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Novel hybrid reactivators of acetylcholinesterases inhibited by organophosphorus chemical warfare agents

Novel hybrid reactivators of acetylcholinesterases inhibited by organophosphorus chemical warfare agents
Novel hybrid reactivators of acetylcholinesterases inhibited by organophosphorus chemical warfare agents
Since their development as pesticides in the 1930s, organophosphorus nerve agents (OPNA) have been weaponised and declared weapons of mass destruction. Their production and stockpiling have been forbidden since 1992, however their presence persists and they have since been employed in several acts of terror. OPNA poisoning also continues to claim lives globally through the use of the agents in the agrochemical sector of developing countries. OPNA poisoning proceeds via the irreversible inhibition of the human acetylcholinesterase (hAChE) enzyme, a key biomolecule found ubiquitously within the body, responsible for nerve impulse propagation.

This research addresses the current unmet need for universal remediation for OPNA inhibited hAChE and shortcomings of existing antidotes. We describe the development of ‘hybridre activators’ that incorporate a peripheral site ligand (PSL) and a reactivator component. The PSL offers initial binding on the surface of AChE, in close proximity to the inhibited active site; found buried within the enzyme. The reactivator, bearing a highly nucleophillic functionality is then able to pass down towards the inhibited active site where it is able to remove the nerve agent,reactivating the enzyme.

Nineteen novel hybrid reactivators based on the quinoline, theobromine, naphthalene andbenzylpiperazine PSL scaffold were designed, synthesised and evaluated against sarin, VX, tabunand paraoxon-inhibited human acetylcholinesterase. A simplified, dehydroxylated pyridine aldoxime reactivator functionality was explored and a novel in silico evaluation assay was developed. A streamlined synthesis has been established towards the development of these compounds, which is able to deliver much larger amounts for biological studies. We have been able to develop a better understanding of structure-activity relationships of novel hybrid reactivators and are now equipped with a computational model for assessing potential new structures without necessitating arduous synthetic efforts.
University of Southampton
Maryan-Instone, Alexander, John
f32b42b8-8920-4d19-9a34-3ae58f0c21d8
Maryan-Instone, Alexander, John
f32b42b8-8920-4d19-9a34-3ae58f0c21d8
Brown, Richard
21ce697a-7c3a-480e-919f-429a3d8550f5

Maryan-Instone, Alexander, John (2019) Novel hybrid reactivators of acetylcholinesterases inhibited by organophosphorus chemical warfare agents. University of Southampton, Doctoral Thesis, 317pp.

Record type: Thesis (Doctoral)

Abstract

Since their development as pesticides in the 1930s, organophosphorus nerve agents (OPNA) have been weaponised and declared weapons of mass destruction. Their production and stockpiling have been forbidden since 1992, however their presence persists and they have since been employed in several acts of terror. OPNA poisoning also continues to claim lives globally through the use of the agents in the agrochemical sector of developing countries. OPNA poisoning proceeds via the irreversible inhibition of the human acetylcholinesterase (hAChE) enzyme, a key biomolecule found ubiquitously within the body, responsible for nerve impulse propagation.

This research addresses the current unmet need for universal remediation for OPNA inhibited hAChE and shortcomings of existing antidotes. We describe the development of ‘hybridre activators’ that incorporate a peripheral site ligand (PSL) and a reactivator component. The PSL offers initial binding on the surface of AChE, in close proximity to the inhibited active site; found buried within the enzyme. The reactivator, bearing a highly nucleophillic functionality is then able to pass down towards the inhibited active site where it is able to remove the nerve agent,reactivating the enzyme.

Nineteen novel hybrid reactivators based on the quinoline, theobromine, naphthalene andbenzylpiperazine PSL scaffold were designed, synthesised and evaluated against sarin, VX, tabunand paraoxon-inhibited human acetylcholinesterase. A simplified, dehydroxylated pyridine aldoxime reactivator functionality was explored and a novel in silico evaluation assay was developed. A streamlined synthesis has been established towards the development of these compounds, which is able to deliver much larger amounts for biological studies. We have been able to develop a better understanding of structure-activity relationships of novel hybrid reactivators and are now equipped with a computational model for assessing potential new structures without necessitating arduous synthetic efforts.

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Published date: April 2019

Identifiers

Local EPrints ID: 433179
URI: http://eprints.soton.ac.uk/id/eprint/433179
PURE UUID: 733f773e-5666-4402-8113-54053dbfcc57
ORCID for Alexander, John Maryan-Instone: ORCID iD orcid.org/0000-0001-7615-1452
ORCID for Richard Brown: ORCID iD orcid.org/0000-0003-0156-7087

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Date deposited: 09 Aug 2019 16:30
Last modified: 30 Jun 2020 04:01

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Contributors

Author: Alexander, John Maryan-Instone ORCID iD
Thesis advisor: Richard Brown ORCID iD

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