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Acetylcholinesterase (AChE) is well-known enzyme studied in many fields of research, e.g. in Alzheimer's disease, Parkinson's disease, or in eco-toxicology as a biological marker. Many inhibitors of AChE have been identified in nature as well as prepared in chemical labs as a result of systematic synthetic efforts. The organophosphorus (OP) inhibitors of AChE are one of the oldest artificial inhibitors being purposely developed as military nerve agents (e.g. sarin, soman, tabun, VX, RVX). Some of the compounds with decreased toxicity are currently used in agriculture as pesticides (e.g. parathion, chlorpyrifos, paraoxon) or in the industry as softening agents and flame retardants. The common mechanism of action of all organophosphate compounds is the irreversible inhibition of AChE via a binding to the hydroxyl group of the serine residue within the active site of the enzyme. Subsequently, AChE loses its ability to fulfill its physiological role in cholinergic transmission, which leads to the cholinergic crisis with the possibility of respiratory failure and death. The reactivators of AChE are classified as strong nucleophilic agents capable to cleave the non-aged organophosphate- serine adduct and thereby restoring the activity of the enzyme. This work provides a unique overview of the most potent oximes reactivators of inhibited AChE since 1955 to the present. In this review article, we have reviewed different synthetic approaches of known and widely used oxime reactivators of AChE such as pralidoxime, methoxime, trimedoxime, obidoxime, asoxime (HI-6), HS-6, HLo-7, K027, K048, K203, K075 and BI-6. The review covers the original articles as well as patented research.

Background: In the last decade, the concept of uncharged reactivators potentially able to penetrate the CNS has been introduced as an alternative to the classic charged oxime reactivators. However, this concept brings with it several associated drawbacks such as higher lipophilicity, difficulty in administration, lower affinity to cholinesterases, and higher toxicity risk. Objective: In this study, we compare data obtained for a set of five classic charged reactivators and a set of three recently published uncharged oximes supplemented by two novel ones. Methods: This time, we used only in silico prediction and in vitro approaches. Results: Our data showed that tested uncharged oximes have low affinity for cholinesterases, do not possess high reactivation potency, and certainly represent a greater toxicity risk due to higher lipophilicity. We assume that balanced physicochemical properties will be required for the successful treatment of OP poisoning. Nevertheless, the compound meeting such criteria and pinpointed in silico (K1280) failed in this particular case. Conclusion: From the presented data, it seems that the concept of uncharged reactivators will have to be modified, at least to improve the bioavailability and to satisfy requirements for in vivo administration.

The Lemieux–Johnson oxidation was employed for the cleavage of the carbon–carbon double bond of shikimic acid derivatives. Through this procedure, a series of the sixteen novel (2S,3S,4R)-2,3,4,7-tetrahydroxy-6-oxoheptanals bearing three contiguous stereocentres have been synthesized in excellent yields.