The organophosphorus antidotes, so-called oximes, are able to restore the enzymatic function of acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) via cleavage of organophosphate from the active site of the phosphylated enzyme. In this work, the charged pyridinium oximes containing thiocarboxamide moiety were designed, prepared and tested. Their stability and pKa properties were found to be analogous to parent carboxamides (K027, K048 and K203). The inhibitory ability of thiocarboxamides was found in low μM levels for AChE and high μM levels for BChE. Their reactivation properties were screened on human recombinant AChE and BChE inhibited by nerve agent surrogates and paraoxon. One thiocarboxamide was able to effectively restore function of NEMP- and NEDPA-AChE, whereas two thiocarboxamides were able to reactivate BChE inhibited by all tested organophosphates. These results were confirmed by reactivation kinetics, where thiocarboxamides were proved to be effective, but less potent reactivators if compared to carboxamides.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- organofosfáty chemická syntéza chemie farmakologie MeSH
- oximy chemická syntéza chemie farmakologie MeSH
- pyridinové sloučeniny chemická syntéza chemie farmakologie MeSH
- sulfhydrylové sloučeniny chemická syntéza 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
The pyridinium-2-carbaldoximes with quinolinium carboxamide moiety were designed and synthesised as cholinesterase reactivators. The prepared compounds showed intermediate-to-high inhibition of both cholinesterases when compared to standard oximes. Their reactivation ability was evaluated in vitro on human recombinant acetylcholinesterase (hrAChE) and human recombinant butyrylcholinesterase (hrBChE) inhibited by nerve agent surrogates (NIMP, NEMP, and NEDPA) or paraoxon. In the reactivation screening, one compound was able to reactivate hrAChE inhibited by all used organophosphates and two novel compounds were able to reactivate NIMP/NEMP-hrBChE. The reactivation kinetics revealed compound 11 that proved to be excellent reactivator of paraoxon-hrAChE better to obidoxime and showed increased reactivation of NIMP/NEMP-hrBChE, although worse to obidoxime. The molecular interactions of studied reactivators were further identified by in silico calculations. Molecular modelling results revealed the importance of creation of the pre-reactivation complex that could lead to better reactivation of both cholinesterases together with reducing particular interactions for lower intrinsic inhibition by the oxime.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- butyrylcholinesterasa metabolismus MeSH
- chinolinové sloučeniny chemická syntéza chemie farmakologie MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- pyridinové sloučeniny chemická syntéza chemie farmakologie MeSH
- rekombinantní proteiny metabolismus MeSH
- simulace molekulového dockingu MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
A series of pentamethinium salts with benzothiazolium and indolium side units comprising one or two positive charges were designed and synthesized to determine the relationships among the molecular structure, charge density, affinity to sulfated polysaccharides, and biological activity. Firstly, it was found that the affinity of the pentamethinium salts to sulfated polysaccharides correlated with their biological activity. Secondly, the side heteroaromates displayed a strong effect on the cytotoxicity and selectivity towards cancer cells. Finally, doubly charged pentamethinium salts possessing benzothiazolium side units exhibited remarkably high efficacy against a taxol-resistant cancer cell line.
- MeSH
- antitumorózní látky chemická syntéza chemie metabolismus farmakologie MeSH
- apoptóza účinky léků MeSH
- benzothiazoly chemická syntéza chemie metabolismus farmakologie MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- estery kyseliny sírové metabolismus MeSH
- glykosaminoglykany metabolismus MeSH
- hydrofobní a hydrofilní interakce MeSH
- indoly chemická syntéza chemie metabolismus farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- pyridinové sloučeniny chemická syntéza chemie metabolismus farmakologie MeSH
- racionální návrh léčiv MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- audiovizuální média MeSH
- časopisecké články MeSH
- práce podpořená grantem MeSH
The influence of three newly developed bispyridinium antinicotinic compounds (the non-oximes MB408, MB442 and MB444) on the therapeutic efficacy of a standard antidotal treatment (atropine in combination with an oxime) of acute poisoning by the organophosphorus nerve agents tabun and soman was studied in mice. 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 LD50 values of the nerve agents and measurement of the survival time after supralethal poisoning. Addition of all the tested non-oximes increased significantly the therapeutic efficacy of atropine in combination with an oxime against tabun poisoning. They also positively influenced the number of surviving mice 6 hr after supralethal poisoning with tabun. However, they were only slightly effective for the treatment of soman poisoning. The benefit of the tested bispyridinium non-oximes was dose-dependent. To conclude, the addition of bispyridinium non-oximes to the standard antidotal treatment of acute poisoning with tabun was beneficial regardless of the chosen non-oxime, but only slightly beneficial in the case of soman poisoning.
- MeSH
- antidota chemická syntéza farmakologie terapeutické užití MeSH
- atropin farmakologie MeSH
- kombinovaná farmakoterapie MeSH
- LD50 MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nervová bojová látka otrava MeSH
- nikotinoví agonisté chemická syntéza farmakologie MeSH
- organofosfáty toxicita MeSH
- otrava organofosfáty farmakoterapie etiologie MeSH
- oximy farmakologie MeSH
- preklinické hodnocení léčiv MeSH
- pyridinové sloučeniny chemická syntéza farmakologie terapeutické užití MeSH
- soman otrava MeSH
- synergismus léků MeSH
- výsledek terapie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The treatment of organophosphate (OP) poisoning consists of the administration of a parasympatholytic agent, an anticonvulsant and an acetylcholinesterase (AChE) reactivator. Since there is no broad AChE reactivator available, a post-treatment strategy currently exploits administration of different types of oximes depending on the exposure of OP. In this contribution, we summarize all the available data about AChE reactivator HLö-7 including its synthesis, physico-chemical properties, pharmacokinetic and pharmacodynamics profile, and its efficacy in vitro and in vitro.
- Klíčová slova
- Hlo-t,
- MeSH
- acetylcholinesterasa fyziologie chemie MeSH
- chemické bojové látky otrava MeSH
- cholinesterasové inhibitory farmakologie terapeutické užití MeSH
- LD50 MeSH
- lidé MeSH
- nervová bojová látka otrava MeSH
- organofosforové sloučeniny MeSH
- otrava organofosfáty * farmakoterapie MeSH
- oximy MeSH
- pesticidy otrava MeSH
- pyridinové sloučeniny * farmakokinetika farmakologie chemická syntéza chemie terapeutické užití MeSH
- reaktivátory cholinesterázy * farmakokinetika farmakologie chemická syntéza chemie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
A method for preparation of a new stable Cu(I) catalyst supported on weakly acidic polyacrylate resin without additional stabilizing ligands is described. A simple and efficient methodology for Ullmann Cu(I) catalyzed C-N cross coupling reactions using this original catalyst is reported. Coupling reactions of 4-chloropyridinium chloride with anilines containing electron donating (EDG) or electron withdrawing (EWG) groups, naphthalen-2-amine and piperazine, respectively, are successfully demonstrated.
- MeSH
- 2-naftylamin chemie MeSH
- akrylové pryskyřice chemie MeSH
- aniliny chemie MeSH
- elektrony * MeSH
- katalýza MeSH
- koncentrace vodíkových iontů MeSH
- měď chemie MeSH
- opakované použití vybavení MeSH
- piperaziny chemie MeSH
- pyridinové sloučeniny chemická syntéza MeSH
- technologie zelené chemie MeSH
- Publikační typ
- časopisecké články MeSH
Nine novel mono-oxime reactivators bearing xylene linker were synthesized in an effort to improve previously prepared xylene bisoximes and monocarbamoyl-monooximes. The novel compounds were tested in vitro on the model of tabun-, paraoxon-, methylparaoxon- and DFP-inhibited human erythrocyte AChE. Their reactivation ability was compared to pralidoxime, asoxime, obidoxime and two previously prepared xylene linked bisoximes (K107, K108). All compounds showed minimal reactivation of tabun-inhibited AChE at selected concentration scale. This finding was explained by molecular modelling study. Bisoximes obidoxime and K108 resulted as the best reactivators for paraoxon-, methylparaoxon- and DFP-inhibited AChE. The loss of nonoxime moiety lead to the loss of reactivation ability within the novel compounds. Though the novel reactivators did not exceed previously known compounds, they confirmed former SAR findings for xylene-linked AChE reactivators.
- MeSH
- cholinesterasové inhibitory chemie MeSH
- enzymatické testy MeSH
- organofosfáty chemie MeSH
- oximy chemická syntéza chemie MeSH
- pyridinové sloučeniny chemická syntéza chemie MeSH
- reaktivátory cholinesterázy chemická syntéza chemie MeSH
- simulace molekulového dockingu MeSH
- vztahy mezi strukturou a aktivitou MeSH
- xyleny chemická syntéza chemie MeSH
- Publikační typ
- časopisecké články MeSH
The potency of the bispyridinium non-oxime compound MB327 [1,1'-(propane-1,3-diyl)bis(4-tert-butylpyridinium) diiodide] to increase the therapeutic efficacy of the standard antidotal treatment (atropine in combination with an oxime) of acute poisoning with organophosphorus nerve agents was studied in vivo. The therapeutic efficacy of atropine alone - or atropine in combination with an oxime, MB327, or both an oxime and MB237 - was evaluated by the determination of LD50 values of several nerve agents (tabun, sarin and soman) in mice with and without treatment. The addition of MB327 increased the therapeutic efficacy of atropine alone, and atropine in combination with an oxime, against all three nerve agents, although differences in the LD50 values only reached statistical significance for sarin. In conclusion, the addition of the compound MB327 to the standard antidotal treatment of acute poisonings with nerve agents was beneficial regardless of the chemical structure of the nerve agent, although at the dose employed, MB327 in combination with atropine, or atropine and an oxime, provided only a modest increase in protection ratio. These results from mice, and previous ones from guinea-pigs, provide consistent evidence for additional, albeit modest, efficacy resulting from the inclusion of the antinicotinic compound MB327 in standard antidotal therapy. Given the typically steep probit slope for the dose-lethality relationship for nerve agents, such modest increases in protection ratio could provide significant survival benefit.
- MeSH
- antidota aplikace a dávkování terapeutické užití toxicita MeSH
- atropin aplikace a dávkování terapeutické užití toxicita MeSH
- inbrední kmeny myší MeSH
- kombinovaná farmakoterapie MeSH
- LD50 MeSH
- molekulární struktura MeSH
- nervová bojová látka otrava MeSH
- otrava farmakoterapie MeSH
- oximy aplikace a dávkování terapeutické užití toxicita MeSH
- pyridinové sloučeniny aplikace a dávkování chemická syntéza terapeutické užití toxicita MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Carbamate inhibitors (e.g., pyridostimine bromide) are used as a pre-exposure treatment for the prevention of organophosphorus poisoning. They work by blocking acetylcholinesterase's (AChE) native function and thus protect AChE against irreversible inhibition by organophosphorus compounds. However, carbamate inhibitors are known for many undesirable side-effects related to the carbamylation of AChE. In this Letter, 19 analogues of SAD-128 were prepared and evaluated as cholinesterase inhibitors. The screening results showed promising inhibitory ability of four compounds better to used standards (pralidoxime, obidoxime, BW284c51, ethopropazine, SAD-128). Four most promising compounds were selected for further molecular docking studies. The SAR was stated from obtained data. The former receptor studies were reported and discussed. The further in vivo studies were recommended in the view of OP pre-exposure treatment.
- MeSH
- acetylcholinesterasa chemie metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- katalytická doména MeSH
- molekulární modely MeSH
- organofosfáty chemie MeSH
- počítačová simulace MeSH
- pyridinové sloučeniny chemická syntéza chemie farmakologie MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
An high-performance liquid chromatography (HPLC) method for identification of quaternary and non-quaternary compounds (parent compounds, intermediates, by-products, and products) within the synthesis of the acetylcholinesterase reactivator HI-6, the most promising antidote of nerve agent poisonings, is described. This HPLC method could be of high interest as a quick purity control for those who are interested in development of new acetylcholinesterase reactivators as well as for those who are interested in the synthesis of HI-6 in laboratory or in large-scale production. An HPLC method for quaternary compounds without using common ion-pairing reagents was developed, too.
