Abstract
The implementation of the Chemical Weapons Convention (CWC) in 1997 was a milestone in the prohibition of chemical warfare agents (CWA). Yet, the repeated use of CWA underlines the ongoing threat to the population. Organophosphorus (OP) nerve agents still represent the most toxic CWA subgroup. Defensive research on nerve agents is mainly focused on the “classical five”, namely tabun, sarin, soman, cyclosarin and VX, although Schedule 1 of the CWC covers an unforeseeable number of homologues. Likewise, an uncounted number of OP pesticides have been produced in previous decades. Our aim was to determine the in vitro inhibition kinetics of selected organophosphono- and organophosphorothioates with human AChE, as well as hydrolysis of the agents in human plasma and reactivation of inhibited AChE, in order to derive potential structure–activity relationships. The investigation of the interactions of selected OP compounds belonging to schedule 1 (V-agents) and schedule 2 (amiton) of the CWC with human AChE revealed distinct structural effects of the P-alkyl, P-O-alkyl and N,N-dialkyl residues on the inhibitory potency of the agents. Irrespective of structural modifications, all tested V-agents presented as highly potent AChE inhibitors. The high stability of the tested agents in human plasma will most likely result in long-lasting poisoning in vivo, having relevant consequences for the treatment regimen. In conclusion, the results of this study emphasize the need to investigate the biological effects of nerve agent analogues in order to assess the efficacy of available medical countermeasures.
Highlights
The implementation of the Chemical Weapons Convention (CWC) in 1997 [1] was a milestone in the prohibition of chemical warfare agents (CWA)
A comparable relationship was recorded for agents residues, the inhibitory potency increased with varying N,N-dialkyl groups in the order methyl (1)
This corresponds to data from previous studies with a series major impact of the O-alkyl residues, with a more than 20-fold increase of ki values comparing of methylphosphonofluoridates showing an almost 90-fold difference between O-n-pentyl and
Summary
The implementation of the Chemical Weapons Convention (CWC) in 1997 [1] was a milestone in the prohibition of chemical warfare agents (CWA). Organophosphorus (OP) nerve agents still represent the most toxic CWA subgroup, with their toxicity being a result of the covalent inhibition of the pivotal enzyme acetylcholinesterase (AChE). Defensive research on nerve agents is mainly focused on the “classical five”, namely tabun, sarin, soman, cyclosarin and VX, Schedule 1 of the CWC covers an unforeseeable number of Molecules 2020, 25, 3029; doi:10.3390/molecules25133029 www.mdpi.com/journal/molecules. An uncounted number of OP pesticides have been produced in the previous number homologues. An uncounted number of OP pesticides have been produced in the decades of [7,8]
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