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.

• Keywords
• acetylcholinesterase, antidote, butyrylcholinesterase, organophosphate, oxime, paraoxon,
• MeSH
• Acetylcholinesterase chemistry   MeSH
• Antidotes chemical synthesis   pharmacology   MeSH
• Butyrylcholinesterase chemistry   MeSH
• Cholinesterase Inhibitors chemistry   MeSH
• Enzyme Assays MeSH
• Erythrocytes drug effects   enzymology   MeSH
• Insecticides antagonists & inhibitors   chemistry   toxicity   MeSH
• Protein Interaction Domains and Motifs MeSH
• Humans MeSH
• Obidoxime Chloride chemistry   pharmacology   MeSH
• Oximes chemical synthesis   pharmacology   MeSH
• Paraoxon antagonists & inhibitors   chemistry   toxicity   MeSH
• Cholinesterase Reactivators chemical synthesis   pharmacology   MeSH
• Protein Structure, Secondary MeSH
• Molecular Docking Simulation MeSH
• Thermodynamics MeSH
• Protein Binding MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Antidotes MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Insecticides MeSH
• Obidoxime Chloride MeSH
• Oximes MeSH
• Paraoxon MeSH
• Cholinesterase Reactivators MeSH

BACKGROUND: Intoxication by nerve agents could be prevented by using small acetylcholinesterase inhibitors (eg, pyridostigmine) for potentially exposed personnel. However, the serious side effects of currently used drugs led to research of novel potent molecules for prophylaxis of organophosphorus intoxication. METHODS: The molecular design, molecular docking, chemical synthesis, in vitro methods (enzyme inhibition, cytotoxicity, and nicotinic receptors modulation), and in vivo methods (acute toxicity and prophylactic effect) were used to study bispyridinium, bisquinolinium, bisisoquinolinium, and pyridinium-quinolinium/isoquinolinium molecules presented in this study. RESULTS: The studied molecules showed non-competitive inhibitory ability towards human acetylcholinesterase in vitro that was further confirmed by molecular modelling studies. Several compounds were selected for further studies. First, their cytotoxicity, nicotinic receptors modulation, and acute toxicity (lethal dose for 50% of laboratory animals [LD50]; mice and rats) were tested to evaluate their safety with promising results. Furthermore, their blood levels were measured to select the appropriate time for prophylactic administration. Finally, the protective ratio of selected compounds against soman-induced toxicity was determined when selected compounds were found similarly potent or only slightly better to standard pyridostigmine. CONCLUSION: The presented small bisquaternary molecules did not show overall benefit in prophylaxis of soman-induced in vivo toxicity.

• Keywords
• AChE inhibitors, nerve agents, pre-treatment, prophylaxis, soman, toxicity,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Cell Line MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• HeLa Cells MeSH
• Small Molecule Libraries chemistry   pharmacology   MeSH
• Humans MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• Nerve Agents adverse effects   MeSH
• Soman adverse effects   MeSH
• Cell Survival drug effects   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Small Molecule Libraries MeSH
• Nerve Agents MeSH
• Soman MeSH