SVIBOR - Project code: 3-01-509

MINISTRY OF SCIENCE AND TECHNOLOGY

Strossmayerov trg 4, HR - 10000 ZAGREB
tel.: +385 1 459 44 44, fax: +385 1 459 44 69
E-mail: ured@znanost.hr

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Project code: 3-01-509


BIOLOGICAL INVESTIGATIONS OF ANTIDOTES AGAINST HIGHLY TOXIC OP-COMPOUNDS, POISONINGS


Main researcher: RADIĆ, BOŽICA (39615)



Assistants
Type of research: basic
Duration from: 06/01/93. to 06/01/96.

Papers on project (total): 6
Papers on project quoted in Current Contents: 4
Institution name: Institut za medicinska istraživanja i medicinu rada, Zagreb (22)
Department/Institute: Laboratory of toxicology
Address: Ksaverska cesta 2
City: 10000 - Zagreb, Croatia
Communication
Phone: 385 (041-434-188)
Fax: 385 (041 -274-572)
E-mail: fuchs¦olimp.irb.hr

Summary: A series of new bis-(pyridinium, pyridinium-imidazolium and imidazolium oximes) linked together with alkane, ether and diether chains, with methyl, benzyl, phenyl and 4-fluorophenyl substituents at position 3 of the imidazole ring, were tested. All compounds have been characterized by elemental analysis, IR and NMR - spectroscopy. In vitro inhibitory effect of the oximes (IC-50) was determined on human erythrocyte AChE, and their acute toxicity (LD-50) determined in male mice. From the preliminary investigations it was shown: the diether linkage highers the inhibitory power in all classes of investigated compounds. The bis-imidazolium oximes are stronger inhibitors than their corresponding piridinium imidazolium analogues. In compounds containing alkane chain, methyl and benzyle groups when compared to phenyl and substituted phenyl groups strenghten the inhibitory power. The inhibitory power (IC-50), reactivation of soman phosphylated AChE and protection of human erythrocyte AChE against inhibition by soman were determined by applying four new synthetized N-phenyl imidazolium oximes and several pyridinium-quinuclidinium oximes. Acute toxicity (LD-50) in male mice was determined "in vivo" as well as the protection against soman intoxication.

Keywords: Acetylcholinesterase reactivators,Oximes Pyridinium oximes,Organophosphorus compounds,Soman, Sarin, WX,Tabun, Nerve agents, Quinuclidinium oximes.

Research goals: It is well known that oximes are reactivators ofacetylcholinesterases inhibited by organophosphorus compounds.Since this property of oximes was observed, numerous compounds ofdifferent structure have been synthetised and tested. The aim ofthis investigation is to test antidotal properties of newsithetised imidazolium oximes against AChE erythrocytes inhibitedby soman and other highly toxic organophosphoruscompounds.Investigations are focused on the biochemicalproperties of tested compounds responsible for antidotal effects against highly toxic poisonings.Their toxicity,reactivationpotency and protective ability against phosphylated AChE will betested. Biological experiments of these new synthetised oximeswill be done "in vivo" on the experimental animals as support ofgiven "in vitro" results. The final goal of this project is to compare the results of thedetermined activity of new synthetised imidazolium oximes withactivities of usualy used antidotes (mono- and bis-pyridiniumoximes) and to achieve better protection effects against thesestrong poisons. The investigation was aimed at finding out to what extent the nature of the p-CH3 substituent in N-phenyl imidazoline oximes effects the "in vitro" inhibitory power (IC-50) on human erythrocyte AChE, reactivation percentage of human erythrocyte AChE inhibited by soman and "in vitro" protection against soman. Acute toxicity (LD-50) in male mice was determined "in vivo" as well as the protection against soman poisoning. In addition several compounds (quinuclidinium oximes) that could have a possible reactivatory ability and their activity were determined also.


COOPERATION - PROJECTS


  1. Name of project: 1-o7-241 Sinteza i biološko djelovanje antidota organofosfornih spojeva
    Name of institution: Prirodoslovno- Matematički fakultet Sveučilišta u Zagrebu
    City: 10000 - Zagreb, Croatia


COOPERATION - INSTITUTIONS


  1. Name of institution: Prirodoslovno-Matematički fakultet Sveučilišta u Zagrebu
    Type of institution: University/Faculty
    Type of cooperation: Joint publishing of scientific papers
    City: 10000 - Zagreb, Croatia

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Last update: 10/02/95
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