Cyclosarin inhibited AChE

Kuca et al (2004a) also synthesized and in vitro tested activity of symmetric bispyridinium dicarbaldoximes against cyclosarin-inhibited AChE (Figure 66.25). 

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). 

With the aim of decreasing the size of the reactivator, one oxime group was withdrawn fi om the trimedoxime structure (48) (Figure 66.41).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). 

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., Musilek, K., Stodulka, P., Marek, J., Hanusova, P., Jun, D., Hrabinova, M., Kassa, J., Dolezal, B. (2007b). Twelve different HI-6 salts and their potency to reactivate cyclosarin inhibited AChE in vitro. Lett. Drug Des. Disc. 4 510-12. 

Contrary to other oximes, cyclosarin significantly increases the strength of methoxime binding to cyclosarin-inhibited AChE because of an improvement of the... 

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-... 

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. 

Musilek, K., Lipka, L., Racakova, V, et al., 2006b. New methods in synthesis of acetylcholinesterase reactivators and evaluation of their potency to reactivate cyclosarin-inhibited AChE. Chem. Papers 60, 48-51. 

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. 

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. 

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...

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). 

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. 

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