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SUMMARY Nerve agents that irreversibly deactivate the enzyme acetylcholinesterase are extremely toxic weapons of mass destruction. Thus, developing methods to detect these lethal agents is important. To create an optical sensor for a surrogate of the nerve agent tabun, as well as a physical barrier that dissolves in response to this analyte, we devise a network hydrogel that decomposes via a self-propagating cascade. A Meldrums acid-derived linker is incorporated into a hydrogel that undergoes a declick reaction in response to thiols, thereby breaking network connections, which releases more thiols, propagating the response throughout the gel. A combination of chemical reactions triggered by the addition of the tabun mimic initiates the cascade. The dissolving barrier is used to release dyes, as well as nanocrystals that undergo a spontaneous aggregation. Thus, this sensing system for tabun generates a physical response and the delivery of chemical agents in response to an initial trigger., Graphical Abstract Lee et al. describe a self-degradable hydrogel that is used as both an optical and physical-change sensor for a nerve agent tabun surrogate. Upon detection, the hydrogel will degrade through a self-propagating cascade. Furthermore, the hydrogel acts as a barrier in an hourglass, as is confirmed using nanocrystals.

In this study, the gas phase MO2 (M = Ti, Zr) assisted detoxication of tabun (nerve agent) is explored by employing DFT, where the energetics of assisted pathways are compared with the respective unimolecular pathways. A total of six detoxication pathways are explored among which γ-H assisted decomposition pathway is the most favored one. The activation barrier of the rate determining step (RDS) of each assisted detoxication pathways is significantly lower than that of the respective unimolecular pathway. Among two assisting reagents, the assisting capability of ZrO2 is found to be better than that of TiO2.

In the present study, the adsorption of tabun molecule on some important nanocages such as Al12N12, Al12P12, B12N12, Be12O12, C12Si12, Mg12O12 and C24 was studied theoretically in details. The calculated adsorption energies (Eads) showed that the Mg12O12 has the highest value of Eads without any chemical change in the structure of tabun while, the Al12N12 has an advantage compared to Mg12O12 which is the destruction of tabun on its surface. The atoms of tabun responsible for the interaction with nanocages were determined. It was found that the O atom of P O bond of tabun interacts with the Al, Be, B, Si and C atoms. The quantum theory of atoms in molecule (QTAIM) was used to determine the nature of the interaction between the tabun and selected nanocages. It was found that the nature of the interaction changes from the van der Waals to nearly covalent. The potential of the nanocages for sensing the tabun was investigated by calculating both the UV absorption spectra of complexes and their density of states (DOS). The calculations showed that the Al12P12, Be12O12, B12N12 and C24 have potential as good sensor for tabun.

We investigated the reactivity and sensitivity of pristine, and Al-doped boron nitride (Al-BN) nanosheets to nerve agents including cyclosarin (GF) and tabun (GA) by means of density functional calculations. A weak interaction is predicted for both GF and GA with the pristine BN sheet with adsorption energies of − 12.0 and − 10.9 kcal/mol, respectively. Calculations show that the carbonyl oxygen atom of both GF and GA are the most nucleophile active site. The electronic sensitivity of the BN nanosheet is predicted to be negligible to these nerve agents. To overcome this problem, we have replaced a B atom of the sheet by an Al atom and investigated the adsorption process. It was found that the reactivity of the sheet in significantly increased to these agents after the Al-doping while the electronic sensitivity is improved only for GA gas. By adsorbing the GA on the Al-BN, its electrical conductivity is largely increased because of a decrease about 32.6% in the HOMO-LUMO energy gap. We have concluded that the Al-doping process helps the BN sheet to detect the GA gas and may be used in its sensor devices.

Commercial gas chromatograph-mass spectrometers, one of which being Inficon's HAPSITE® ER, have demonstrated chemical detection and identification of nerve agents (G-series) and blistering agents (mustard gas) in the field; however most analyses relies on self-contained or external calibration that inherently drifts over time. We describe an analytical approach that uses target-based thermal desorption standards, called focusing agents, to accurately calculate concentrations of chemical warfare agents that are analyzed by gas chromatograph-mass spectrometry. Here, we provide relative response factors of focusing agents (2-chloroethyl ethyl sulfide, diisopropyl fluorophosphate, diethyl methylphosphonate, diethyl malonate, methyl salicylate, and dichlorvos) that are used to quantify concentrations of tabun, sarin, soman, cyclosarin and sulfur mustard loaded on thermal desorption tubes (Tenax® TA). Aging effects of focusing agents are evaluated by monitoring deviations in quantification as thermal desorption tubes age in storage at room temperature and relative humidity. The addition of focusing agents improves the quantification of tabun, sarin, soman, cyclosarin and sulfur mustard that is analyzed within the same day as well as a 14-day period. Among the six focusing agents studied here, diisopropyl fluorophosphate has the best performance for nerve agents (G-series) and blistering agents (mustard gas) compared to other focusing agents in this work and is recommended for field use for quantification. The use of focusing agent in the field leads to more accurate and reliable quantification of Tabun (GA), Sarin (GB), Soman (GD), Cyclosarin (GF) and Sulfur Mustard (HD) than the traditional internal standard. Future improvements on the detection of chemical, biological, radiological, nuclear, and explosive materials (CBRNE) can be safely demonstrated with standards calibrated for harmful agents.

TABUN nerve agent has taken hundreds thousands of lives during the last century. This chemical warfare was widely used against peoples in many areas of the world, and brought painful death for the victims. Therefore, this hazardous gas has been known as one of the most important chemical agents for the crime of mass killing. Following efforts of many researchers throughout the worlds to control the unwanted effects of mass killing warfares, in this project, we have made efforts of find a way to inactive this dangerous species by adsorption of this molecule by C20 fullerene and its boron and nitrogen doped derivatives. Moreover, by using the density of state DOS plots, the changes of electrical conductivity of C20 fullerene both in presence and in absence of Tabun gas were investigated to know is C20 fullerene able to be used as a sensor for detecting the existence of this species?

We report herein a study of the hydrolysis of Tabun mimic DCNP in the presence of different amines, aminoalcohols and glycols as potential suitable organocatalysts for DCNP degradation. Experiments were performed in CD3CN in the presence of 5% D2O, which is a suitable solvent mixture to follow the DCNP hydrolysis. These studies allowed the definition of different DCNP depletion paths, resulting in the formation of diethylphosphoric acid, tetraethylpyrophosphate and phosphoramide species as final products. Without organocatalysts, DCNP hydrolysis occurred mainly via an autocatalysis path. Addition of tertiary amines in sub-stoichiometric amounts largely enhanced DCNP depletion whereas non-tertiary polyamines reacted even faster. Glycols induced very slight increment in the DCNP hydrolysis, whereas DCNP hydrolysis increased sharply in the presence of certain aminoalcohols especially, 2-(2-aminoethylamino)ethanol. For the latter compound, DCNP depletion occurred ca. 80-fold faster than in the absence of organocatalysts. The kinetic studies revealed that DCNP hydrolysis in the presence of 2-(2-aminoethylamino)ethanol occurred via a catalytic process, in which the aminoalcohol was involved. DCNP hydrolysis generally depended strongly on the structure of the amine, and it was found that the presence of the OH CH2 CH2 N moiety in the organocatalyst structure seems important to induce a fast degradation of DCNP., This research has been supported by the Ministerio de Educacion y Ciencia (MAT2012-38429-004). A.B.B. acknowledges being awarded a pre-doctoral FPI fellowship. SCSIE (Universidad de Valencia) is gratefully acknowledged for all the equipment employed shown in this document.

A highly sensitive method for the detection and identification of the G-nerve agent tabun (GA) was developed. 2-[(Dimethylamino)methyl]phenol (2-DMAMP), which was recently developed for the derivatization of GB, GD and GF, was also found to be efficient for the derivatization of GA. The optimized derivatization procedure in an aqueous medium was the addition of 2-DMAMP followed by 5 min of stirring at ambient temperature and subsequent LC-ESI(+)-MS/MS analysis. Derivatized GA was more stable than intact GA, and with detection nearly two orders of magnitude more sensitive. Its ESI-MS/MS spectrum shows two major product ions at m/z 242 and m/z 214. The developed method is more sensitive than any other LC-MS or GC-MS-based method and clearly demonstrates the new concept of “freezing the clock” for determining reactive GA in an aqueous medium, with a limit of detection (LOD) of 10 pg/mL in drinking water. The derivatization reaction efficiencies were evaluated with aqueous extracts of soil, asphalt, cloth, formica and linoleum spiked with GA and found to be similar to that with drinking water. The method was also found to be useful for enhancing the sensitivity of the detection method for other members of the GA family, namely, the GA hydrolysis product (O-ethyl phosphorylcyanidate) obtained under acidic conditions and the diethylamino analog of GA, which both possess a good leaving group (e.g., CN−). The method is appropriate for routine use for verification and evaluation of contamination in cases where trace level detection is required.

During the taphonomic and archaeozoological reappraisal of Garrod's material from Tabun Cave (Mount Carmel, Israel) a distinctive dark colouring of bones was observed in the Level C and D assemblages. Based on several geochemical tests, the presence of insoluble manganese oxides in those coatings was confirmed. The origin of this mineral, given the geological context, could be attributed to the decomposition of large quantities of organic matter due to an intensive human occupation of the site in MIS 5. This fact reinforces the hypothesis of the existence of a larger logistic mobility around more permanent residential sites among anatomically modern humans in the Levantine Middle Palaeolithic, which constitutes early evidence of a more complex economic behaviour.

In the present study, we report the first in vivo toxicokinetic study of tabun (O-ethyl-N,N-dimethylphosphoramidocyanidate). The toxicokinetics of the enantiomers of tabun were investigated in anesthetized swine after intravenous administration of 3 × LD50 (161.4 μg/kg) tabun. Blood samples were taken for gas chromatographic–mass spectrometric determination of the tabun enantiomers and for measurement of the activity of red blood cell acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE). The tabun enantiomers could be quantified in swine blood to a minimum concentration of 3.0 pg/ml (18.5 pM) and could be detected to a minimum concentration of 1.0 pg/ml (6.2 pM). The concentration–time profiles of both tabun enantiomers were best described by a bi-exponential equation. The elimination of (+)-tabun and (−)-tabun were comparable in the initial phase. In the terminal phase a remarkable difference was found, with terminal half lives of 11.5 min for (+)-tabun and 23.1 min for (−)-tabun. (+)-Tabun showed a markedly longer persistence in vivo than (+)-enantiomers of other G-type nerve agents and could be detected in all swine at least up to 30 min post-injection, (−)-tabun at least up to 90 min post-injection. These results demonstrate a rather rapid elimination of tabun enantiomers in vivo and may provide a toxicokinetic basis for the further development and optimization of medical countermeasures against this nerve agent.

An electronic nose system (E-nose) with metal oxide semiconductor sensors (MOS) has been designed to discriminate and quantify different chemical warfare agents (CWA) mimics. The E-nose consists of an array of commercial MOS for different gases, two sensors for temperature sensing, a sample handling system, a data acquisition system and a laptop with the data acquisition system control. With this device, discrimination studies have been carried out to detect specific CWA simulants (diethyl chlorophosphonate (DCP), diethyl cyanophosphate (DCNP), diisipropyl fluoride (DFP)), their derivatives (diethyl 1-phenylethyl phosphonate (OP-1), diethyl (2- cyanoethyl)phosphonate (OP-2), dimethyl methyl phosphonate (OP-3) and diethyl (2-oxopropyl)phosphonate (OP-4)) and some potential interfering substances (sulfuric acid, ammonia, ethanol and acetone). Principal components analyses (PCA) show that it is possible to discriminate the studied organophosphorous CWA mimics (DCP, DCNP and DFP) from the other studied derivatives and potential interfering agents. In addition, DCNP quantification studies have been done by using partial least squares (PLS) and a mathematical model has been obtained to predict DCNP concentrations in air. In this model, the coefficient of determination (R2) is 0.9567, the root mean square error of prediction (RMSEP) is 30 and the limit of detection (LOD) is 5 ppm so the model is considered valid. These results suggest that this E-nose system is capable to discriminate and quantify CWA mimics and it would be a feasible system to be used in a real scenario., Financial support from the Spanish Government (MAT2009-14564-C04-02 and MAT2009-14564-C04-01), the Grant BES-2010-034031 from the FPI-MINECO Subprogram and the Spanish Government and European FEDER funds (MAT2012-38429-C04-04) are gratefully acknowledged.

A humid electronic nose device based on pulse voltammetry has been applied to detect nerve agentsimulants in gas phase. The humid electronic nose consists in a polypropylene piece which containsan array of eight metallic electrodes (i.e., Ir, Rh, Pt, Au Ag, Co, Cu and Ni) divided into two sets of fourworking electrodes housed inside a homemade steel cylinder, and a salt bridge connection to a referenceelectrode. The electrochemical system is fitted to a nylon membrane damped with a background solutionof sodium tetraborate 0.01 M by a second polypropylene piece. The PCA analysis demonstrated that thesystem is able to discern principal organophosphorous nerve agent mimics (DCP, DCNP and DFP) fromorganophosphorous derivatives and some other potential interferents. Besides, the PLS quantificationanalysis showed sound accuracy in the concentration prediction for DCNP in air, good linearity and alimit of detection (LOD) of some a few ppm., Financial support from the Spanish Government (project MAT2012-38429-004) and the Generalitat Valenciana (project PROMETEO/2009/016) is gratefully acknowledged. L.P. is grateful to the Universitat Politecnica de Valencia for her grant.

The ability of 13 β-cyclodextrin and 2 glucose derivatives containing substituents with oxime groups as nucleophilic components to accelerate the degradation of tabun at physiological pH has been evaluated. To this end, a qualitative and a quantitative enzymatic assay as well as a highly sensitive enantioselective GC–MS assay were used. In addition, an assay was developed that provided information about the mode of action of the investigated compounds. The results show that attachment of pyridinium-derived substituents with an aldoxime group in 3- or 4-position to a β-cyclodextrin ring affords active compounds mediating tabun degradation. Activities differ depending on the structure, the number, and the position of the substituent on the ring. Highest activity was observed for a β-cyclodextrin containing a 4-formylpyridinium oxime residue in 6-position of one glucose subunit, which detoxifies tabun with a half-time of 10.2 min. Comparison of the activity of this compound with that of an analog in which the cyclodextrin ring was replaced by a glucose residue demonstrated that the cyclodextrin is not necessary for activity but certainly beneficial. Finally, the results provide evidence that the mode of action of the cyclodextrin involves covalent modification of its oxime group rendering the scavenger inactive after reaction with the first tabun molecule.

Cholinesterases are the main target of organophosphorus nerve agents (OPs). Their inhibition results in cholinergic syndrome and death. The enzymes are inhibited by phosphylation of the catalytic serine enzyme, but can be reactivated by oximes to some extent. However, phosphylated cholinesterases undergo a side reaction that progressively prevents their reactivatability. This unimolecular reaction, termed "aging", has been investigated for decades. It was shown that most OP-ChE conjugates aged by O-dealkylation of an alkoxy substituent of the phosphorus atom, a mechanism involving the stabilization of a transient carbocation. In this paper we present structural data supporting a substitution-based mechanism for aging of the huBChE conjugate of an N-mono-methyl analogue of tabun. This mechanism involves an adjacent nucleophilic attack followed by Berry pseudorotation. A similar adjacent attack and subsequent rearrangement of the transition state have been recently proposed for tabun phosphylation of AChE. We suggest that a similar mechanism is also possible for oxime reactivation of phosphylated cholinesterases. This opens new perspectives in terms of reactivator design.

Monoquaternary N -benzyl-4-hydroxyiminomethylpyridinium bromide (Py-4-H) and its analogous with diverse substituents introduced into the phenyl ring (Py-4-CH 3 , Py-4-Br, Py-4-Cl and Py-4-NO2) were synthesized in order to examine their potency as reactivators of tabun-inhibited human erythrocyte acetylcholinesterase (AChE; EC 3.1.1.7). Within 24 h, the reactivation of tabun-inhibited AChE reached 80% with Py-4-CH 3 , Py-4-Br and Py-4-Cl, 40% with Py-4-NO2, and 30% with Py-4-H. The overall reactivation rate constants were up to 5.0min- 1 M -1 . All oximes inhibited human AChE reversibly, and the inhibition potency increased in the following order Py-4-Br < Py-4-Cl

Mouse blood contains four esterases that detoxify organophosphorus compounds: carboxylesterase, butyrylcholinesterase, acetylcholinesterase, and paraoxonase-1. In contrast human blood contains the latter three enzymes but not carboxylesterase. Organophosphorus compound toxicity is due to inhibition of acetylcholinesterase. Symptoms of intoxication appear after approximately 50% of the acetylcholinesterase is inhibited. However, complete inhibition of carboxylesterase and butyrylcholinesterase has no known effect on an animal's well being. Paraoxonase hydrolyzes organophosphorus compounds and is not inhibited by them. Our goal was to determine the effect of plasma carboxylesterase deficiency on response to sublethal doses of 10 organophosphorus toxicants and one carbamate pesticide. Homozygous plasma carboxylesterase deficient ES1(-/-) mice and wild-type littermates were observed for toxic signs and changes in body temperature after treatment with a single sublethal dose of toxicant. Inhibition of plasma acetylcholinesterase, butyrylcholinesterase, and plasma carboxylesterase was measured. It was found that wild-type mice were protected from the toxicity of 12.5mg/kg parathion applied subcutaneously. However, both genotypes responded similarly to paraoxon, cresyl saligenin phosphate, diisopropylfluorophosphate, diazinon, dichlorvos, cyclosarin thiocholine, tabun thiocholine, and carbofuran. An unexpected result was the finding that transdermal application of chlorpyrifos at 100mg/kg and chlorpyrifos oxon at 14mg/kg was lethal to wild-type but not to ES1(-/-) mice, showing that with this organochlorine, the presence of carboxylesterase was harmful rather than protective. It was concluded that carboxylesterase in mouse plasma protects from high toxicity agents, but the amount of carboxylesterase in plasma is too low to protect from low toxicity compounds that require high doses to inhibit acetylcholinesterase.

Acetylcholinesterase reactivators are crucial antidotes for the treatment of organophosphate intoxication. Eighteen monoquaternary reactivators of acetylcholinesterase with modified side chain were developed in an effort to extend the properties of pralidoxime. The known reactivators (pralidoxime, HI-6, obidoxime, trimedoxime, methoxime) and the prepared compounds were tested in vitro on a model of tabun- and paraoxon-inhibited AChE. Monoquaternary reactivators were not able to exceed the best known compounds for tabun poisoning, but some of them did show reactivation better or comparable with pralidoxime for paraoxon poisoning. However, extensive differences were found by a SAR study for various side chains on the non-oxime part of the reactivator molecule.

One of the therapeutic approaches to organophosphate poisoning is to reactivate AChE with site-directed nucleophiles such as oximes. However, pyridinium oximes 2-PAM, HI-6, TMB-4 and obidoxime, found as the most effective reactivators, have limiting reactivating potency in tabun poisoning. We tested oximes varying in the type of ring (pyridinium and/or imidazolium), the length and type of the linker between rings, and in the position of the oxime group on the ring to find more effective oximes to reactivate tabun-inhibited human erythrocyte AChE. Three of our tested pyridinium oximes K027, K048, K074, along with TMB-4, were the most promising for AChE reactivation. Promising oximes were further tested in vivo on tabun poisoned mice not only as antidotes in combination with atropine but also as pretreatment drug. Herein, we showed that a promising treatment in tabun poisoning by selected oximes and atropine could be improved if oximes are also used in pretreatment. Since the reactivating efficacy of the oximes in vitro corresponded to their therapeutic efficacy in vivo, it seems that pharmacological effect of these oximes is indeed primarily related to the reactivation of tabun-phosphorylated AChE.

Improving the efficacy of antidotal treatment of poisonings with nerve agents is still a challenge for the scientific community. This study investigated the interactions of four bispyridinium oximes with human erythrocyte acetylcholinesterase (AChE) and their effects on soman- and tabun-poisoned mice. Oximes HI-6 and TMB-4 were used for comparison. These oximes inhibited AchE with inhibitory potency (IC 50 ) ranging from 0.02 to 1.0 mM. The best reactivating potency (%R) was obtained with K074, when AChE was inhibited by tabun. The protective potency (P 50 ) of all oximes in human erythrocyte AChE inhibited by soman and tabun could not be determined. In tabun-poisoned mice very good antidotal efficacy was obtained with K027, K048, and K074, which makes them interesting for future investigation. The combination of HI-6 and atropine is the therapy of choice for soman poisoning.

Kinetic parameters were evaluated for inhibition of native and reactivation of tabun-inhibited human erythrocyte acetylcholinesterase (AChE, EC 3.1.1.7) and human plasma butyrylcholinesterase (BChE, EC 3.1.1.8) by three bispyridinium para -aldoximes with butane (K074), but-2-ene (K075) or xylene-like linker (K114). Tested aldoximes reversibly inhibited both cholinesterases with the preference for binding to the native AChE. Both cholinesterases showed the highest affinity for K114 ( K i was 0.01 mM for AChE and 0.06 mM for BChE). The reactivation of tabun-inhibited AChE was efficient by K074 and K075. Their overall reactivation rate constants were around 2000 min −1 M −1 , which is seven times higher than for the classical bispyridinium para -aldoxime TMB-4. The reactivation of tabun-inhibited AChE assisted by K114 was slow and reached 90% after 20 h. Since the aldoxime binding affinity of tabun-inhibited AChE was similar for all tested aldoximes (and corresponded to their K i ), the rate of the nucleophilic displacement of the phosphoryl-moiety from the active site serine was the limiting factor for AChE reactivation. On the other hand, none of the aldoximes displayed a significant reactivation of tabun-inhibited BChE. Even after 20 h, the reactivation maximum was 60% for 1 mM K074 and K075, and only 20% for 1 mM K114. However, lower BChE affinities for K074 and K075 compared to AChE suggest that the fast tabun-inhibited AChE reactivation by these compounds would not be obstructed by their interactions with BChE in vivo .

Application of human antidotes against nerve agent intoxications to microcrustacean Daphnia magna (Crustacea, Cladocera) intoxicated by a nerve agent tabun (O-ethyl-N,N-dimethylphosphoramidocyanidate) and their efficacy was investigated. It was found that antidotes can be successfully applied to intoxicated daphnids. Three different treatment regimens were tested: the combination of atropine and acetylcholinesterase reactivator (trimedoxime was chosen), atropine only and trimedoxime alone, too. The most efficient was the combination of atropine and trimedoxime followed by treatment with atropine only. The proportion of recovered animals increased with time not only in treated groups but also in the control as well. This can be explained by a spontaneous reactivation of tabun-inhibited cholinesterase in daphnids probably indicating a difference between mammalian and crustacean cholinesterases.

In this paper we assess the evidence for on-site manufacture and re-sharpening of handaxes in the Lower Paleolithic layers of Tabun Cave by examining the ratio of thinning flakes, the typical waste of bifacial manufacture, to handaxes. Our study of twenty nine assemblages ranging from the Acheulean to the Acheulo-Yabrudian complex, combining results from Jelinek's and Ronen's excavations, shows that thinning flakes are scarce throughout the entire sequence. Results indicate that handaxes were commonly not manufactured or re-sharpened in the excavated area and that these activities were most likely conducted outside the site. The late Lower Paleolithic in various parts of Eurasia and Africa is characterized by high variability in lithic technology, which in the case of the Levant is best reflected in the Acheulo-Yabrudian complex. This study aids our understanding of variability in the Levantine late Lower Paleolithic by adding the concept of segmentation of reduction as an integral part of late Lower Paleolithic lithic technology. Significantly, in Tabun Cave the segmentation of reduction that characterizes handaxe manufacture differs from the patterns observed in Amudian blade production and Yabrudian scraper manufacture, which were both regularly conducted on site. The extent of variability and flexibility is thus reflected not only in the technologies employed, but also in how different reduction sequences were segmented and executed across the landscape, suggesting a link between technical knowledge, mobility patterns and landscape exploitation.

The repeated misuse of highly toxic organophosphorus compound (OP) based chemical warfare agents in military conflicts and terrorist attacks poses a continuous threat to the military and civilian sector. The toxic symptomatology of OP poisoning is mainly caused by inhibition of acetylcholinesterase (AChE, E.C. 3.1.1.7) resulting in generalized cholinergic crisis due to accumulation of the neurotransmitter acetylcholine (ACh) in synaptic clefts. Beside atropine as competitive antagonist of ACh at muscarinic ACh receptors oximes as reactivators of OP-inhibited AChE are a mainstay of standard antidotal treatment. However, human AChE inhibited by certain OP is rather resistant to oxime-induced reactivation. The development of more effective oxime-based reactivators may fill the gaps. To get more insight into a potential structure–activity relationship between human AChE, OPs and oximes in vitro studies were conducted to investigate interactions of different tabun and sarin analogues with human AChE and the oximes obidoxime and HI 6 by determination of various kinetic constants. Rate constants for the inhibition of human AChE by OPs, spontaneous dealkylation and reactivation as well as reactivation by obidoxime and HI 6 of OP-inhibited human AChE were determined. The recorded kinetic data did not allow a general statement concerning a structure–activity relationship between human AChE, OP and oximes.

Up to now, intensive attempts to synthesize a universal reactivator able to reactivate cholinesterases inhibited by all types of nerve agents/organophosphates were not successful. Therefore, another approach using a combination of two reactivators differently reactivating enzyme was used: in rats poisoned with tabun and treated with combination of atropine (fixed dose) and different doses of trimedoxime and HI-6, changes of acetylcholinesterase activities (blood, diaphragm and different parts of the brain) were studied. An increase of AChE activity was observed following trimedoxime treatment depending on its dose; HI-6 had very low effect. Combination of both oximes showed potentiation of their reactivation efficacy; this potentiation was expressed for peripheral AChE (blood, diaphragm) and some parts of the brain (pontomedullar area, frontal cortex); AChE in the basal ganglia was relatively resistant. These observations suggest that the action of combination of oximes in vivo is different from that observed in vitro.

Acetylcholinesterase reactivators are crucial antidotes for the treatment of organophosphate intoxication. Fifteen new monooxime reactivators of acetylcholinesterase with a (E)-but-2-ene linker were developed in an effort to extend the properties of K-oxime (E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide (K203). The known reactivators (pralidoxime, HI-6, obidoxime, K075, K203) and the new compounds were tested in vitro on a model of tabun- and paraoxon-inhibited AChE. Monooxime reactivators were not able to exceed the best known compounds for tabun poisoning, but some of them did show reactivation comparable with known compounds for paraoxon poisoning. However, extensive differences were found by a SAR study for various substitutions on the non-oxime part of the reactivator molecule.

Conformational studies have been carried out on the two different enantiomers of tabun at the density functional and second order Moller–Plesset perturbation levels of theory to generate low energy potential energy surfaces in the gas phase as well as in aqueous environment. The structures of the low energy conformers together with their molecular electrostatic potential surfaces have been compared with those of the non-aged acetylcholinesterase–tabun complex to locate the active conformer of this molecule.

Deux chronologies independantes ont ete etablies pour la sequence de Tabun par ESR et par thermoluminescence. Des nouvelles analyses ont ete effectuees sur Tabun C1 par ESR et les isotopes de l'U. Les resultats donnent une chronologie plus ancienne pour Tabun avec un âge de 122+-16ka.

Six novel AChE reactivators with a (Z)-but-2-ene linker were synthesized using the known synthetic pathways. Their ability to reactivate AChE, which had been previously inhibited by nerve agent tabun or pesticide paraoxon, was tested in vitro and compared to pralidoxime, HI-6, obidoxime, and K075. The novel synthesized compounds were found to be ineffective against GA-inhibited AChE but the ability of (Z)-1,4-bis(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide to reactivate paraoxon-inhibited AChE was comparable with that of oxime K075. Notably, the oxime group in position four substantially increased the ability of the novel compounds to reactivate paraoxon-inhibited AChE.

Interactions of tabun (GA) with non-hydroxylated and hydroxylated CaO clusters have been studied using density functional (DFT) and Moller–Plesset second order perturbation (MP2) levels of theory. The nature of interactions has been further investigated from the topology of charge distribution (using Atoms in Molecules formalism) and molecular electrostatic potential (MEP) surfaces. These adsorption studies indicate that GA adsorbs strongly on the non-hydroxylated CaO cluster through its P O bond, while interactions of GA on the hydroxylated cluster are weak. These model studies could thus be useful to characterize inorganic oxides for efficient detection and disposal of GA.

Inhibition of acetylcholinesterase (AChE) by organophosphorus compounds (OPs) such as pesticides and nerve agents causes acute toxicity or death of the intoxicated individual. The inhibited AChE may be reactivated by certain oximes as antidotes for clinical treatment of OP-intoxications. Crystal structures of the oximes HI-6, Ortho-7 and obidoxime in complex with Mus musculus acetylcholinesterase (mAChE) reveal different roles of the peripheral anionic site (PAS) in the binding of the oximes. A limited structural change of the side chains of Trp286 and Asp74 facilitates the intercalation of the 4-carboxylamide pyridinium ring of HI-6 between the side chains of Tyr124 and Trp286. The 2-carboxyimino pyridinium ring of HI-6 is accommodated at the entrance of the catalytic site with the oximate forming a hydrogen bond to the main-chain nitrogen atom of Phe295. In contrast to HI-6, the coordination of Ortho-7 and obidoxime within the PAS is facilitated by an extended structural change of Trp286 that allows one of the carboxyimino pyridinium rings to form a cation-π interaction with the aromatic groups of Tyr72 and Trp286. The central chain of Ortho-7 and obidoxime is loosely coordinated in the active-site gorge, whereas the second carboxyimino pyridinium ring is accommodated in the vicinity of the phenol ring of Tyr337. The structural data clearly show analogous coordination of Ortho-7 and obidoxime within the active-site gorge of AChE. Different ability to reactivate AChE inhibited by tabun is shown in end-point reactivation experiments where HI-6, Ortho-7 and obidoxime showed an efficiency of 1, 45 and 38%, respectively. The low efficiency of HI-6 and the significantly higher efficiency of Ortho-7 and obidoxime may be explained by the differential binding of the oximes in the PAS and active-site gorge of AChE.

The ability of two types of pharmacological pretreatment (pyridostigmine alone or pyridostigmine in combination with two anticholinergic drugs) to increase the resistance of rats and mice against tabun and to increase the therapeutic efficacy of common antidotal treatment of tabun-poisoned rats and mice was compared. A significant decrease in the LD50 values of tabun was observed when mice as well as rats were pretreated with the prophylactic antidotal mixture consisting of pyridostigmine, benactyzine and trihexyphenidyle, designated PANPAL. Pyridostigmine-pretreated rats were also more resistant against acute lethal effects of tabun but pyridostigmine-induced resistance of rats was not so high as PANPAL-induced resistance. In addition, the pharmacological pretreatment with pyridostigmine alone was not able to protect mice against tabun-induced acute toxicity. The pharmacological pretreatment with pyridostigmine alone was able to increase the efficacy of currently used antidotal treatment (obidoxime in combination with atropine and diazepam) of tabun-induced poisoning, but PANPAL-induced increase in the efficacy of the same antidotal treatment was significantly higher than an increase induced by pyridostigmine alone. PANPAL-induced increase in the efficacy of antidotal treatment of tabun poisoning was also observed in mice. These findings confirm that PANPAL pretreatment of tabun-poisoned rats and mice seems to be much more suitable than currently used pyridostigmine alone.

The important Lower and Middle Palaeolithic site of Tabun has been previously dated using ESR, U-series and TL. ESR ages throughout the site are substantially younger than TL dates, although these methods have been shown to agree at other sites in Israel and elsewhere. All previous ESR dates have been obtained on museum specimens using only attached sediments for dosimetry. Here we report the first ESR and U-series analyses of a tooth found in situ in an area equivalent to the lowest part of layer Ed. We obtain a combined ESR/U-series age of 387+49−36ka, in good agreement with a TL age of 340±33 ka for similar levels, and substantially older than an ESR/U-series age using attached or nearby sediment for dosimetry. We conclude that the most likely explanation for the previous shorter ESR chronology was the use of inappropriate gamma dose rates based on sediments attached to teeth.