Organophosphorus (OP) compounds are used as both chemical weapons and pesticides. However, these agents are very dangerous and toxic to humans, animals, and the environment. Thus, investigations with reactivators have been deeply developed in order to design new antidotes with better efficiency, as well as a greater spectrum of action in the acetylcholinesterase (AChE) reactivation process. With that in mind, in this work, we investigated the behavior of trimedoxime toward the Mus musculus acetylcholinesterase (MmAChE) inhibited by a range of nerve agents, such as chemical weapons. From experimental assays, reactivation percentages were obtained for the reactivation of different AChE-OP complexes. On the other hand, theoretical calculations were performed to assess the differences in interaction modes and the reactivity of trimedoxime within the AChE active site. Comparing theoretical and experimental data, it is possible to notice that the oxime, in most cases, showed better reactivation percentages at higher concentrations, with the best result for the reactivation of the AChE-VX adduct. From this work, it was revealed that the mechanistic process contributes most to the oxime efficiency than the interaction in the site. In this way, this study is important to better understand the reactivation process through trimedoxime, contributing to the proposal of novel antidotes.

• Klíčová slova
• acetylcholinesterase, computational methods, mechanistic studies, nerve agents, reactivation, trimedoxime,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota farmakologie   MeSH
• cholinesterasové inhibitory metabolismus   farmakologie   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• myši MeSH
• nervová bojová látka chemie   MeSH
• organofosforové sloučeniny chemie   MeSH
• oximy chemie   MeSH
• reaktivátory cholinesterázy chemie   farmakologie   MeSH
• trimedoxim farmakologie   terapeutické užití   MeSH
• výpočetní biologie metody   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• antidota MeSH
• cholinesterasové inhibitory MeSH
• nervová bojová látka MeSH
• organofosforové sloučeniny MeSH
• oximy MeSH
• reaktivátory cholinesterázy MeSH
• trimedoxim MeSH

BACKGROUND: Based on in vitro and in vivo rat experiments, the newly developed acetylcholinesterase (AChE) reactivator, K203, appears to be much more effective in the treatment of tabun poisonings than currently fielded oximes. METHODS: To determine if this reactivating efficacy would extend to humans, studies were conducted in vitro using human brain homogenate as the source of AChE. The efficacy of K203 was compared with commercially available oximes; pralidoxime, obidoxime and asoxime (HI-6). RESULTS: Reactivation studies showed that K203 was the most effective reactivator with a second order kinetic constant (kr) of 2142 min- 1. M- 1, which was 51 times higher than that obtained for obidoxime (kr = 42 min- 1. M- 1). Both pralidoxime and asoxime (HI-6) failed to significantly reactivate tabun-inhibited human AChE. DISCUSSION: According to these results and previous studies, using K203, it appears that oxime K203 is the most effective reactivator of tabun-inhibited cholinesterase in several species including humans and should be considered as a possible medical countermeasure to tabun exposure.

• Klíčová slova
• Antidotes, Chemical warfare agents, Oxime, Poisoning, Reactivator, Treatment,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota metabolismus   MeSH
• cholinesterasové inhibitory metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• mozek enzymologie   MeSH
• organofosfáty metabolismus   MeSH
• oximy metabolismus   MeSH
• pyridinové sloučeniny metabolismus   MeSH
• reaktivátory cholinesterázy metabolismus   MeSH
• simulace molekulového dockingu MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)but-2-ene MeSH Prohlížeč
• acetylcholinesterasa MeSH
• antidota MeSH
• cholinesterasové inhibitory MeSH
• organofosfáty MeSH
• oximy MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterázy MeSH
• tabun MeSH Prohlížeč

The complexes of Fe(II), Mn(II) and Ni(II) with a combination of a Schiff base, nitrogen-donor ligand or macrocyclic ligand and trithiocyanuric acid (ttcH3) were prepared and characterized by elemental analysis and spectroscopies. Crystal and molecular structures of the iron complex of composition [Fe(L1)](ttcH2)(ClO4)·EtOH·H2O (1), where L1 is Schiff base derived from tris(2-aminoethyl)amine and 2-pyridinecarboxaldehyde, were solved. It was found that the Schiff base is coordinated to the central iron atom by six nitrogens forming deformed octahedral arrangement, whereas trithiocyanurate(1-) anion, perchlorate and solvent molecules are not coordinated. The X-ray structure of the Schiff base sodium salt is also presented and compared with the iron complex. The anticholinesterase activity of the complexes was also studied.

• MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• cholinesterasy metabolismus   MeSH
• enzymatické testy MeSH
• ethylendiaminy chemie   MeSH
• komplexní sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• komplexní směsi chemie   MeSH
• krysa rodu Rattus MeSH
• krystalografie rentgenová MeSH
• ligandy MeSH
• mangan chemie   MeSH
• mozek účinky léků   enzymologie   MeSH
• nikl chemie   MeSH
• pyridiny chemie   MeSH
• Schiffovy báze chemie   MeSH
• triaziny chemie   MeSH
• železo chemie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cholinesterasové inhibitory MeSH
• cholinesterasy MeSH
• ethylendiaminy MeSH
• komplexní sloučeniny MeSH
• komplexní směsi MeSH
• ligandy MeSH
• mangan MeSH
• nikl MeSH
• picolinaldehyde MeSH Prohlížeč
• pyridiny MeSH
• Schiffovy báze MeSH
• triaziny MeSH
• tris(2-aminoethyl)amine MeSH Prohlížeč
• trithiocyanuric acid MeSH Prohlížeč
• železo MeSH

Preparation of 1-(4-hydroxy-iminomethylpyridinium)-3-pyridiniumpropane dibromide is described. This compound represents a new acetylcholinesterase (AChE) reactivator, which has no substituents on the second pyridinium ring as found in other commonly used AChE reactivators. The reactivation ability of this reactivator was tested on tabun- and cyclosarin-inhibited AChE. According to the results obtained, the new compound (without substitution and with decreased molecule size) showed increased reactivation potency in case of cyclosarin inhibited AChE. A potent oxime for treatment of tabun and cyclosarin-caused intoxications was thus obtained via slight modification of the reactivator structure (compared to trimedoxime and K027).

• MeSH
• acetylcholinesterasa MeSH
• lidé MeSH
• organofosfáty antagonisté a inhibitory   MeSH
• organofosforové sloučeniny antagonisté a inhibitory   MeSH
• oximy chemická syntéza   MeSH
• pyridinové sloučeniny chemická syntéza   MeSH
• reaktivátory cholinesterázy chemická syntéza   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-(4-hydroxyiminomethylpyridinium)-3-pyridiniumpropane MeSH Prohlížeč
• acetylcholinesterasa MeSH
• cyclohexyl methylphosphonofluoridate MeSH Prohlížeč
• organofosfáty MeSH
• organofosforové sloučeniny MeSH
• oximy MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterázy MeSH
• tabun MeSH Prohlížeč

The newly developed and very promising acetylcholinesterase reactivator (E)-1-(2-hydroxyiminomethylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide was prepared using two different pathways via a two-step synthesis involving the appropriate (E)-1-(4-bromobut-2-enyl)-2- or 4-hydroxyiminomethyl-pyridinium bromides. Afterwards, purities and yields of the desired product prepared by both routes were compared. Finally, its potency to reactivate several nerve agent-inhibited acetylcholinesterases was tested.

• MeSH
• bromované uhlovodíky chemická syntéza   MeSH
• pyridinové sloučeniny chemická syntéza   MeSH
• reaktivátory cholinesterázy chemická syntéza   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• (E)-1-(2-hydroxyiminomethylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide MeSH Prohlížeč
• bromované uhlovodíky MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterázy MeSH