The increased concern about terrorist use of
nerve agents prompted us to search for new more effective
oximes against
tabun and
soman poisoning. We investigated the interactions of five bispyridinium
oximes: K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)
propane dibromide], K048 [1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)
butane dibromide], K033 [1,4-bis(2-hydroxyiminomethylpyridinium)
butane dibromide],
TMB-4 [1,3-bis(4-hydroxyiminomethylpyridinium)
propane dibromide] and
HI-6 [(1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane dichloride)] with human erythrocyte
acetylcholinesterase (AChE; E.C. 3.1.1.7) and their effects on
tabun- and
soman-poisoned mice. All the
oximes reversibly inhibited AChE, and the
enzyme-
oxime dissociation constants were between 17 and 180 microM.
Tabun-inhibited AChE was completely reactivated by
TMB-4, K027 and K048, with the overall reactivation rate constants of 306, 376 and 673 min(-1)M(-1), respectively. The reactivation of
tabun-inhibited AChE by K033 reached 50% after 24h, while
HI-6 failed to reactivate any AChE at all.
Soman-inhibited AChE was resistant to reactivation by 1mM
oximes. All studied
oximes protected AChE from phosphorylation with both
soman and
tabun. In vivo experiments showed that the studied
oximes were relatively toxic to mice; K033 was the most toxic (LD50=33.4 mg/kg), while K027 was the least toxic (LD50=672.8 mg/kg). The best antidotal efficacy was obtained with K048, K027 and
TMB-4 for
tabun poisoning, and
HI-6 for
soman poisoning. Moreover, all tested
oximes showed no cytotoxic effect on several cell lines in concentrations up to 0.8mM. The potency of the
oximes K048 and K027 to protect mice from five-fold LD50 of
tabun and their low toxicity make these compounds leading in the
therapy of
tabun poisoning. The combination of
HI-6 and
atropine is the
therapy of choice for
soman poisoning.