Tabun inhibited AChE

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. 

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). 

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. 

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). 

Another five monoquatemary oximes were prepared and tested in Croatia by Dr Kovarik s group (47) (Figure 66.40). All oximes inhibited human AChE reversibly. All prepared oximes reached reactivation of tabun-inhibited AChE within 24 h from 30 to 80% (Odzak et al., 2007). 

With the aim of decreasing the size of the reactivator, one oxime group was withdrawn fi om the trimedoxime structure (48) (Figure 66.41). Such modification of the trimedoxime stmcture decreased its reactivation activity in the case of tabun-inhibited AChE. On the contrary, it increased its reactivation activity in the case of cyclosarin-inhibited AChE (Kuca et al., 2007c). 

FIGURE 66.23. Synthesis of reactivator K048 for tabun-inhibited AChE. 

Generally, the ability of currently available oximes including H oximes to reactivate tabun-inhibited AChE in peripheral as well as central compartment is relatively low. On the contrary of other nerve agents, obidoxime has a higher potency to reactivate tabun-inhibited AChE than HI-6 especially in the central compartment (25). 

There were and are some attempts to synthesize new reactivators with the aim of making them universal or more effective, especially against soman- or tabun-inhibited AChE, both in the past (D13, D14, D15) and presently (K41, K42, K43, K44) (for review, see, e.g., P9). A number of alternative oximes have been shown to be significantly more effective and have a broader spectrum of action than the pralidoxime and several of these may be as or more effective than HI-6 (K30). However, the results obtained up to now are not of enough interest to introduce them into medical practice. An exhaustive review on cholinesterase reactivators has been published by Kassa (K7). 

FIGURE 72.5 Reactivator of oximes K048 and K027 for tabun-inhibited AChE (Kuca et al., 2003a,b). 

In the same laboratory, a new series of four monoquaternary compounds (6 Figure 72.7), using the original synthetic strategy was prepared (Kuca et al., 2004b). The reactivation potency was examined in vitro on rat brain AChE. All tested compounds were less effective reactivators of sarin, cyclosarin, VX, and tabun-inhibited AChE than pralidoxime. 

A series of seven novel, uncharged compounds (Renou et al., 2013) combining 3-hydroxy-2-p5Tidinealdoxime with different PSLs was prepared and examined for VX- and tabxm-inhibited human AChE (44 Figure 72.33). Concerning in vitro reactivation of VX-hAChE, they were more efficient than pralidoxime, but less efficient than obidoxime and asoxime. Regarding tabun-inhibited AChE, only one compound reached a reactivation potency comparable to pralidoxime. 

Kuca, K., Cabal, J., Musilek, K., et al., 2005a. Effective bisquaternary reactivators of tabun-inhibited AChE. J. Appl. Toxicol. 25, 491 95. 

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