Organophosphorus poisoning caused by some pesticides and nerve agents is a life-threating condition that must be swiftly addressed to avoid casualties. Despite the availability of medical countermeasures, the clinically available compounds lack a broad spectrum, are not effective towards all organophosphorus toxins, and have poor pharmacokinetics properties to allow them crossing the blood-brain barrier, hampering cholinesterase reactivation at the central nervous system. In this work, we designed and synthesised novel isatin derivatives, linked to a pyridinium 4-oxime moiety by an alkyl chain with improved calculated properties, and tested their reactivation potency against paraoxon- and NEMP-inhibited acetylcholinesterase in comparison to the standard antidote pralidoxime. Our results showed that these compounds displayed comparable in vitro reactivation also pointed by the in silico studies, suggesting that they are promising compounds to tackle organophosphorus poisoning.

• Klíčová slova
• Isatin, antidotes, cholinesterase reactivators, nerve agents, organophosphorus poisoning, pyridine oximes,
• MeSH
• acetylcholinesterasa účinky léků   MeSH
• isatin farmakologie   MeSH
• počítačová simulace MeSH
• pyridiny farmakologie   MeSH
• reaktivátory cholinesterasy farmakologie   MeSH
• techniky in vitro MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• isatin MeSH
• pyridine MeSH Prohlížeč
• pyridiny MeSH
• reaktivátory cholinesterasy MeSH

In the present work, we performed a complementary quantum mechanical (QM) study to describe the mechanism by which deprotonated pralidoxime (2-PAM) could reactivate human (Homo sapiens sapiens) acetylcholinesterase (HssAChE) inhibited by the nerve agent VX. Such a reaction is proposed to occur in subsequent addition-elimination steps, starting with a nucleophile bimolecular substitution (SN2) mechanism through the formation of a trigonal bipyramidal transition state (TS). A near attack conformation (NAC), obtained in a former study using molecular mechanics (MM) calculations, was taken as a starting point for this project, where we described the possible formation of the TS. Together, this combined QM/MM study on AChE reactivation shows the feasibility of the reactivation occurring via attack of the deprotonated form of 2-PAM against the Ser203-VX adduct of HssAChE.

• Klíčová slova
• 2-PAM, QM/MM method, VX, acetylcholinesterase,
• MeSH
• acetylcholinesterasa chemie   účinky léků   MeSH
• katalytická doména MeSH
• kvantová teorie MeSH
• lidé MeSH
• molekulární konformace MeSH
• organothiofosforové sloučeniny farmakologie   MeSH
• pralidoximové sloučeniny chemie   farmakologie   MeSH
• protony MeSH
• serin chemie   MeSH
• simulace molekulární dynamiky MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• organothiofosforové sloučeniny MeSH
• pralidoxime MeSH Prohlížeč
• pralidoximové sloučeniny MeSH
• protony MeSH
• serin MeSH
• VX MeSH Prohlížeč

7-methoxytacrine-4-pyridinealdoxime (7-MEOTA-4-PA, named hybrid 5C) is a compound formerly synthesized and evaluated in vitro, together with 4-pyridine aldoxime (4-PA) and commercial reactivators of acetylcholinesterase (AChE). This compound was designed with the purpose of being a prophylactic reactivator, capable of interacting with different subdomains of the active site of AChE. To investigate these interactions, theoretical results from docking were first compared with experimental data of hybrid 5C, 4-PA, and two commercial oximes, on the reactivation of human AChE (HssAChE) inhibited by VX. Then, further docking studies, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area calculations, were carried out to investigate reactivation performances, considering the near attack conformation (NAC) approach, prior to the nucleophilic substitution mechanism. Our results helped to elucidate the interactions of such molecules with the different subdomains of the active site of HssAChE. Additionally, NAC poses of each oxime were suggested for further theoretical studies on the reactivation reaction.

• Klíčová slova
• 7-MEOTA-4-PA, Acetylcholinesterase, NAC, VX, molecular modeling,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• obidoxim chlorid chemie   farmakologie   MeSH
• organothiofosforové sloučeniny chemie   farmakologie   MeSH
• oximy chemie   farmakologie   MeSH
• pralidoximové sloučeniny chemie   farmakologie   MeSH
• pyridiny chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 7-methoxytacrine-4-pyridinealdoxime MeSH Prohlížeč
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• obidoxim chlorid MeSH
• organothiofosforové sloučeniny MeSH
• oximy MeSH
• pralidoxime MeSH Prohlížeč
• pralidoximové sloučeniny MeSH
• pyridine-4-aldoxime MeSH Prohlížeč
• pyridiny MeSH
• VX MeSH Prohlížeč

Six quinoline-piperonal hybrids were synthesized and evaluated as potential drugs against Alzheimer's disease (AD). Theoretical analysis of the pharmacokinetic and toxicological properties of the compounds suggest that they present good oral bio-availability and are also capable of penetrating the blood-brain barrier, qualifying as leads for new drugs against AD. Evaluation of their inhibitory capacity against acetyl- and butyrilcholinesterases (AChE and BChE) through Ellmann's test showed that three compounds present promising results with one of them being capable of inhibiting both enzymes. Further docking studies of the six compounds synthesized helped to elucidate the main interactions that may be responsible for the inhibitory activities observed.

• Klíčová slova
• Alzheimer’s disease, acetylcholinesterase, guanil-hydrazones, piperonal, quinolines,
• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• benzaldehydy * chemie   MeSH
• benzodioxoly * chemie   MeSH
• chinoliny * chemie   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakokinetika   farmakologie   MeSH
• kinetika MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie MeSH
• molekulární struktura MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• techniky syntetické chemie MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzaldehydy * MeSH
• benzodioxoly * MeSH
• chinoliny * MeSH
• cholinesterasové inhibitory MeSH
• piperonal MeSH Prohlížeč
• quinoline MeSH Prohlížeč

Therapeutic application of newly developed oximes is limited due to their adverse effects on different tissues. Within this article, it has been investigated which morphological changes could be observed in Wistar rats after the treatment with increasing doses of selected acetyl cholinesterase reactivators - asoxime, obidoxime, K027, K048, and K075. Subsequently, heart, diaphragm and musculus popliteus were obtained for pathohistological and semiquantitative analysis 24 hrs and 7 days after im administration of a single dose of 0.1 LD50, 0.5 LD50, and 1.0 LD50 of each oxime. Different muscle damage score was based on an estimation scale from 0 (no damage) to 5 (strong damage). In rats treated with 0.1 LD50 of each oxime, muscle fibres did not show any change. The intensive degeneration was found in all muscles after treatment with 0.5 LD50 of asoxime and obidoxime, respectively. Acute toxic muscle injury was developed within 7 days following treatment with 0.5 LD50 and 1.0 LD50 of each oxime, with the highest values in K048 and K075 group (P < 0.001 vs. control and asoxime), respectively. The early muscle alterations observed in our study seem to contribute to the pathogenesis of the oxime-induced toxic muscle injury, which probably manifests as necrosis and/or inflammation.

• MeSH
• bránice účinky léků   zranění   MeSH
• kosterní svaly účinky léků   zranění   MeSH
• krysa rodu Rattus MeSH
• myozitida chemicky indukované   MeSH
• nekróza MeSH
• oximy toxicita   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny toxicita   MeSH
• srdce účinky léků   MeSH
• svaly účinky léků   patologie   MeSH
• testy akutní toxicity MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide MeSH Prohlížeč
• 1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)butane MeSH Prohlížeč
• K075 compound MeSH Prohlížeč
• oximy MeSH
• pyridinové sloučeniny MeSH

Nerve agents and oxon forms of organophosphorus pesticides act as strong irreversible inhibitors of two cholinesterases in the human body: acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8), and are therefore highly toxic compounds. For the recovery of inhibited AChE, antidotes from the group of pyridinium or bispyridinium aldoxime reactivators (pralidoxime, obidoxime, HI-6) are used in combination with anticholinergics and anticonvulsives. Therapeutic efficacy of reactivators (called “oximes”) depends on their chemical structure and also the type of organophosphorus inhibitor. Three novel oximes (K131, K142, K153) with an oxime group in position four of the pyridinium ring were designed and then tested for their potency to reactivate human (Homo sapiens sapiens) AChE (HssACHE) and BChE (HssBChE) inhibited by the pesticide paraoxon (diethyl 4-nitrophenyl phosphate). According to the obtained results, none of the prepared oximes were able to satisfactorily reactivate paraoxon-inhibited cholinesterases. On the contrary, extraordinary activity of obidoxime in the case of paraoxon-inhibited HssAChE reactivation was confirmed. Additional docking studies pointed to possible explanations for these results.

• Klíčová slova
• acetylcholinesterase, antidote, butyrylcholinesterase, organophosphate, oxime, paraoxon,
• MeSH
• acetylcholinesterasa chemie   MeSH
• antidota chemická syntéza   farmakologie   MeSH
• butyrylcholinesterasa chemie   MeSH
• cholinesterasové inhibitory chemie   MeSH
• enzymatické testy MeSH
• erytrocyty účinky léků   enzymologie   MeSH
• insekticidy antagonisté a inhibitory   chemie   toxicita   MeSH
• interakční proteinové domény a motivy MeSH
• lidé MeSH
• obidoxim chlorid chemie   farmakologie   MeSH
• oximy chemická syntéza   farmakologie   MeSH
• paraoxon antagonisté a inhibitory   chemie   toxicita   MeSH
• reaktivátory cholinesterasy chemická syntéza   farmakologie   MeSH
• sekundární struktura proteinů MeSH
• simulace molekulového dockingu MeSH
• termodynamika MeSH
• vazba proteinů MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• antidota MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• insekticidy MeSH
• obidoxim chlorid MeSH
• oximy MeSH
• paraoxon MeSH
• reaktivátory cholinesterasy 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 cholinesterasy 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 cholinesterasy MeSH
• tabun MeSH Prohlížeč