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Review
. 2020 Mar 12;10(3):436.
doi: 10.3390/biom10030436.

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

Alexandre A de Castro  1 , Letícia C Assis  1 , Flávia V Soares  1 , Kamil Kuca  2 , Daniel A Polisel  1 , Elaine F F da Cunha  1 , Teodorico C Ramalho  1   2
Affiliations
Review

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

Alexandre A de Castro et al. Biomolecules. .

Abstract

Acetylcholinesterase (AChE) is the key enzyme responsible for deactivating the ACh neurotransmitter. Irreversible or prolonged inhibition of AChE, therefore, elevates synaptic ACh leading to serious central and peripheral adverse effects which fall under the cholinergic syndrome spectra. To combat the toxic effects of some AChEI, such as organophosphorus (OP) nerve agents, many compounds with reactivator effects have been developed. Within the most outstanding reactivators, the substances denominated oximes stand out, showing good performance for reactivating AChE and restoring the normal synaptic acetylcholine (ACh) levels. This review was developed with the purpose of covering the new advances in AChE reactivation. Over the past years, researchers worldwide have made efforts to identify and develop novel active molecules. These researches have been moving farther into the search for novel agents that possess better effectiveness of reactivation and broad-spectrum reactivation against diverse OP agents. In addition, the discovery of ways to restore AChE in the aged form is also of great importance. This review will allow us to evaluate the major advances made in the discovery of new acetylcholinesterase reactivators by reviewing all patents published between 2016 and 2019. This is an important step in continuing this remarkable research so that new studies can begin.

Keywords: acetylcholinesterase; new trends in reactivators; organophosphorus compounds; reactivation process; therapeutic potential.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Neuron structure and nerve impulse transmission process.
Figure 2
Figure 2
Representation of the acetylcholine (ACh) hydrolysis scheme.
Figure 3
Figure 3
General structure of organophosphorus compounds.
Figure 4
Figure 4
General structure of carbamates.
Figure 5
Figure 5
Chemical structures of the main warfare nerve agents.
Figure 6
Figure 6
General representation of the (a) inhibition and (b) aging mechanisms [47].
Figure 7
Figure 7
Chemical structures of some important pesticides.
Figure 8
Figure 8
Representation of the chemical structures of atropine and diazepam.
Figure 9
Figure 9
General representation of the reactivation process of the inhibited acetylcholinesterase (AChE).
Figure 10
Figure 10
Representation of the chemical structures of oximes.
Figure 11
Figure 11
Chemical structures of 4-amino-2-(diethylaminomethyl)phenol (ADOC) and 1,1’-(propane-1,3-diyl)bis(4-tert-butylpyridinium)di(iodide) (MB327).
Figure 12
Figure 12
Formula I of the compounds developed in this patent.
Figure 13
Figure 13
Representation of the chemical structure of some molecules synthesized.
Figure 14
Figure 14
Proposed resurrection process for aged AChE.
Figure 15
Figure 15
Representation of the chemical structures of some organophosphorus (OP) used in the patent.
Figure 16
Figure 16
Representation of the general chemical formula for the oxime molecules investigated.
Figure 17
Figure 17
Representation of the general formula of oxime [90].
Figure 18
Figure 18
Representation of Formula II developed in the patent [90].
Figure 19
Figure 19
Formula III of an oxime developed in the patent [90].
Figure 20
Figure 20
Formula IV for the novel molecules developed in the patent.
See this image and copyright information in PMC

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