Reactivation of cyclosarin-inhibition

Owing to the fact that HI-6 is at the present time considered as the reactivator of first choice, there are many efforts to improve its application. One approach is the choice of the right counteranion of the reactivator. The anion could influence the solubility and stability of the reactivator in the solution. In 2007,12 different salts of HI-6 (sulfate, chloride, acetate, bromide, phosphate, mesylate, tartarate, iodide, malonate, salicylate, maleinate, tosylate) were prepared and tested to discover how the anion can influence the self-reactivation process. It was found that there is no difference in the reactivation of cyclosarin-inhibited AChE (Kuca et al, 2007b). 

As shown, the ideal length of the reactivator s linker for satisfactory activity of tabun, sarin, or VX-inhibited AChE is three or four methylenes. On the other hand, one methylene group seems to be the most potent reactivator of cyclosarin-inhibited AChE. 

Kuca, K., Patocka, J. (2004). Reactivation of cyclosarin-inhibited rat brain acetylcholinesterase by pyridinium-oximes. J. Enzyme Inhib. Med. Chem. 19 39 3. 

Kuca, K., Cabal, J., Patocka, J., Kassa, J. (2004a). Synthesis of bisquatemary symmetric - ), 5-bis(2-hydroxyiminomethyl-pyridinium)alkane dibromides and their reactivation of cyclosarin-inhibited acetylcholinesterase. Lett. Org. Chem. 1 84-6. 

Presently used pralidoxime and obidoxime are also very poor reactivators of cyclosarin-inhibited AChE in vivo (28,29). On the other hand, H oximes seem to be very good reactivators of cyclosarin-inhibited AChE in peripheral and central compartments (30). The efficacy of methoxime to reactivate cyclosarin-in-... 

MMB-4 was also less effective in reactivation of cyclosarin-inhibited rat brain AChE and sarin-inhibited human or monkey AChE compared with HI-6 (Kuca and Patocka, 2004 Lundy et al., 2011). MMBM was found to be a weak reactivator of tabun-inhibited human AChE (Worek et al., 2004). However, experimental data indicate that MMB-4 was superior to PAM-2 in reactivating OP-inhibited AChE and in preventing lethality in OP-poisoned animals (Worek et al., 2010). It was also reported that MMB-4 was the most effective oxime in reactivation of ChE in blood and peripheral tissues in guinea pigs poisoned by sarin, cyclosarin, VX, and VR (Shih et al., 2010). In addition, MMB-4 was reported to be a better AChE reactivator than PAM-2 in paraoxon-poisoned and methylparaoxon-poisoned rats (Petroianu et al., 2006,2007). 

Kuca et al. (2004a) also synthesized and tested activity of symmetrical bispyridinium dicarbaldoximes (4-5 Figure 72.6) in vitro against cyclosarin-inhibited AChE. The compound l,4-bis(2-hydroxyiminomethylpyridin-ium)butane dibromide (4 K033) gave promising results in in vitro reactivation of cyclosarin-inhibited AChE compared to commonly used pralidoxime. 

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. 

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). 

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. 

Kim, T.H., Kuca, K., Jun, D., Jung, Y.S. (2005). Design and synthesis of new bis-pyridinium oximes as cyclosarin-inhibited acetylcholinesterase reactivators. Bioorg. Med. Chem. Lett. 15 2914-17. 

Musilek, K., Lipka, L., Racakova, V., Kuca, K., Jun, D., Dohnal, V., Dolezal, V. (2006b). New methods in synthesis of acetylcholinesterase reactivators and evaluation of their potency to reactivate cyclosarin-inhibited AChE. Chem. Papers 60 48-51. 

Kuca, K., Cabal, J. and Kassa, J. A comparison of the efficacy of a bispyridinium oxime-1,4-bis-(2-hydro-xyiminomethylpyridinium) butane dibromide and currently used oximes to reactivate sarin, tabun or cyclosarin-inhibited acetylcholinesterase by in vitro methods, Pharmazie, 59, 795, 2004. 

Figure 4. Comparison of the reactivation efficiencies of various oximes on sarin-, VX- and cyclosarin-inhibited human and guinea-pig AChE. The ratios of the second-order rate constants, k, between human and guinea-pig AChE are given...

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 library of novel AChE reactivators based on imidazole aldoximes and N-substituted 2-hydroxyiminoacet-amides (35-36 Figure 72.28) was screened by Sit et al. (2011). Compounds were screened for reactivation of sarin-, cyclosarin-, VX-, and paraoxon-inhibited human AChE. Reactivators exhibited reactivation activity that was comparable or greater than that of pralidoxime, monoisonitrosoacetone (MINA), and 2,3-butanedione monooxime. Unfortunately, standard substances used in this field (i.e., obidoxime and asoxime) were not compared in this study. More recently, some oximes from this library were tested against tabun-inhibited human AChE (Kovarik et al., 2013). Some selected compounds were able to reactivate tabim inhibition with a performance comparable to pralidoxime, but they were not as effective as the bisquatemary standards trimedoxime and obidoxime. Radic et al. (2012) published presented pyridinium and non-pyridinium oxime reactivators derived from pralidoxime and edrophonium (37-39 Figure 72.29). Compounds were tested on cyclosarin-, VX-, and paraoxon-inhibited human AChE and BChE and compared to pralidoxime and asoxime. Some novel compounds were found to be better reactivators than... 

Kuca, K., Cabal, J., Jim, D., Hrahinova, M. (2007). Potency of five structurally different acetylcholinesterase reactivators to reactivate human brain cholinesterases inhibited by cyclosarin. Clin. Toxicol. (Phila.) 45 512-15. 

Kuca, K., Cabal, J., Jun, D., Kassa, K., Bartosova, L., Kunesova, G. (2005c). In vitro reactivation potency of some acetylcholinesterase reactivators against sarin and cyclosarin-induced inhibitions. J. Appl. Toxicol. 25 296-300. 

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