Tabun reactivity

Organophosphorons componnds snch a zarin, zoman, and tabun are some of the most toxic chemical componnds known that are nsed as poisonons snbstances in weapons. They cause rapid deterioration of enzymes and cannot nndergo reactivation. Therefore, there is no appropriate therapy for the treatment of snch poisons. 

The kinetic scheme for the reactivation of OP-inhibited AChE is depicted in equation 20 for pyridinium-based aldoximes, where R = CH3 or an alkoxy group, and = alkyl or aryl. The nerve agents that generate the covalent OP-AChE conjugates are those with R = CH3 and R = ethyl(VX), isopropyl (sarin), cyclohexyl (cyclosarin) and pinacolyl (soman). For tabun-inhibited AChE, R = Af,A-dimethylamido and R = ethyl. 

De Jong, L.P.A., Wolring, G.Z. (1978). Effect of l-(AR)alkyl-2-hydroxyimino methyl-pyridium salts on reactivation and aging of actylcholinesterase inhibited by ethyl dimethyl-phosphor-amidocyanidate (tabun). Biochem. Pharmacol. 27 2229-35. 

In contrast to the results for mipafox-inhibited NTE, early limited studies indicated that mipafox-inhibited BChE or AChE undergo irreversible aging, because the enzymes could be reactivated soon after inhibition, but not after 18 h (Milatovic and Johnson, 1993). The chemistry of phosphoramidates suggest that aging could involve hydrolytic loss of an alkylamino group. For example, acid-catalyzed P-N bond fission has been observed for certain A-alkyl phosphoramidates (Eto, 1974) and the aging of tabun-inhibited AChE has been shown to proceed via P-N bond scission with loss of dimethylamine (Elhanany et ah, 2001). 

Clement, J.G. (1982). HI-6 reactivation of central and peripheral acetylcholinersterase following inhibition by soman, sarin and tabun in vivo in the rat. Biochem. Pharmacol. 31 1283-7. 

Pralidoxime was synthesized in the USA in 1955 (Wilson and Ginsburg, 1955). Its four salts - chloride (2-PAM Cl), methiodide, methylsulfate, and mesylate (P2S) - were investigated and introduced into practice. 2-PAM is very efficient in reactivating of AChE inhibited with sarin or VX (Johnson and Stewart, 1970 Sidell and Groff, 1974 Harris and Stitcher, 1983 Mesic et al, 1991 Masuda et al, 1995 Nozaki and Aikawa, 1995), but was not successful in reactivation of the tabun- or soman-inhibited enzyme (Inns... 

DeJong, L.P.A., Verhagen, M., Langenberg, J., Hagedom, I., Loffler, M. (1989). The bispyridinium oxime HLd-7, a potent reactivator for acetylcholinesterase inhibited by the stereoisomers of tabun and soman. Biochem. Pharmacol. 38 633-40. 

Stojiljkovic, M.P., Pantelic, D., Maksimovic, M. (2001). Tabun, sarin, soman and VX poisoning in rats kinetics of inhibition of central and peripheral acetylcholinesterase, ageing, spontaneous and oxime-facilitated reactivation. Vll International Symposium on Protection against Chemical and Biological Agents. Stockholm, Sweden, June 15-19,... 

Reactivation activity of the above-mentioned compounds was tested in vitro on human erythrocyte AChE and compared to pralidoxime, obidoxime, and HI-6. Some of these (6b, 7b) had better reactivating activity against sarin or tabun than commonly used reference compounds. 

Reactivation in vitro was performed on human erythrocyte AChE inhibited by sarin, VX, tabun, or soman without promising results. Toxicity of all these compounds was tested in vitro on human erythrocyte AChE. 

A broad spectrum of pharmacological data was acquired by in vivo experiments on mice, guinea pigs, and dogs. The reactivation experiments were performed in vitro on bovine erythrocyte AChE with soman, sarin, or tabun compared to HI-6, and showed that the methanesulfonate salt of HL6-7 is superior to HI-6 in reactivating soman- or sarin-inhibited AChE and exceeds HI-6 in reactivation of tabim-inhibited AChE. 

Reactivation in vitro was performed on hiunan erythrocyte AChE inhibited by sarin, VX, tabun, or soman. 

Kuca et al. (2003a) tried to find a reactivator with good efficacy against tabun. The synthesis was made using a subsequent approach under the following scheme (Figure 66.23). 

The in vitro test on rat brain homogenate showed that oxime K048 has higher efficacy to reactivate tabun-inhibi-ted AChE than pralidoxime or HI-6, which is comparable with obidoxime. 

The reactivation potency was examined in vitro on rat brain AChE. All tested compounds were less effective reactivators of sarin, cyclosarin, VX, or tabun-inhibited AChE compared to pralidoxime. 

In 2006, a new group of 3-oxapentane linker-containing reactivators (36) was prepared in Korea (Figure 66.29) (Kim et al, 2005). Among them, several derivatives were found to be promising in case of pesticide and tabun-inhibited... 

Among them, oxime K203 seemed to be the best one (Figure 66.38). According to our present knowledge, it is considered to be number one in the case of reactivation of tabun-inhibited AChE (Musilek et al, 2007f). 

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