The limited effectiveness of the established oximes obidoxime and pralidoxime resulted in ongoing research on novel oximes for the reactivation of acetylcholinesterase (AChE) inhibited by organophosphorus compounds (OP). In order to get more insight into the ability of bispyridinium oximes to reactivate human AChE inhibited by structurally different OP the reactivation kinetics of 31 compounds was determined with tabun-, cyclosarin- and paraoxon-inhibited AChE under identical experimental conditions. The determined affinity (KD), reactivity (kr) and hybrid reactivation rate constants (kr2) enabled theoretical calculations and gave insight into distinct structural features which are important for the reactivation of AChE inhibited by different OP. Several oximes with superior reactivating potency towards selective OP-AChE conjugates were identified but none of the tested oximes can be considered as a broad spectrum reactivator. In the end, the data of this and previous studies gives rise to the question whether further modifications of the bispyridinium structure could ever result in a universal reactivator or whether future research should be directed to different templates.

Bundeswehr Institute of Pharmacology and Toxicology Munich Germany

University of Hradec Kralove Faculty of Science Department of Chemistry Hradec Králové Czech Republic

University of Hradec Kralove Faculty of Science Department of Chemistry Hradec Králové Czech Republic; University Hospital Hradec Kralove Biomedical Research Center Hradec Králové Czech Republic

References provided by Crossref.org

Strategies for enhanced bioavailability of oxime reactivators in the central nervous system

Charged pyridinium oximes with thiocarboxamide moiety are equally or less effective reactivators of organophosphate-inhibited cholinesterases compared to analogous carboxamides

Reactivation of VX-Inhibited Human Acetylcholinesterase by Deprotonated Pralidoxime. A Complementary Quantum Mechanical Study

Molecular modeling studies on the interactions of 7-methoxytacrine-4-pyridinealdoxime, 4-PA, 2-PAM, and obidoxime with VX-inhibited human acetylcholinesterase: a near attack conformation approach

Molecular Modeling and In Vitro Studies of a Neutral Oxime as a Potential Reactivator for Acetylcholinesterase Inhibited by Paraoxon

Acetylcholinesterase Inhibitors and Drugs Acting on Muscarinic Receptors- Potential Crosstalk of Cholinergic Mechanisms During Pharmacological Treatment

The Evaluation of the Reactivating and Neuroprotective Efficacy of Two Newly Prepared Bispyridinium Oximes (K305, K307) in Tabun-Poisoned Rats-A Comparison with Trimedoxime and the Oxime K203