In Vitro Evaluation of Neutral Aryloximes as Reactivators for Electrophorus eel Acetylcholinesterase Inhibited by Paraoxon

Abstract

Casualties caused by organophosphorus pesticides are a burden for health systems in developing and poor countries. Such compounds are potent acetylcholinesterase irreversible inhibitors, and share the toxic profile with nerve agents. Pyridinium oximes are the only clinically available antidotes against poisoning by these substances, but their poor penetration into the blood-brain barrier hampers the efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in future SAR studies, we evaluated neutral aryloximes as reactivators for paraoxon-inhibited Electrophorus eel acetylcholinesterase. Our findings may result into lead compounds, useful for development of more active compounds for emergencies and supportive care.

Acetylcholinesterase: The “Hub” for Neurodegenerative Diseases and Chemical Weapons Convention

“…Structurally related to nerve agents, some pesticides, such as chlorpyrifos 22 and aldicarb 23 ( Figure 6), paraoxon 38 ( Figure 12) (used in many studies for development of antidotes towards cholinesterase inhibitors), and malathion 39 (Figure 12), a compound still used as aerosol to combat arboviruses vectors in developing countries ( Figure 12) [3][4][5][6]8,19,45,46,50,53,54,[151][152][153][154]. The toxicity related to organophosphorus compounds may be explained through the high affinity of phosphorus and oxygen, with higher energy bonds, 335 and 544 kJ/mol, for P-O and P=O bonds, respectively [155]. Poisoning and environmental contamination by organophosphorus pesticides poses a serious public health challenge in countries with lack of control of these substances.…”

“…The World Health Organization (WHO) estimated more than 200,000 casualties per year by poisoning with organophosphorus pesticides in developing countries. Recently in India, more than 20 children died after eating a meal prepared with oil stored in monocrotophos-contaminated The toxicity related to organophosphorus compounds may be explained through the high affinity of phosphorus and oxygen, with higher energy bonds, 335 and 544 kJ/mol, for P-O and P=O bonds, respectively [155]. Poisoning and environmental contamination by organophosphorus pesticides poses a serious public health challenge in countries with lack of control of these substances.…”

Trends in the Recent Patent Literature on Cholinesterase Reactivators (2016–2019)

“…Several recent works aimed at improving current antidotes by studying factors that may boost their efficiency and increase their crossing through BBB. Kuca and co-workers, for example, in in vitro tests with aryloximes and some neutral derivatives, have shown promising data on the effect of substituents, either electron-donating or electron-withdrawing with potential for existing oximes improvements, such the reactivator's potentiality as pharmacokinetics [65]. In the same line of reasoning, in a study with bisoxime, a three positive charge oxime, it was shown that even with its hydrophilicity, the reactivator was able to be stabilized in the Sarin and VX-inhibited AChE cavity through interactions with some amino acid residues, such as Tyr124 and Tyr337.…”

Design, synthesis, in silico studies and in vitro evaluation of isatin-pyridine oximes hybrids as novel acetylcholinesterase reactivators

“…These compounds have been used as pesticides (but some are now prohibited in many countries), and some are listed in the "Annex on Chemicals" of the Chemical Weapons Convention as chemical warfare agents (nerve agents). Examples of these toxic chemicals are paraoxon (PXN, 4), sarin (5), VX (6) and A-230 (7), which structures are illustrated in Figure 1 [6][7][8][9][10][11] .…”