The newly developed and very promising acetylcholinesterase reactivator (E)-1-(2-hydroxyiminomethylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide was prepared using two different pathways via a two-step synthesis involving the appropriate (E)-1-(4-bromobut-2-enyl)-2- or 4-hydroxyiminomethyl-pyridinium bromides. Afterwards, purities and yields of the desired product prepared by both routes were compared. Finally, its potency to reactivate several nerve agent-inhibited acetylcholinesterases was tested.

Department of Toxicology Faculty of Military Health Sciences Trebesska 1575 500 01 Hradec Kralove Czech Republic

Zobrazit více v PubMed

Marrs T.C. Organophosphate poisoning. Pharmacol. Therap. 1993;58:51–66. doi: 10.1016/0163-7258(93)90066-M. PubMed DOI

Bajgar J. Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment. Adv. Clin. Chem. 2004;38:151–216. PubMed

Kuca K., Jun D., Musilek K. Structural requirements of acetylcholinesterase reactivators. Mini-Rev. Med. Chem. 2006;6:269–277. PubMed

Pang YP., Kollmeyer TM., Hong F., Lee JC., Hammond PI., Haugabouk SP., Brimijoin S. Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators. Chem. Biol. 2003;10:491–502. doi: 10.1016/S1074-5521(03)00126-1. PubMed DOI

Musilek K., Kuca K., Jun D., Dohnal V., Dolezal M. Synthesis of the novel series of bispyridinium compounds bearing (E)-but-2-ene linker and evaluation of their reactivation activity against chlorpyrifos-inhibited acetylcholinesterase. Biorg. Med. Chem. Lett. 2006;16:622–627. PubMed

Kim T.H., Kuca K., Jun D., Jung Y.S. Design and synthesis of new bis-pyridinium oximes as cyclosarin-inhibited acetylcholinesterase reactivators. Bioorg. Med. Chem. Lett. 2005;15:2914–2917. doi: 10.1016/j.bmcl.2005.03.060. PubMed DOI

Musilek K., Holas O., Hambalek J., Kuca K., Jun D., Dohnal V., Dolezal M. Synthesis of Bispyridinium Compounds bearing Propane Linker and Evaluation of their Reactivation Activity against Tabun- and Paraoxon-Inhibited Acetylcholinesterase. Lett. Org. Chem. 2006;3:831–835. doi: 10.2174/157017806779117012. PubMed DOI

Musilek K., Kuca K, Jun D., Dolezal M. Progress in synthesis of new acetylcholinesterase reactivators during the period 1990-2004. Curr. Org. Chem. 2007;11:229–238.

Kuca K., Bielavsky J., Cabal J., Bielavska M. Synthesis of a potential reactivator of acetylcholinesterase 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium)-propane dibromide. Tetrahedron Lett. 2003;44:3123–3125.

Kuca K., Kassa J. In vitro reactivation of acetylcholinesterase using of the oxime K027. Vet. Hum. Toxicol. 2004;46:15–18. PubMed

Kassa J., Kuca K., Cabal J., Paar M. A comparison of the efficacy of new asymmetric bispyridinium oximes (K027, K048) with currently available oximes against tabun by in vitro and in vivo methods. J. Toxicol. Env. Health. 2006;69:1875–1882. PubMed

Calic M., Lucic-Vrdoljak A., Radic B., Jelic D., Jun D., Kuca K., Kovarik Z. In vitro and in vivo evaluation of pyridinium oximes: mode of interaction with acetylcholinesterase, effect on tabun- and soman-poisoned mice and their cytotoxicity. Toxicology. 2006;219:85–96. doi: 10.1016/j.tox.2005.11.003. PubMed DOI

Petroianu GA., Arafat K., Kuca K., Kassa J. Five oximes (K-27, K-33, K-48, BI-6 and methoxime) in comparison with pralidoxime: in vitro reactivation of red blood cell acetylcholinesterase inhibitied by paraoxon. J. Appl. Toxicol. 2006;26:64–71. doi: 10.1002/jat.1108. PubMed DOI

Petroianu GA., Nurulain SM., Nagelkerke N., Al-Sultan MAH., Kuca K., Kassa J. Five oximes (K-27, K-33, K-48, BI-6 and methoxime) in comparison with pralidoxime: survival in rats exposed to the organophosphate paraoxon. J. Appl. Toxicol. 2006;26:262–268. PubMed

Tekes K., Hasan MY., Sheen R., Kuca K., Petroianu G. HPLC determination of the serum concentration of K-27, a novel oxime-type cholinesterase reactivator. J. Chromatogr. A. 2006;1122:84–87. doi: 10.1016/j.chroma.2006.04.016. PubMed DOI

Lucic-Vrdoljak A., Calic M., Radic B., Berend S., Kuca K., Kovarik Z. Pre-treatment with pyridinium oximes improves antidotal therapy against tabun poisoning. Toxicology. 2006;228:41–50. PubMed

Gupta R. Cl Cholinesterase inhibitors as chemical warfare agents: Community preparedness guidelines. Elsevier Academic Press; London: 2006. Toxicology of organophosphate & carbamate compounds; pp. 47–68.

Kuca K., Jun D., Musilek K., Bajgar J. Structure-activity relationship for the reactivators of acetylcholinesterase inhibited by nerve agent VX. Toxicol. Lett. 2006;164:S51–S52. doi: 10.1016/j.toxlet.2006.06.109. PubMed DOI

Kuca K., Cabal J. Evaluation of newly synthesized reactivators of the brain cholinesterase inhibited by sarin-nerve agent. Toxicol. Mech. Meth. 2005;15:247–252. PubMed

Experimental and Established Oximes as Pretreatment before Acute Exposure to Azinphos-Methyl