engleski

Oxime derivatives as antidotes in experimental poisoning by organophosphates in relation to the oxime molecular structure

We summarize published data on the antidotal efficiency of oxime compounds synthesized over the past 30 years at the Department of Organic Chemistry, Faculty of Science, University of Zagreb, Croatia. The compounds contained one or two oxime groups on quaternary derivatives of pyridinium, imidazolium or quinuclidinium. They were tested on mice or rats poisoned by Soman, Tabun, Sarin or VX. Usually, one fourth of the oxime LD50 was given intraperitoneally together with atropine, immediatelly after a subcutaneous administration of the organophosphorus compound (OP). The antidotal efficiency was expressed as the therapeutic factor (TF = LD50(OP+oxime) / LD50(OP only). Of the 20 compounds tested on Sarin and VX almost all had TF higher than 2, and were equally or even more efficient than the standard oximes PAM-2, HI-6, Toxogonin and TMB-4. They were pyridinium or pyridinium-imidazolium oximes and the best was bis(2-hydroxyimino-pyridinium linked by 2-oxapropane-1, 3-diyl to pyridinium), with TF 9.0 for Sarin, and higher than 20 for VX. The same compounds were also efficient against Soman and Tabun. Among 44 compounds tested on Soman, seven had the TF higher than 2.9 thus ensuring better protection than any standard oxime. The best antidote for Soman (TF=5.3) was a carbamoylated quinuclidinium linked by 2-oxapropane-1, 3-diyl to 2-hydroxyimino-methylimidazolium. The same compound had TF 4.3 in poisoning by Tabun. The best against Tabun (TF: 4.9 and 4.4) were N-benzyl-2-hydroxyimino-imidazolium linked by 2-oxapropane-1, 3-diyl to N-benzyl-2-hydroxyimino-imidazolium and N-benzyl-2-hydroxyimino-imidazolium linked by 2-oxapropane-1, 3-diyl to 2-hydroxyimino-pyridinium. These two compounds also reactivated acetylcholinesterase inhibited by Tabun in vitro. Almost all oximes efficient in vivo against Sarin or VX, also reactivated acetylcholinesterase inhibited by these agents in vitro. Of the 13 tested quinuclidinium derivatives, eleven oximes were efficient antidotes in Soman poisoning. Many of the prepared oximes seem promising as antidotes for Soman and Tabun and it would be therefore worthwhile to investigate systematically the most efficient compounds against these two OPs in order to disclose a likely structure-activity relationship concerning in vitro reactivation, in vivo and in vitro protection, and therapy.

organophosphorus compounds; antidotes; oximes; structure/activity relationship

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