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The Effects of Synthetic Phosphonates on Living Systems
Published in Richard L. Hilderbrand, The Role of Phosphonates in Living Systems, 2018
An oxime, such as pyridine-2-aldoxime or obidoxime chloride (Figure 2), can be used to reactivate the inhibited enzyme. The proposed mechanism of this reactivation is that the positive charge on the oxime is attracted to the anionic site of the AChE. An inhibited enzyme-reactivator complex is formed and the nucleophilic group of the reactivator is in close proximity to the active site. The reactivation is then essentially a nucleophilic displacement reaction on the phosphorus atom to regenerate the hydroxyl of the enzyme. This mechanism and the chemical parameters affecting it are discussed extensively by Eto.36
Anticholinesterases
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
The spontaneous hydrolysis of the phosphorylated enzyme occurs extremely slowly. Reversal of the inhibition may, however, be effected by nucleophilic agents including hydroxylamine (NH2OH), hydroxamic acids (RCONH-OH) and oximes (RCH = NOH). By adding a quaternary nitrogen that could interact with the anionic site of the enzyme, 2-pyridine aldoxime methiodide (2-PAM or pralidoxime) was developed as an effective oxime for enzyme reactivation (Holmstedt 1959) (Table 10.3). The oxime group combines with the phosphate or phosphonate group that is covalently bound to the serine hydroxyl group at the esteratic site. The link is broken by nucleophilic attack, which splits off the oxime–phosphorus moiety, leaving the regenerated enzyme (Figure 10.6). The rate of reactivation of the phosphorylated enzyme by the oxime depends upon the type of group that phosphorylates the enzyme. The order of decreasing reversal rates is essentially the same as for the spontaneous recovery, which is dimethylphosphoryl (eg malathion) > diethylphosphoryl (eg paraoxon) > diisopropylphosphoryl (DFP), and so forth. Several bisquaternary oximes, such as obidoxime, have been shown to have greater potency as enzyme reactivators and antidotes to nerve gas poisoning (Table 10.3). Pralidoxime is effective against tabun and sarin poisoning, but not against soman. The reason for this is that the inhibited enzyme is said to ‘age’. Aging occurs quite rapidly, within minutes or hours, depending upon the phosphorylating moiety. Phosphonates containing tertiary alkoxy groups (eg soman) age more readily than do those with secondary (eg sarin) or primary alkoxy groups (eg tabun).
Synthesis, in vitro screening and molecular docking of isoquinolinium-5-carbaldoximes as acetylcholinesterase and butyrylcholinesterase reactivators
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
David Malinak, Rafael Dolezal, Vendula Hepnarova, Miroslava Hozova, Rudolf Andrys, Petr Bzonek, Veronika Racakova, Jan Korabecny, Lukas Gorecki, Eva Mezeiova, Miroslav Psotka, Daniel Jun, Kamil Kuca, Kamil Musilek
For BChE, compounds 17–18 (inhibition of hBChE over 100 µM) and 30–32 (inhibition of hBChE over 1000 µM) were selected and tested for reactivation potential against sarin, VX or paraoxon inhibited hBChE and compared to obidoxime (Table 3). The obidoxime was found to have some reactivation ability for sarin and VX, but markedly lower for paraoxon. Apparently, some novel compounds (17–18) showed markedly improved reactivation than obidoxime for sarin (17), VX (17–18) and paraoxon (17) when tested at 100 µM. This finding seems to be important since obidoxime formerly resulted as the best reactivator of hBChE inhibited by tabun23, although its reactivation was found not appropriate for constructing a pseudo-catalytic scavenger. More interestingly, these symmetrical isoquinolinium carbaldoximes with three or four-member linkers were found better hBChE reactivators than obidoxime at 10 µM for sarin and VX. On the other hand, the isoquinolinium carbaldoximes with pyridinium amide moiety (30–32) which were poor BChE inhibitors were endowed with minimal reactivation for all tested OPs.
Novichok: a murderous nerve agent attack in the UK
Published in Clinical Toxicology, 2018
J. Allister Vale, Timothy C. Marrs, Robert L. Maynard
Pralidoxime salts are the most widely used oximes in treating patients poisoned with organophosphorus compounds, though other oximes, including obidoxime (Toxogonin) and the H (Hagedorn) series, for example, HI-6 and HLö-7, have also been employed. With the possible exception of the treatment of cyclosarin and soman poisoning, when HI-6 might be preferred, there are no clinically important differences between pralidoxime, obidoxime and HI-6 in the treatment of nerve agent poisoning [23]. Oxime regimens are also based on those in use for organophosphorus insecticide poisoning. Pralidoxime chloride 30 mg/kg by intravenous injection should also be administered as soon as possible and repeated at 4–6 h intervals; alternatively an intravenous infusion of 8–10 mg/kg/h may be employed [24]. Obidoxime 250 mg intravenously, followed by a continuous infusion at a dose of 750 mg/day, is an alternative [25]. Combined oxime therapy has been proposed [26].
Pyridinium-2-carbaldoximes with quinolinium carboxamide moiety are simultaneous reactivators of acetylcholinesterase and butyrylcholinesterase inhibited by nerve agent surrogates
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Hyun Myung Lee, Rudolf Andrys, Jakub Jonczyk, Kyuneun Kim, Avinash G. Vishakantegowda, David Malinak, Adam Skarka, Monika Schmidt, Michaela Vaskova, Kamil Latka, Marek Bajda, Young-Sik Jung, Barbara Malawska, Kamil Musilek
The next step of our analysis was focussed on the oxime conformation in the pre-reactivation state referring to that observed in the crystal structure (PDB code: 5FPP)34. Using the position of pyridinium moiety with oxime of asoxime as a template we reproduced the pre-reactivation position of the tested reactivators. It allowed us to check which of the novel compounds was the best suited to the protein when the reactivation process began. The results of the standard compounds 2 and 3 brought many interesting observations. Most importantly, the poses of individual oximes in the pre-reactivation complexes with sarin-, VX-, and POX-inhibited AChE indicated the existence of repetitive interactions with particular amino acids (Figure 3(S)). The asoxime (3) exhibited the largest number of interactions in a complex with sarin-inhibited AChE. These were π–π stacking and cation–π interactions with TYR341, the CH-π interaction with TYR124 and π–π stacking with TRP286. A slight shift of asoxime position was observed in the complex with VX-AChE and it led to weaker interaction with TYR124. In the POX-AChE adduct, such shifted position was even more apparent and it prevented the formation of aromatic interactions with TYR124 and TRP286. The lack of interactions with particular amino acids may explain the observed decline in asoxime reactivation ability for POX-inhibited hrAChE (Table 1). In contrast to asoxime, the number of specific interactions for obidoxime (2) was only slightly changed. The previously mentioned interactions occurred with the additional ionic interaction with ASP74 presented in all OP-AChE adducts. In the case of POX-AChE, the cation–π interaction with TYR72 was observed. These findings were consistent with the results of in vitro experiments in which obidoxime (2) maintained the high reactivation ability for all tested OP-AChE adducts.