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.

• Keywords
• Cholinesterase, Nerve agent, Nucleophile, Organophosphate, Oxime, Reactivation,
• MeSH
• Acetylcholinesterase * metabolism   drug effects   MeSH
• Butyrylcholinesterase * metabolism   MeSH
• Chemical Warfare Agents toxicity   MeSH
• Cholinesterase Inhibitors * toxicity   pharmacology   MeSH
• Halogenation MeSH
• Rats MeSH
• Nerve Agents * toxicity   MeSH
• Organothiophosphorus Compounds * toxicity   MeSH
• Oximes * pharmacology   chemistry   MeSH
• Rats, Wistar MeSH
• Pyridinium Compounds pharmacology   MeSH
• Cholinesterase Reactivators * pharmacology   chemistry   MeSH
• Sarin * toxicity   MeSH
• Drug Stability MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase * MeSH
• Butyrylcholinesterase * MeSH
• Chemical Warfare Agents MeSH
• Cholinesterase Inhibitors * MeSH
• Nerve Agents * MeSH
• Organothiophosphorus Compounds * MeSH
• Oximes * MeSH
• Pyridinium Compounds MeSH
• Cholinesterase Reactivators * MeSH
• Sarin * MeSH
• VX MeSH Browser

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.

• Keywords
• CB7, K027, acetylcholinesterase, antidote, cucurbit[7]uril, cucurbiturils, in vivo, mouse, paraoxon, pesticide,
• MeSH
• Atropine chemistry   MeSH
• Blood-Brain Barrier MeSH
• Imidazoles chemistry   MeSH
• Mice MeSH
• Oximes chemistry   MeSH
• Paraoxon chemistry   toxicity   MeSH
• Computer Simulation MeSH
• Bridged-Ring Compounds chemistry   MeSH
• Pyridinium Compounds chemistry   MeSH
• Cholinesterase Reactivators chemistry   toxicity   MeSH
• Molecular Docking Simulation MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide MeSH Browser
• Atropine MeSH
• cucurbit(7)uril MeSH Browser
• Imidazoles MeSH
• Oximes MeSH
• Paraoxon MeSH
• Bridged-Ring Compounds MeSH
• Pyridinium Compounds MeSH
• Cholinesterase Reactivators MeSH