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Design, synthesis and biological of novel uncharged bifunctional hybrid reactivators for organophosphorous nerve agent-inhibited human acetylcholinesterase

Design, synthesis and biological of novel uncharged bifunctional hybrid reactivators for organophosphorous nerve agent-inhibited human acetylcholinesterase
Design, synthesis and biological of novel uncharged bifunctional hybrid reactivators for organophosphorous nerve agent-inhibited human acetylcholinesterase
Remediation of both acute and chronic intoxications by organophosphorus nerve agents, both chemical warfare agents and pesticides, continues to be a challenge of paramount importance. These manmade poisons act as covalent and irreversible inhibitors of acetylcholinesterase, a key enzyme mostly located in the nervous system, through phosphylation of its active site. The phosphylated active site residues do not undergo spontaneous hydrolysis. However, hydrolysis can be achieved through the use of strong nucleophiles (also called acetylcholinesterase reactivators) able to enter the buried active site of the protein. Our research is based on the rational design of hybrid structures containing two key elements: a neutral reactivator to restore the enzyme activity, and a peripheral site ligand giving selectivity by targeted binding to a site at the entrance of the enzyme active site gorge. Nine novel reactivators based on acridine, quinoline and original oxoassoanine analogues were synthesised, evaluated and are herein described. Delightfully, most of these hybrids proved to be equally or more potent than the drugs currently in use. Outstandingly, we have discovered the first broad-spectrum reactivator that outperformed all known reactivators (standard and lead compounds) for both chemical warfare agent and pesticide intoxications.
De Sousa, Julien Alain Albino
c6395c10-0455-40ea-952a-dcb626f0ba85
De Sousa, Julien Alain Albino
c6395c10-0455-40ea-952a-dcb626f0ba85
Brown, Richard
21ce697a-7c3a-480e-919f-429a3d8550f5

De Sousa, Julien Alain Albino (2016) Design, synthesis and biological of novel uncharged bifunctional hybrid reactivators for organophosphorous nerve agent-inhibited human acetylcholinesterase. University of Southampton, Chemistry, Doctoral Thesis, 313pp.

Record type: Thesis (Doctoral)

Abstract

Remediation of both acute and chronic intoxications by organophosphorus nerve agents, both chemical warfare agents and pesticides, continues to be a challenge of paramount importance. These manmade poisons act as covalent and irreversible inhibitors of acetylcholinesterase, a key enzyme mostly located in the nervous system, through phosphylation of its active site. The phosphylated active site residues do not undergo spontaneous hydrolysis. However, hydrolysis can be achieved through the use of strong nucleophiles (also called acetylcholinesterase reactivators) able to enter the buried active site of the protein. Our research is based on the rational design of hybrid structures containing two key elements: a neutral reactivator to restore the enzyme activity, and a peripheral site ligand giving selectivity by targeted binding to a site at the entrance of the enzyme active site gorge. Nine novel reactivators based on acridine, quinoline and original oxoassoanine analogues were synthesised, evaluated and are herein described. Delightfully, most of these hybrids proved to be equally or more potent than the drugs currently in use. Outstandingly, we have discovered the first broad-spectrum reactivator that outperformed all known reactivators (standard and lead compounds) for both chemical warfare agent and pesticide intoxications.

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Published date: 18 February 2016
Organisations: University of Southampton, Chemistry

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Local EPrints ID: 392910
URI: http://eprints.soton.ac.uk/id/eprint/392910
PURE UUID: 09e7ee10-6293-474c-9f66-b8ee565da150
ORCID for Richard Brown: ORCID iD orcid.org/0000-0003-0156-7087

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Date deposited: 22 Apr 2016 13:45
Last modified: 30 Apr 2021 04:01

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Contributors

Author: Julien Alain Albino De Sousa
Thesis advisor: Richard Brown ORCID iD

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