hs-6 and cyclohexyl-methylphosphonofluoridate

The oximes 4-carbamoyl-1-[({2-[(E)-(hydroxyimino) methyl] pyridinium-1-yl} methoxy) methyl] pyridinium (known as HI-6) and 3-carbamoyl-1-[({2-[(E)-(hydroxyimino) methyl] pyridinium-1-yl} methoxy) methyl] pyridinium (known as HS-6) are isomers differing from each other only by the position of the carbamoyl group on the pyridine ring. However, this slight difference was verified to be responsible for big differences in the percentual of reactivation of acetylcholinesterase (AChE) inhibited by the nerve agents tabun, sarin, cyclosarin, and VX. In order to try to find out the reason for this, a computational study involving molecular docking, molecular dynamics, and binding energies calculations, was performed on the binding modes of HI-6 and HS-6 on human AChE (HssAChE) inhibited by those nerve agents.

Topics: Acetylcholinesterase; Chemical Warfare Agents; Cholinesterase Inhibitors; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Nerve Agents; Organophosphates; Organophosphorus Compounds; Organothiophosphorus Compounds; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Sarin

Cyclosarin (GF-agent; O-cyclohexylmethylfluorophosphonate) belongs to highly toxic organophosphorus compounds. Potential for exposure to chemical warfare organophosphosphorus nerve agents, such as cyclosarin exists on the battlefield, or in the civilian sector as a threat by a terrorist group, as well as an accident as part of current demilitarization efforts. Cyclosarin was not in a front of scientific interest for long time. The research interest was increased after Operation Desert Shield and Desert Storm with the possibility (later confirmed by the UN special commission) that cyclosarin constituted the Iraqi chemical agent inventory. In this study, the neurotoxicity of cyclosarin and therapeutic efficacy of three oximes [HI-6(1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxa-propane dichloride), BI-6(2-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)-but-2-ene dibromide), HS-6(2-hydroxyiminomethylpyridinium)-3-(3-carbamoylpyridinium)-2-oxa-propane dichloride)] as acetylcholinesterase reactivators in combination with atropine was studied in rats. The therapy was administered intramusculary (i.m.) 1 min after i.m. GF-agent challenge (1 LD50). Testing of cyclosarin-induced neurotoxicity progress was carried out using the method of Functional observational battery (FOB). The experimental animals were observed at 24 h and 7 days following cyclosarin administration. The results were compared to the condition of control rats that received physiological solution instead of cyclosarin and treatment. All tested antidotal compounds induced neuroprotective efficacy, because decrease of neurotoxicity signs was recorded. There were no poisoned experimental group treated with atropine only, because our preliminary study showed no therapeutical effect of atropine alone. Cyclosarin caused a marked statistically significant change in most of the neurobehavioral parameters (FOB) at 24 h and 7 days after exposure, compared to the saline control group. Survival was 7/10 at 24 h and 5/10 at 7 days. Oxime (BI-6, HS-6 or HI-6) + atropine treatment caused a progressing recovery of the neurobehavioral disturbances caused by cyclosarin at 24 h and 7 days after exposure.

Topics: Animals; Antidotes; Behavior, Animal; Chemical Warfare Agents; Injections, Intramuscular; Male; Molecular Structure; Neurotoxicity Syndromes; Organophosphorus Compounds; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Rats, Wistar

The present study was performed to assess and compare a therapeutic efficacy of obidoxime, HI-6, BI-6 and HS-6 administered in equimolar doses and combined with atropine in cyclosarin-poisoned mice and rats. It was demonstrated that all the therapeutic regimens tested, were able to decrease the cyclosarin-induced toxicity significantly - at least 1.5 times. Higher therapeutic ratios, almost three times, were achieved in rats in comparison with mice. The highest therapeutic ratio was achieved for therapeutic regimen consisting of HI-6 and atropine in both mice and rats. Obidoxime was the least effective oxime in the treatment of cyclosarin intoxication. The BI-6 oxime was significantly more efficacious than obidoxime (in both mice and rats) and HS-6 (in rats) but its effectiveness did not reach the efficacy of HI-6.

Topics: Animals; Cholinesterase Reactivators; Female; Mice; Obidoxime Chloride; Organophosphate Poisoning; Organophosphorus Compounds; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats