Reactivators
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In this review, the current progress in the research and development of butyrylcholinesterase (BChE) reactivators is summarised and the advantages or disadvantages of these reactivators are critically discussed. Organophosphorus compounds such as nerve agents (sarin, tabun, VX) or pesticides (chlorpyrifos, diazinon) cause irreversible inhibition of acetylcholinesterase (AChE) and BChE in the human body. While AChE inhibition can be life threatening due to cholinergic overstimulation and crisis, selective BChE inhibition has presumably no adverse effects. Because BChE is mostly found in plasma, its activity is important for the scavenging of organophosphates before they can reach AChE in the central nervous system. Therefore, this enzyme in combination with its reactivator can be used as a pseudo-catalytic scavenger of organophosphates. Three structural types of BChE reactivators were found, i.e. bisquaternary salts, monoquaternary salts and uncharged compounds. Although the reviewed reactivators have certain limitations, the promising candidates for BChE reactivation were found in each structural group.
- MeSH
- acetylcholinesterasa metabolismus chemie MeSH
- butyrylcholinesterasa * metabolismus chemie MeSH
- cholinesterasové inhibitory * chemie farmakologie chemická syntéza MeSH
- lidé MeSH
- molekulární struktura MeSH
- organofosforové sloučeniny * chemie farmakologie MeSH
- reaktivátory cholinesterasy farmakologie chemie chemická syntéza MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Nervově paralytická látka tabun inhibuje enzym acetylcholinesterasu (AChE; EC 3.1.1.7) za vzniku kovalentní vazby. Díky tomu nemůže tento enzym plnit v organizmu svou funkci a následně dochází k cholinergní krizi. Reaktivátory AChE (pralidoxim, obidoxim a HI-6) se užívají jakožto kauzální antidota při otravách nervově paralytickými látkami. Jejich úkolem je štěpit vzniklou vazbu mezi enzymem a inhibitorem. Bohužel jejich schopnost reaktivovat tabunem inhibovanou AChE je nízká. Cílem této práce bylo najít nejúčinnější reaktivátor AChE inhibované tabunem. Bylo otestováno osm reaktivátorů AChE – pralidoxim, obidoxim, trimedoxim, HI-6, methoxim, Hlö-7 a nově syntetizované reaktivátory K027 a K048. Všechny látky byly testovány standardním in vitro reaktivačním testem (pH 8, 25 °C, inhibice 30 min, reaktivace 10 min). Z výsledků vyplývá, že jen trimedoxim dosáhl 50 % reaktivace enzymu. Této poměrně silné reaktivační schopnosti bylo dosaženo při vysoké koncentraci reaktivátoru (10-2 M). Pouze čtyři látky (trimedoxim, obidoxim, K027 a K048) reaktivovaly tabunem-inhibovanou AChE při nižší koncentraci 10-4 M (pravděpodobně dosažitelné in vivo) v rozmezí od 10 do 18 %.
The nerve agent tabun inhibits acetylcholinesterase (AChE; EC 3.1.1.7) by the formation of a covalent bond with the enzyme. Afterwards, AChE is not able to fulfil its role in the organism and subsequently cholinergic crisis occurs. AChE reactivators (pralidoxime, obidoxime and HI-6) as causal antidotes are used for the cleavage of the bond between the enzyme and nerve agent. Unfortunately, their potency for reactivation of tabun-inhibited AChE is poor. The aim of the study was to choose the most potent reactivator of tabun-inhibited AChE. We have tested eight AChE reactivators – pralidoxime, obidoxime, trimedoxime, HI-6, methoxime, Hlö-7 and our newly synthesized oximes K027 and K048. All reactivators were tested using our standard in vitro reactivation test (pH 8, 25°C, time of inhibition by the nerve agent 30 minutes, time of reactivation by AChE reactivator 10 minutes). According to our results, only trimedoxime was able to achieve 50% reactivation potency. However, this relatively high potency was achieved at high oxime concentration (10-2 M). At a lower concentration of 10-4 M (the probably attainable concentration in vivo), four AChE reactivators (trimedoxime, obidoxime, K027, and K048) were able to reactivate AChE inhibited by tabun reaching from 10 to 18 %.
Acetylcholinesterase (AChE) is the key enzyme responsible for deactivating the ACh neurotransmitter. Irreversible or prolonged inhibition of AChE, therefore, elevates synaptic ACh leading to serious central and peripheral adverse effects which fall under the cholinergic syndrome spectra. To combat the toxic effects of some AChEI, such as organophosphorus (OP) nerve agents, many compounds with reactivator effects have been developed. Within the most outstanding reactivators, the substances denominated oximes stand out, showing good performance for reactivating AChE and restoring the normal synaptic acetylcholine (ACh) levels. This review was developed with the purpose of covering the new advances in AChE reactivation. Over the past years, researchers worldwide have made efforts to identify and develop novel active molecules. These researches have been moving farther into the search for novel agents that possess better effectiveness of reactivation and broad-spectrum reactivation against diverse OP agents. In addition, the discovery of ways to restore AChE in the aged form is also of great importance. This review will allow us to evaluate the major advances made in the discovery of new acetylcholinesterase reactivators by reviewing all patents published between 2016 and 2019. This is an important step in continuing this remarkable research so that new studies can begin.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- GPI-vázané proteiny metabolismus MeSH
- lidé MeSH
- oximy chemie terapeutické užití MeSH
- patenty jako téma MeSH
- reaktivátory cholinesterasy * chemie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
The acetylcholinesterase (AChE) reactivators (e.g., obidoxime, asoxime) became an essential part of organophosphorus (OP) poisoning treatment, together with atropine and diazepam. They are referred to as a causal treatment of OP poisoning, because they are able to split the OP moiety from AChE active site and thus renew its function. In this approach, fifteen novel AChE reactivators were determined. Their molecular design originated from former K-oxime compounds K048 and K074 with remaining oxime part of the molecule and modified part with heteroarenium moiety. The novel compounds were prepared, evaluated in vitro on human AChE (HssAChE) inhibited by tabun, paraoxon, methylparaoxon or DFP and compared to commercial HssAChE reactivators (pralidoxime, methoxime, trimedoxime, obidoxime, asoxime) or previously prepared compounds (K048, K074, K075, K203). Some of presented oxime reactivators showed promising ability to reactivate HssAChE comparable or higher than the used standards. The molecular modelling study was performed with one compound that presented the ability to reactivate GA-inhibited HssAChE. The SAR features concerning the heteroarenium part of the reactivator's molecule are described.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory toxicita MeSH
- hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
- inhibiční koncentrace 50 MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie s uhlíkem 13C MeSH
- organofosforové sloučeniny toxicita MeSH
- protonová magnetická rezonanční spektroskopie MeSH
- reaktivátory cholinesterasy chemická syntéza chemie farmakologie MeSH
- rekombinantní proteiny metabolismus MeSH
- simulace molekulového dockingu * MeSH
- techniky in vitro MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Organophosphorus compounds (OP) make up an important class of inhibitors, mostly employed as pesticides, even as chemical weapons. These toxic substances act through the inhibition of the acetylcholinesterase (AChE) enzyme, which results in elevated synaptic acetylcholine (ACh) levels, leading to serious adverse effects under the cholinergic syndrome. Many reactivators have been developed to combat the toxic effects of these AChE inhibitors. In this line, the oximes highlight because of their good reactivating power of cholinesterase enzymes. To date, no universal antidotes can reactivate AChE inhibited by any OP agent. This review summarizes the intoxication process by neurotoxic OP agents, along with the development of reactivators capable of reversing their effects, approaching aspects like the therapeutic and toxicological profile of these antidotes. Computational methods and conscious in vitro studies, capable of significantly predicting the toxicological profile of these drug candidates, might support the process of development of these reactivators before entering in vivo studies in animals, and then clinical trials. These approaches can assist in the design of safer and more effective molecules, reducing related cost and time for the process.
- MeSH
- acetylcholinesterasa chemie MeSH
- antidota * farmakologie terapeutické užití chemie MeSH
- cholinesterasové inhibitory toxicita MeSH
- organofosforové sloučeniny MeSH
- oximy terapeutické užití toxicita MeSH
- reaktivátory cholinesterasy * terapeutické užití toxicita MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Oxime cholinesterase reactivators (oximes) are used to counteract organophosphate intoxication. Charged oximes are administered via intramuscular or intravenous injection when the majority of dose is unmetabolized and is excreted as urine. In this study, the effects of selected double charged oximes were determined in the HK-2 cell line as a model for renal toxicity screening. Some effects on dehydrogenase activity were found for obidoxime, asoxime (syn. HI-6), K027, and K203. The effects of K868 and K869 were found to be unreliable due to rapid degradation of both chlorinated oximes in the assay medium, resulting for K868 in an isoxazole-pyridinium product.
- MeSH
- buněčné linie MeSH
- ledviny účinky léků metabolismus MeSH
- lidé MeSH
- molekulární struktura MeSH
- oximy aplikace a dávkování škodlivé účinky chemie MeSH
- reaktivátory cholinesterasy aplikace a dávkování škodlivé účinky chemie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Casualties caused by organophosphorus pesticides are a burden for health systems in developing and poor countries. Such compounds are potent acetylcholinesterase irreversible inhibitors, and share the toxic profile with nerve agents. Pyridinium oximes are the only clinically available antidotes against poisoning by these substances, but their poor penetration into the blood-brain barrier hampers the efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in future SAR studies, we evaluated neutral aryloximes as reactivators for paraoxon-inhibited Electrophorus eel acetylcholinesterase. Our findings may result into lead compounds, useful for development of more active compounds for emergencies and supportive care.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Electrophorus metabolismus MeSH
- enzymové reaktivátory chemie farmakologie MeSH
- molekulární struktura MeSH
- oximy chemie farmakologie MeSH
- paraoxon toxicita MeSH
- rybí proteiny metabolismus MeSH
- techniky in vitro MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Oxime reactivators of acetylcholinesterase (AChE) are used as causal antidotes for intended and unintended poisoning by organophosphate nerve agents and pesticides. Despite all efforts to develop new AChE reactivators, none of these drug candidates replaced conventional clinically used oximes. In addition to the therapeutic efficacy, determining the safety profile is crucial in preclinical drug evaluation. The exact mechanism of oxime toxicity and the structure-toxicity relationship are subjects of ongoing research, with oxidative stress proposed as a possible mechanism. In the present study, we investigated four promising bispyridinium oxime AChE reactivators, K048, K074, K075, and K203, and their ability to induce oxidative stress in vitro. Cultured human hepatoma cells were exposed to oximes at concentrations corresponding to their IC50 values determined by the MTT assay after 24 h. Their potency to generate reactive oxygen species, interfere with the thiol antioxidant system, and induce lipid peroxidation was evaluated at 1, 4, and 24 h of exposure. Reactivators without a double bond in the four-carbon linker, K048 and K074, showed a greater potential to induce oxidative stress compared with K075 and K203, which contain a double bond. Unlike oximes with a three-carbon-long linker, the number of aldoxime groups attached to the pyridinium moieties does not determine the oxidative stress induction for K048, K074, K075, and K203 oximes. In conclusion, our results emphasize that the structure of oximes plays a critical role in inducing oxidative stress, and this relationship does not correlate with their cytotoxicity expressed as the IC50 value. However, it is important to note that oxidative stress cannot be disregarded as a potential contributor to the side effects associated with oximes.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- antidota farmakologie MeSH
- buňky Hep G2 MeSH
- cholinesterasové inhibitory toxicita MeSH
- lidé MeSH
- organofosfáty toxicita MeSH
- oxidační stres MeSH
- oximy farmakologie chemie MeSH
- pyridinové sloučeniny farmakologie chemie MeSH
- reaktivátory cholinesterasy * farmakologie chemie MeSH
- uhlík MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
