Brown RCD

References (4)

Title : The risk associated with organophosphorus nerve agents: from their discovery to their unavoidable threat, current medical countermeasures and perspectives - Voros_2024_Chem.Biol.Interact__110973
Author(s) : Voros C , Dias J , Timperley CM , Nachon F , Brown RCD , Baati R
Ref : Chemico-Biological Interactions , :110973 , 2024
Abstract : The first organophosphorus nerve agent was discovered accidently during the development of pesticides, shortly after the first use of chemical weapons (chlorine, phosgene) on the battlefield during World War I. Despite the Chemical Weapons Convention banning these substances, they have still been employed in wars, terrorist attacks or political assassinations. Characterised by their high lethality, they target the nervous system by inhibiting the acetylcholinesterase (AChE) enzyme, preventing neurotransmission, which, if not treated rapidly, inevitably leads to serious injury or the death of the person intoxicated. The limited efficacy of current antidotes, known as AChE reactivators, pushes research towards new treatments. Numerous paths have been explored, from modifying the original pyridinium oximes to developing hybrid reactivators seeking a better affinity for the inhibited AChE. Another crucial approach resides in molecules more prone to cross the blood-brain barrier: uncharged compounds, bio-conjugated reactivators or innovative formulations. Our aim is to raise awareness on the threat and toxicity of organophosphorus nerve agents and to present the main synthetic efforts deployed since the first AChE reactivator, to tackle the task of efficiently treating victims of these chemical warfare agents.
ESTHER : Voros_2024_Chem.Biol.Interact__110973
PubMedSearch : Voros_2024_Chem.Biol.Interact__110973
PubMedID: 38574837

Title : Structure-Based Optimization of Nonquaternary Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Nerve Agents - Santoni_2018_J.Med.Chem_61_7630
Author(s) : Santoni G , de Sousa J , De la Mora E , Dias J , Jean L , Sussman JL , Silman I , Renard PY , Brown RCD , Weik M , Baati R , Nachon F
Ref : Journal of Medicinal Chemistry , 61 :7630 , 2018
Abstract : Acetylcholinesterase (AChE), a key enzyme in the central and peripheral nervous systems, is the principal target of organophosphorus nerve agents. Quaternary oximes can regenerate AChE activity by displacing the phosphyl group of the nerve agent from the active site, but they are poorly distributed in the central nervous system. A promising reactivator based on tetrahydroacridine linked to a nonquaternary oxime is also an undesired submicromolar reversible inhibitor of AChE. X-ray structures and molecular docking indicate that structural modification of the tetrahydroacridine might decrease inhibition without affecting reactivation. The chlorinated derivative was synthesized and, in line with the prediction, displayed a 10-fold decrease in inhibition but no significant decrease in reactivation efficiency. X-ray structures with the derivative rationalize this outcome. We thus show that rational design based on structural studies permits the refinement of new-generation pyridine aldoxime reactivators that may be more effective in the treatment of nerve agent intoxication.
ESTHER : Santoni_2018_J.Med.Chem_61_7630
PubMedSearch : Santoni_2018_J.Med.Chem_61_7630
PubMedID: 30125110
Gene_locus related to this paper: torca-ACHE

Title : Buchwald-Hartwig Amination Approach for the Synthesis of Functionalized 1,2,3,4-Tetrahydroacridine Derivatives - de Sousa_2014_European.J.Org.Chem_2014_3468
Author(s) : de Sousa J , Brown RCD , Baati R
Ref : European J Org Chem , 2014 :3468 , 2014
Abstract : Electrophilic 1,2,3,4-tetrahydroacridin-9-yl trifluoromethanesulfonates have been prepared and applied for the first time in the synthesis of functionalized tacrines with high efficacy by using the Buchwald-Hartwig amination reaction. Remarkably, secondary, poor nucleophilic, and functionalized amines also reacted efficiently by using our conditions. The versatility and convenience of these highly reactive derivatives is illustrated through their application in other valuable C-C (Sonogashira, Suzuki, and cyanation cross-coupling), C-S, and C-O bond-forming reactions under palladium catalysis.
ESTHER : de Sousa_2014_European.J.Org.Chem_2014_3468
PubMedSearch : de Sousa_2014_European.J.Org.Chem_2014_3468
PubMedID:

Title : Detection of nerve agent via perturbation of supramolecular gel formation - Hiscock_2013_Chem.Commun.(Camb)_49_9119
Author(s) : Hiscock JR , Piana F , Sambrook MR , Wells NJ , Clark AJ , Vincent JC , Busschaert N , Brown RCD , Gale PA
Ref : Chem Commun (Camb) , 49 :9119 , 2013
Abstract : The formation of tren-based tris-urea supramolecular gels in organic solvents is perturbed by the presence of the nerve agent soman providing a new method of sensing the presence of organophosphorus warfare agents.
ESTHER : Hiscock_2013_Chem.Commun.(Camb)_49_9119
PubMedSearch : Hiscock_2013_Chem.Commun.(Camb)_49_9119
PubMedID: 23994877