Journal Article

SAR study to find optimal cholinesterase reactivator against organophosphorous nerve agents and pesticides

Gorecki, Lukas, Malinak, David, Soukup, Ondrej, Musilek, Kamil, Jun, Daniel, Nepovimova, Eugenie, Dolezal, Rafael, Korabecny, Jan, Kuca, Kamil

2016

Overview

Irreversible inhibition of acetylcholinesterase (AChE) by organophosphates leads to many failures in living organism and ultimately in death. Organophosphorus compounds developed as nerve agents such as tabun, sarin, soman, VX and others belong to the most toxic chemical warfare agents and are one of the biggest threats to the modern civilization. Moreover, misuse of nerve agents together with organophosphorus pesticides (e.g. malathion, paraoxon, chlorpyrifos, etc.) which are annually implicated in millions of intoxications and hundreds of thousand deaths reminds us of insufficient protection against these compounds. Basic treatments for these intoxications are based on immediate administration of atropine and acetylcholinesterase reactivators which are currently represented by mono- or bis-pyridinium aldoximes. However, these antidotes are not sufficient to ensure 100 % treatment efficacy even they are administered immediately after intoxication, and in general, they possess several drawbacks. Herein, we have reviewed new efforts leading to the development of novel reactivators and proposition of new promising strategies to design novel and effective antidotes. Structure–activity relationships and biological activities of recently proposed acetylcholinesterase reactivators are discussed and summarized. Among further modifications of known oximes, the main attention has been paid to dual binding site ligands of AChE as the current mainstream strategy. We have also discussed new chemical entities as potential replacement of oxime functional group.

• Publisher: Springer Berlin Heidelberg,Springer Nature B.V
• Subject: Acetylcholinesterase / Acetylcholinesterase - chemistry / Acetylcholinesterase - metabolism / Animals / Antidotes / Antidotes - chemistry / Antidotes - pharmacology / Antidotes - therapeutic use / Atropine / Binding Sites / Biological & chemical weapons / Biological activity / Biomedical and Life Sciences / Biomedicine / Catalytic Domain / Chemical warfare / Chemical warfare agents / Chlorpyrifos / Cholinesterase / Cholinesterase Inhibitors - chemistry / Cholinesterase Inhibitors - toxicity / Cholinesterase Reactivators - chemistry / Cholinesterase Reactivators - pharmacology / Cholinesterase Reactivators - therapeutic use / Drug Design / Effectiveness / Environmental Health / Fatalities / Functional groups / Humans / Intoxication / Ligands / Malathion / Molecular Conformation / Molecular Structure / Nerve agents / Nerve Agents - chemistry / Nerve Agents - toxicity / Nerves / Occupational Medicine/Industrial Medicine / Organic phosphorus / Organophosphate Poisoning - drug therapy / Organophosphate Poisoning - etiology / Organophosphate Poisoning - metabolism / Organophosphates / Organophosphorus compounds / Organophosphorus Compounds - antagonists & inhibitors / Organophosphorus Compounds - toxicity / Organophosphorus pesticides / Oximes / Paraoxon / Pesticides / Pesticides - antagonists & inhibitors / Pesticides - toxicity / Pharmacology/Toxicology / Protein Conformation / Pyridinium / Pyridinium Compounds - chemistry / Pyridinium Compounds - pharmacology / Review Article / Sarin / Soman / Structure-Activity Relationship / Studies / Tabun