engleski

Review of some oximes as antidotes against organophosphate poisoning

We have recently summarized the synthesis of 157 oximes that were prepared in Croatia over the past 30 years. The oximes were mono- and bis-quaternary derivatives of pyridinium, imidazolium and quinuclidiniuim compounds, and conjugates which contained two different moieties in the same molecule. Some in vitro and in vivo properties of these compounds are reviewed in this presentation. Out of 86 oximes screened as inhibitors of human erythrocyte acetylcholinesterase (AChE), ten compounds had a high affinity for the enzyme (I-50 values in the micromolar range), while all other oximes had affinities similar to the standard oximes like PAM-2 and Toxogonin. Only seven compounds were studied for their binding sites on AChE, and these were shown to have affinity for both the catalytic and the allosteric site in the enzyme. Compounds that bind to both sites on AChE protected better the AChE from inhibition by organophosphates, than compounds binding only to one site of the enzyme. Out of 109 oximes screened as reactivators of phosphylated AChE, 24 compounds reactivated well the AChE-Sarin and AChE-VX conjugates, five compounds reactivated the AChE-Tabun conjugate, and two compound (pyridinium-imidazolium and pyridinium-quinuclidinium derivatives) reactivated even the AChE-Soman conjugate. Between 15 to 21 oximes protected mice or rats against intoxication by nerve agents. The most efficient compound against Soman and Tabun was one imidazolium-quinuclidinium derivative. No structure/activity relationships could be derived from these studies, but compounds that proved effective as antidotes would be worthwhile studying in more detail.

acetylcholinesterase; inhibition; reactivation; protection; warfare agents

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