by the oxime.

• Klíčová slova
• Organophosphate, acetylcholinesterase, butyrylcholinesterase, oxime, reactivator,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• chinolinové sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• pyridinové sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• rekombinantní proteiny metabolismus   MeSH
• simulace molekulového dockingu MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• chinolinové sloučeniny MeSH
• cholinesterasové inhibitory MeSH
• pyridinové sloučeniny MeSH
• rekombinantní proteiny MeSH

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 cholinesterasy 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 cholinesterasy MeSH

Certain AChE reactivators, asoxime, obidoxime, K027, K048, and K075, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure the different organs. As a continuation of previously published data, in this study, Wistar rats have sacrificed 24 hrs and 7 days after single im application of 0.1LD50, 0.5LD50 and 1.0LD50 of each reactivator, and examinated tissue samples were obtained for pathohistological and semiquantitative analysis. A severity of tissue alteration, expressed as different tissue damage scores were evaluated. Morphological structure of examinated tissues treated with of 0.1LD50 of all reactivators was comparable with the control group of rats. Moderate injuries were seen in visceral tissues treated with 0.5LD50 of asoxime, obidoxime and K027. Acute damages were enlarged after treatment with 0.5LD50 and 1.0LD50 of all reactivators during the next 7 days. The most prominent changes were seen in rats treated with 1.0LD50 of K048 and K075 (P < 0.001 vs. control and asoxime-treated group). All reactivators given by a single, high, unitary dose regimen, have an adverse effect not only on the main visceral tissue, but on the whole rat as well, but the exact mechanism of cellular injury remains to be confirmed in further investigation.

• MeSH
• biopsie MeSH
• chemické bojové látky škodlivé účinky   chemie   toxicita   MeSH
• histocytochemie MeSH
• krysa rodu Rattus MeSH
• LD50 MeSH
• molekulární struktura MeSH
• orgánová specificita MeSH
• oximy aplikace a dávkování   škodlivé účinky   chemie   toxicita   MeSH
• plíce účinky léků   metabolismus   patologie   MeSH
• vnitřnosti účinky léků   patologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• žaludek účinky léků   patologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chemické bojové látky MeSH
• oximy MeSH