Nerve Agent Sarin Research Articles

Neurosteroid and benzodiazepine combination therapy reduces status epilepticus and long-term effects of whole-body sarin exposure in rats.

ObjectiveOur objective was to evaluate the protective efficacy of the neurosteroid pregnanolone (3α‐hydroxy‐5β pregnan‐20‐one), a GABAA receptor‐positive allosteric modulator, as an adjunct to benzodiazepine therapy against the chemical warfare nerve agent (CWNA) sarin (GB), using whole‐body exposure, an operationally relevant route of exposure to volatile GB.MethodsRats implanted with telemetry transmitters for the continuous measurement of cortical electroencephalographic (EEG) activity were exposed for 60 minutes to 3.0 LCt50 of GB via whole‐body exposure. At the onset of toxic signs, rats were administered an intramuscular injection of atropine sulfate (2 mg/kg) and the oxime HI‐6 (93.6 mg/kg) to increase survival rate and, 30 minutes after seizure onset, treated subcutaneously with diazepam (10 mg/kg) and intravenously with pregnanolone (4 mg/kg) or vehicle. Animals were evaluated for GB‐induced status epilepticus (SE), spontaneous recurrent seizures (SRS), impairment in spatial memory acquisition, and brain pathology, and treatment groups were compared.ResultsDelayed dual therapy with pregnanolone and diazepam reduced time in SE in GB‐exposed rats compared to those treated with delayed diazepam monotherapy. The combination therapy of pregnanolone with diazepam also prevented impairment in the Morris water maze and reduced the neuronal loss and neuronal degeneration, evaluated at one and three months after exposure.SignificanceNeurosteroid administration as an adjunct to benzodiazepine therapy offers an effective means to treat benzodiazepine‐refractory SE, such as occurs following delayed treatment of GB exposure. This study is the first to present data on the efficacy of delayed pregnanolone and diazepam dual therapy in reducing seizure activity, performance deficits and brain pathology following an operationally relevant route of exposure to GB and supports the use of a neurosteroid as an adjunct to standard anticonvulsant therapy for the treatment of CWNA‐induced SE.

A Versatile Photoinduced Electron Transfer‐Based Upconversion Fluorescent Biosensing Platform for the Detection of Disease Biomarkers and Nerve Agent

AbstractUpconversion nanoparticles (UCNPs) have emerged to be a new family of fluorescent probes for bioanalytical applications. In a typical design, the UCNPs act as the energy donors in a fluorescence resonance energy transfer (FRET) system, in which the target molecules mediate the energy transfer from the UCNPs to the acceptors, and their quantity information is consequently converted into the “on‐off” upconverting signals for readout. However, each UCNP contains thousands of emitting center ions and most of them are beyond the FRET critical distance, which hinders the fluorescence energy transfer efficiency, resulting in a low signal‐to‐background ratio (SBR). Herein, a new design is presented in which the energy of UCNPs is transferred to the o‐quinones on their surface via the photoinduced electron transfer (PET) mechanism. In this system, the quenching efficiency of UCNPs' fluorescence can be up to 94.73%, providing a high SBR. The performance of the PET‐based design is systematically testified, and the high‐sensitivity detection of disease biomarkers (tyrosinase and alkaline phosphatase) is demonstrated. Moreover, this UCNP‐PET platform is also capable of sensing the simulant of nerve agent sarin. This work will pave new ways to the design of UCNP‐based platforms toward bioanalytical applications.

Cover Feature: Screening for Improved Nerve Agent Simulants and Insights into Organophosphate Hydrolysis Reactions from DFT and QSAR Modeling (Chem. Eur. J. 39/2019)

Density functional theory screening was used to suggest improved simulants for mimicking the reactivity of the nerve agents sarin and soman. Five highly predictive, less-toxic molecules were identified as candidates for safer and more accurate experimental studies of chemical warfare agent degradation. Through quantitative structure–activity relationship modeling and statistical analysis, the most significant molecular descriptors for describing the energetics of alkaline organophosphate hydrolysis reactions are also determined. More information can be found in the Full Paper by M. L. Mendoca and R. Q. Snurr on page 9217.

Screening for Improved Nerve Agent Simulants and Insights into Organophosphate Hydrolysis Reactions from DFT and QSAR Modeling.

The effective detoxification of chemical warfare agents, specifically nerve agents, is a pressing issue in the modern world. Due to the high toxicity of these molecules, simulants are often used in experiments as substitutes for the agents. However, there is little reason to believe that the current simulants used in the literature are optimal predictors of nerve agent reactivity. Density functional theory calculations were performed on the alkaline hydrolysis of over 100 organophosphate molecules to identify improved simulants for the G-series nerve agents soman and sarin, based on low toxicity and similarity to nerve agent hydrolysis energetics and degradation mechanism. This screening highlighted 5 molecules that have nearly identical reaction barriers to the actual agents, while being far less toxic. Quantitative structure-activity relationship (QSAR) models were also derived to determine the most significant molecular descriptors for describing the hydrolysis free energy barriers of these reactions. The optimal QSAR model was subjected to a thorough statistical analysis and validation procedure to confirm its predictive capacity, showing excellent quantitative and ranking accuracy. It was further shown that the model trained on G-series agents can reliably predict energetics for other organophosphate classes as well, including VX. Through these computational insights, experimentalists may be aided in accurately and safely studying these reactions with less toxic simulants.

Methylation protocol for the retrospective detection of isopropyl-, pinacolyl- and cyclohexylmethylphosphonic acids, indicative markers for the nerve agents sarin, soman and cyclosarin, at low levels in soils using EI-GC–MS

A practical and efficient protocol for the derivatization and detection by GC-EI-MS of isopropyl-, pinacolyl- and cyclohexylmethylphosphonic acids, key diagnostic degradation products of the nerve agents sarin, soman and cyclosarin respectively, in six different types of soil matrices is presented. The method involves the in situ conversion of the phosphonic acids to their respective methyl esters using trimethyloxonium tetrafluoroborate when present in the soils at low levels (10 μg g−1) without any prior extractions or soil preparation. The soils employed in our study were Nebraska EPA soil, Georgia soil, silt, Virginia type A soil, regular sand and Ottawa sand and were chosen for their vast differences in composition and physical features. Appealing attributes of the protocol include its rapidity (t < 30 min), mildness (ambient temperature), and practicality that includes the production of the phosphonic methyl esters that can be easily detected by GC-EI–MS and corroborated with the instrument's internal NIST spectral library or the Organisation for the Prohibition of Chemical Weapons (OPCW) central analytical database (OCAD v.21_2019). The overall efficacy of the protocol was then tested on a soil sample featured in the 44th OPCW PT that our laboratory participated in. After preparing the soil so as to give pinacolyl methylphosphonic acid at a 5 μg g−1 concentration, the acid was successfully methylated and detected by GC-EI-MS. The protocol's performance mirrors that of the universally employed diazomethane protocol but accomplishes this without any of the explosive hazards and time consuming reagent preparation commonly associated with it.

Time dependent dual effect of anti-inflammatory treatments on sarin-induced brain inflammation: Suggested role of prostaglandins

A common consequence of exposure to organophosphate nerve agents is the centrally mediated seizure activity that appears even after conventional treatment with atropine and oximes. We have previously demonstrated a major inflammatory response with subsequent brain damage which was correlated with the duration of the sarin-induced seizures (Chapman et al., 2006). In the present work seizures were induced by the nerve agent sarin (1.2 LD50) insufficiently treated 1 min later by atropine and trimedoxime bromide (TA), with additional midazolam treatment either 5 or 30 min after continuous seizure activity. The efficacy of both steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs), as well as other drugs that were reported as beneficial in neuroprotection, were evaluated for their contribution as adjunct treatment against sarin induced seizures and the ensuing inflammatory brain damage. Results show that both steroids and NSAIDs were harmful when administered during convulsions, and steroids were at best ineffective if administered at their termination. However, if administered at termination of convulsions, the NSAID ibuprofen, the selective COX 2 inhibitor nimesulide and the PLA2 inhibitor quinacrine were partially effective in reducing brain inflammatory markers. Administration of exogenous analogs of prostaglandins (PGE2) immediately following sarin-induced convulsions was found to have a beneficial effect in reducing brain inflammatory markers measured at 24 h and one week post sarin exposure. These findings support the hypothesis that elevated levels of PGE2 have a beneficial role immediately following sarin induced seizures, and that early inhibition of PGE2 production by both steroids and NSAID is contraindicative.

Electrospun n-p WO3/CuO heterostructure nanofibers as an efficient sarin nerve agent sensing material at room temperature

Organophosphate agents are a fatal inhibitor of acetylcholinesterase and damage nerve function. To find a suitable gas sensing material has high response and rapid response/recovery times to detect the chemical warfare agents remain a big challenge. Herein, n-p heterojunction Composite WO3/CuO nanofibers, pristine WO3 nanofibers, CuO nanofibers were successfully fabricated using a single capillary electrospinning technique and following calcination treatment. The nanostructure and chemical composition were characterized by XRD, XPS, SEM, TEM, and BET, respectively. Excellent improvements of the gas sensing performance were detected to composite WO3/CuO NFs in comparison with pristine WO3 and CuO NFs. The WO3/CuO NFs were shown an excellent selectivity toward a trace of DMMP (Dimethylmethylphosphonate, a simulant gas of sarin nerve gas) at room temperature among various VOCs. The 1D-nanocomposite structure and n-p heterojunction between CuO and WO3 crystals provided sufficient oxygen vacancies to absorb and desorb the oxygen ions and achieved a high response (19.3) toward 10 ppm DMMP at 25 °C. Composite WO3/CuO NFs shows a remarkable response (6.2) to 0.5 ppm DMMP at RT. The synthesized n-p nanocomposite WO3/CuO nanofibers promise to be an effective sarin nerve agent sensor with high performance.

Human small bowel as model for poisoning with organophosphorus compounds

In previous experiments, human and rat small bowel samples have been successfully used to study the spasmolytic effect of (potential) therapeutics in carbamate-constricted bowel specimens. Additionally, transferability from rat to human data was shown in the previous study. In the present study, the effects of atropine, scopolamine, MB327, HI-6 as well as obidoxime were examined in organophosphorus-poisoned human small bowel specimens. All substances were tested with at least seven concentrations in samples previously exposed to the nerve agent sarin. Furthermore, the cholinesterase reactivation potential of all substances was investigated. The test substances displayed a spasmolytic effect allowing the calculation of dose-response curves and EC50s. The parasympatholytic compound scopolamine had the strongest relaxing effect (EC50 = 0.05 μM) followed by atropine (EC50 = 0.07 μM). HI-6 and obidoxime were capable to reactivate the sarin-inhibited cholinesterase activity in small bowel samples. Both substances restored AChE activity in a dose-dependent way, with HI-6 being more potent (HI-6 EC50 = 3.8 μM vs obidoxime EC50 = 197.8 μM). Summarizing, our isolated human small bowel setup is a suitable tool to investigate the smooth muscle relaxing effect of (candidate) therapeutics for organophosphorus compound poisoning i.e. sarin exposure in a complex 3D tissue model.

Comparative efficacy of valnoctamide and sec‐butylpropylacetamide (SPD) in terminating nerve agent–induced seizures in pediatric rats

Children and adults are likely to be among the casualties in a civilian nerve agent exposure. This study evaluated the efficacy of valnoctamide (racemic-VCD), sec-butylpropylacetamide (racemic-SPD), and phenobarbital for stopping nerve agent seizures in both immature and adult rats. Female and male postnatal day (PND) 21, 28, and 70 (adult) rats, previously implanted with electroencephalography (EEG) electrodes were exposed to seizure-inducing doses of the nerve agents sarin or VX and EEG was recorded continuously. Five minutes after seizure onset, animals were treated with SPD, VCD, or phenobarbital. The up-down method was used over successive animals to determine the anticonvulsant median effective dose (ED50 ) of the drugs. SPD-ED50 values in the VX model were the following: PND21, 53mg/kg (male) and 48mg/kg (female); PND28, 108mg/kg (male) and 43mg/kg (female); and PND70, 101mg/kg (male) and 40mg/kg (female). SPD-ED50 values in the sarin model were the following: PND21, 44mg/kg (male) and 28mg/kg (female); PND28, 79mg/kg (male) and 34mg/kg (female); and PND70, 53mg/kg (male) and 53mg/kg (female). VCD-ED50 values in the VX model were the following: PND21, 34mg/kg (male) and 43mg/kg (female); PND28, 165mg/kg (male) and 59mg/kg (female); and PND70, 87mg/kg (male) and 91mg/kg (female). VCD-ED50 values in the sarin model were the following: PND21, 45mg/kg (male), 48mg/kg (female); PND28, 152mg/kg (male) 79mg/kg (female); and PND70, 97mg/kg (male) 79mg/kg (female). Phenobarbital-ED50 values in the VX model were the following: PND21, 43mg/kg (male) and 18mg/kg (female); PND28, 48mg/kg (male) and 97mg/kg (female). Phenobarbital-ED50 values in the sarin model were the following: PND21, 32mg/kg (male) and 32mg/kg (female); PND28, 58mg/kg (male) and 97mg/kg (female); and PND70, 65mg/kg (female). SPD and VCD demonstrated anticonvulsant activity in both immature and adult rats in the sarin- and VX-induced status epilepticus models. Phenobarbital was effective in immature rats, whereas in adult rats, higher doses were required that were accompanied by toxicity. Overall, significantly less drug was required to stop seizures in PND21 animals than in the older animals, and overall, males required higher amounts of drug than females.

A long-lasting poison scavenger

Drug Development Nerve agents are neurotoxic compounds found in pesticides and chemical weapons. They act by blocking the transmission of nerve impulses to the muscles, and exposure can be fatal within minutes. Zhang et al. developed a nanoparticle-based bioscavenger that breaks down organophosphate nerve agents into innocuous compounds. Prophylactic treatment of rats and guinea pigs confirmed low immunogenicity and good biodistribution. Treated animals were protected from repeated exposure to the nerve agent sarin over 7 days. This nanoscavenger might thus help prevent nerve-agent poisoning in at-risk subjects. Sci. Transl. Med. 11 , eaau7091 (2019).

3D hybrid Ni-Multiwall carbon nanotubes/carbon nanofibers for detecting sarin nerve agent at room temperature

3D Ni-Multiwall carbon nanotubes/carbon nanofibers nanostructure has received many attentions due to the large specific surface and excellent electrochemical performance. The aggregation of CNTs and high-cost manufacturing are challenges facing the preparation of hybrid 3D Ni-MWCNTs/CNFs nanomaterials. In this article, MWCNTs have grown on electrospun CNFs by using low-cost reagents and an efficient production process. The direct growth of CNTs on electrospun CNFs completed via one-step process electrospinning of Ni (AC)/PVP/PAN solution and following CVD treatment. The hybrid 3D Ni-MWCNTs/CNFs showed a large surface area of 530 m2/g higher than Ni/CNFs of 375 m2/g. The diameter of the electrospun CNFs and grown CNTs about 150 and 20 nm of hierarchical 3D Ni-MWCNTs/CNFs observed by SEM and TEM images, respectively. The hybrid structure and full carbonization were confirmed by XRD and Raman spectrums. The 3D Ni-MWCNTs/CNFs showed a comparable gas sensing properties with high response and rapid response-recovery times versus Ni/CNFs, electrospun CNFs, and commercial CNTs at RT toward 100 ppb DMMP gas (Dimethyl methyl phosphonate is a simulant gas for sarin nerve agent) with excellent selectivity. In fact, the synthetic procedure promises to be an effective approach to synthesize the hybrid 3D CNTs/CNFs nanomaterials with high sensing performance.

Development of a radiative transfer model for the determination of toxic gases by Fourier transform–infrared spectroscopy with a support vector machine algorithm

This report describes a radiative transfer model for Fourier transform-infrared (FT-IR) spectroscopy to create close-to-reality toxic gas spectra by reflecting the unique spectral responses of detectors and using the atmospheric radiative transfer code, MODTRAN. This system can be highly useful in overcoming the limitations for measuring toxic gases in open environments. The emulated gas spectra can be used to train support vector machine (SVM) for chemical gas detection. Its detection performance is evaluated with nerve agents (tabun, sarin, soman, and cyclosarin) and a simulant gas (sulfur hexafluoride) for indoor and outdoor experiments by using two off-the-shelf FT-IR gas detectors. The experimental results show that the proposed SVM algorithm successfully detected and classified targeted gases while reducing false negative and false positive detection rates.

Pyridinium Oximes with Ortho-Positioned Chlorine Moiety Exhibit Improved Physicochemical Properties and Efficient Reactivation of Human Acetylcholinesterase Inhibited by Several Nerve Agents.

Six chlorinated bispyridinium mono-oximes, analogous to potent charged reactivators K027, K048, and K203, were synthesized with the aim of improving lipophilicity and reducing the p Ka value of the oxime group, thus resulting in a higher oximate concentration at pH 7.4 compared to nonchlorinated analogues. The nucleophilicity was examined and the p Ka was found to be lower than that of analogous nonchlorinated oximes. All the new compounds efficiently reactivated human AChE inhibited by nerve agents cyclosarin, sarin, and VX. The most potent was the dichlorinated analogue of oxime K027 with significantly improved ability to reactivate the conjugated enzyme due to improved binding affinity and molecular recognition. Its overall reactivation of sarin-, VX-, and cyclosarin-inhibited AChE was, respectively, 3-, 7-, and 8-fold higher than by K027. Its universality, PAMPA permeability, favorable acid dissociation constant coupled with its negligible cytotoxic effect, and successful ex vivo scavenging of nerve agents in whole human blood warrant further analysis of this compound as an antidote for organophosphorus poisoning.

Differential proteome analysis of rat plasma after diisopropyl fluorophosphate (DFP) intoxication, a surrogate of nerve agent sarin

Diisopropyl fluorophosphate (DFP), a surrogate of nerve agent sarin, is an organophosphorus (OP) compound which inhibits neuronal enzyme acetylcholinesterase (AChE). Exposure of this compound leads to a wide range of toxic symptoms and survivors may exhibit long term neurotoxicity related to cognitive and memory defects. Due to ease of availability and similar mechanism of action to other highly toxic nerve agent, DFP is widely used as model compound to trace changes associated with nerve agent exposures. Proximal fluids are widely used for the elucidation of biomarkers for exposure to toxic substances and to study the mechanism of toxicity. Using a rat model of OP intoxication, the present study was carried out to elucidate proteomic changes in plasma associated with DFP intoxication. Rats were exposed to a single dose (0.5 LD50) of DFP and their plasma proteome was studied, one day post exposure by two dimensional gel electrophoresis - mass spectrometry (2DE-MS). Some of the milestone changes were validated by Western blot analysis. A total 15 proteins showed significant fold changes in expression with respect to control after 1 day of DFP intoxication. Most of the proteins showing changes in expression at initial stages were related to immunogenic function, acute phase response, blood coagulation, and stress response. Experiments reported here demonstrate that 0.5 LD50 DFP intoxication leads to AChE inhibition, modulation of immunogenic function, and generation of stress at an early stage. Although, some proteins and their putative functional ramifications indicated similarity with those observed in our previous plasma proteome study, neurodegenerative changes were not observed in plasma of 0.5 LD50 DFP treated animals.

Room temperature decomposition of dimethyl methylphosphonate on cuprous oxide yields atomic phosphorus

Organophosphorus compounds have a wide range of reactivity depending on the coordination and oxidation state of the P atom. Due to their toxicity, certain organophosphonates are used as pesticides, herbicides, and, notoriously, as chemical nerve agents. The organophosphonate decomposition mechanism depends strongly on the substrate material, which motivates careful analysis of a range of potential materials for decontamination and sensing applications. Here, we present a study of the decomposition of dimethyl methylphosphonate (DMMP), a simulant molecule for the nerve agent sarin, on polycrystalline cuprous oxide surfaces (Cu2O). We use ambient pressure X-ray photoelectron spectroscopy (APXPS) and near-edge X-ray absorption fine structure (NEXAFS) spectroscopy to monitor the pressure-dependent surface chemistry during exposure to DMMP vapor. At room temperature, we observe extensive degradation of DMMP, which includes the formation of reduced P products on the sample surface. We identify five unique P-containing species in the P 2p APXPS spectra, including atomic P and a surface-bound phosphinate [OPH(OCH3)OCu]. We propose a DMMP decomposition pathway whereby accumulation of this phosphinate species leads to an autocatalytic reaction on the Cu2O surface which yields reduced P species. After DMMP exposure, heating the Cu2O sample to 265 °C leads to complete removal of all carbonaceous species and accumulation of a phosphate layer with stoichiometry similar to P2O5. These results introduce a new mechanism of room-temperature DMMP decomposition on metal oxides, which could be leveraged for the design of tailored metal oxide materials for catalyzing organophosphonate decomposition.

Removal of nerve agent sarin simulant from aqueous solution using the ZSM-5/CoFe2O4 NPs adsorbent

The zeolite ZSM-5 (MFI-5) was synthesized by the hydrothermal method. The cobalt ferrite spinel nanoparticles (29.4 wt% of CoFe2O4 NPs) were immobilized over it via the ultrasound assisted dispersion route to acquire the novel zeolite ZSM-5/CoFe2O4 NPs adsorbent. The synthesized samples were characterized by XRD, FTIR, VSM, AFM, FESEM, TEM, EDAX, and X-ray dot-mapping. The ZSM-5/CoFe2O4 has been proposed for the effective removal of DMMP (dimethyl methyl phosphonate) a simulant of nerve agent sarin from aqueous solution. The analysis results from both GC-FID and GC–MS clearly proved the substantial adsorption–degradation phenomenon. Further, the effect of several factors including contact time, initial concentration, adsorbent dose, and adsorbent type on the removal of DMMP were surveyed. The GC-FID analysis data confirmed the maximum removal of 94.3% for DMMP. The parameters namely: contact time (50 min), adsorbent dose (0.1 g), and initial concentration (50 mg/L) were considered as optimized values for the reaction. Moreover, the reaction kinetic was studied applying first order model. The half-life (t1/2) and rate constant (k) were calculated as 13.27 min and 0.0522 min−1, respectively. Ultimately, the less toxic methyl phosphoric acid as the degradation and hydrolysis product of the DMMP by the ZSM-5/CoFe2O4 NPs was emerged and identified.

Midazolam-Resistant Seizures and Brain Injury after Acute Intoxication of Diisopropylfluorophosphate, an Organophosphate Pesticide and Surrogate for Nerve Agents.

Organophosphates (OP) such as the pesticide diisopropylfluorophosphate (DFP) and the nerve agent sarin are lethal chemicals that induce seizures, status epilepticus (SE), and brain damage. Midazolam, a benzodiazepine modulator of synaptic GABA-A receptors, is currently considered as a new anticonvulsant for nerve agents. Here, we characterized the time course of protective efficacy of midazolam (0.2-5 mg/kg, i.m.) in rats exposed to DFP, a chemical threat agent and surrogate for nerve agents. Behavioral and electroencephalogram (EEG) seizures were monitored for 24 hours after DFP exposure. The extent of brain injury was determined 3 days after DFP exposure by unbiased stereologic analyses of valid markers of neurodegeneration and neuroinflammation. Seizures were elicited within ∼8 minutes after DFP exposure that progressively developed into persistent SE lasting for hours. DFP exposure resulted in massive neuronal injury or necrosis, neurodegeneration of principal cells and interneurons, and neuroinflammation as evident by extensive activation of microglia and astrocytes in the hippocampus, amygdala, and other brain regions. Midazolam controlled seizures, neurodegeneration, and neuroinflammation when given early (10 minutes) after DFP exposure, but it was less effective when given at 40 minutes or later. Delayed therapy (≥40 minutes), a simulation of the practical therapeutic window for first responders or hospital admission, was associated with reduced seizure protection and neuroprotection. These results strongly reaffirm that the DFP-induced seizures and brain damage are progressively resistant to delayed treatment with midazolam, confirming the benzodiazepine refractory SE after OP intoxication. Thus, novel anticonvulsants superior to midazolam or adjunct therapies that enhance its efficacy are needed for effective treatment of refractory SE.

Discovery of a potent non-oxime reactivator of nerve agent inhibited human acetylcholinesterase

Organophosphorous (OP) compounds (such as nerve agents) inhibit the enzyme acetylcholinesterase (AChE) by covalent phosphylation of a key serine residue in the active site of the enzyme resulting in severe symptoms and ultimately death. OP intoxications are currently treated by administration of certain oxime compounds. The presently fielded oximes reactivate OP-inhibited AChE by liberating the phosphylated serine. Recent research towards new reactivators was predominantly devoted to design, synthesis and evaluation of new oxime-based compounds dedicated to overcoming some of the major limitations such as their intrinsic toxicity, their permanent charge which thwarts penetration of brain tissues and their inability to effectively reactivate all types of nerve agent inhibited AChEs. However, in over six decades of research only limited success has been achieved, indicating that there is a need for alternative classes of compounds that could reactivate OP-inhibited AChE. Recently, a number of non-oxime compounds was discovered in which the 4-amino-2-((diethylamino)methyl)phenol (ADOC) motif proved to be able to reactivate OP-inhibited AChE to some extent. In this paper several structural derivatives of ADOC were synthesized and screened for their ability to reactivate human AChE (hAChE) inhibited by the nerve agents VX, sarin, tabun, cyclosarin and paraoxon. We here disclose that one of those compounds showed a remarkable ability to reactivate OP-inhibited hAChE in vitro and that it is the most potent non-oxime reported to date.

Some benefit from non-oximes MB408, MB442 and MB444 in combination with the oximes HI-6 or obidoxime and atropine in antidoting sarin or cyclosarin poisoned mice

The effect of three newly developed bispyridinium non-oxime compounds (MB408, MB442, and MB444) on the therapeutic efficacy of a standard antidotal treatment (atropine in combination with the oxime HI-6 or obidoxime) of acute poisoning by two nerve agents (sarin and cyclosarin) in mice was studied. The therapeutic efficacy of atropine in combination with an oxime with or without one of the bispyridinium non-oximes was evaluated by determination of the 24 h LD50 values of the nerve agents studied and by measurement of the survival time after supralethal poisoning. Addition of all tested non-oximes increased the therapeutic efficacy of atropine in combination with an oxime against sarin poisoning; however, the differences were not significant. The non-oximes also positively influenced the number of surviving mice 6 h after supralethal poisoning with sarin. In the case of cyclosarin, they were also slightly beneficial in the treatment of acute poisoning. The higher dose of MB444 was able to significantly increase the therapeutic efficacy of standard antidotal treatment of poisoning with cyclosarin. The benefit of each bispyridinium non-oxime compound itself was obviously dose-dependent. In summary, the addition of MB compounds to the standard antidotal treatment of acute nerve agent poisoning was beneficial for the antidotal treatment of sarin or cyclosarin poisoning, although their benefit at 24 h after poisoning was not significant, with the exception of the higher dose of MB444 against cyclosarin.

Structural Characterization of Pristine and Defective [Zr12(μ3-O)8(μ3-OH)8(μ2-OH)6]18+ Double-Node Metal–Organic Framework and Predicted Applications for Single-Site Catalytic Hydrolysis of Sarin

Periodic PBE-D3 and M06-L calculations predict the lowest-energy proton topology of a [Zr6(μ3-O)4(μ3-OH)4(μ2-OH)3]2 ZrIV–MOF (J. Am. Chem. Soc. 2017, 139, 7004–7011), which has a unique double-node structure, to be 73.4 and 64.2 kcal/mol more stable than that originally proposed. Mono- and bidefective Zr12 secondary building units derived from this topology and built by removing one and two bridging terphenyldicarboxylate linkers and saturating the remaining open ZrIV metal sites with hydroxyl and aqua groups, are predicted to exhibit higher reactivity for the hydrolysis of sarin nerve agent than other coordinatively unsaturated Zr6-based MOFs reported to date.