Baati R


Full name : Baati Rachid

First name : Rachid

Mail : Universite de Strasbourg UMR CNRS 7515 ICPEES, 25 rue Becquerel, F67087 Strasbourg cedex 2, Illkirch

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Country : France

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References (18)

Title : No-observed-adverse-effect-level (NOAEL) assessment as an optimized dose of cholinesterase reactivators for the treatment of exposure to warfare nerve agents in mice - Trancart_2024_Chem.Biol.Interact__110929
Author(s) : Trancart M , Hanak AS , Dambrune C , Madi M , Voros C , Baati R , Calas AG
Ref : Chemico-Biological Interactions , :110929 , 2024
Abstract : Despite the international convention on the prohibition of chemical weapons ratified in 1997, the threat of conflicts and terrorist attacks involving such weapons still exists. Among these, organophosphorus-nerve agents (OPs) inhibit cholinesterases (ChE) causing cholinergic syndrome. The reactivation of these enzymes is therefore essential to protect the poisoned people. However, these reactivating molecules, mainly named oximes, have major drawbacks with limited efficacy against some OPs and a non-negligible ChE inhibitor potential if administered at an inadequate dose, an effect that they are precisely supposed to mitigate. As a result, this project focused on assessing therapeutic efficacy, in mice, up to the NOAEL dose, the maximum dose of oxime that does not induce any observable toxic effect. NOAEL doses of HI-6 DMS, a reference oxime, and JDS364. HCl, a candidate reactivator, were assessed using dual-chamber plethysmography, with respiratory ventilation impairment as a toxicity criterion. Time-course modeling parameters and pharmacodynamic profiles, reflecting the interaction between the oxime and circulating ChE, were evaluated for treatments at their NOAEL and higher doses. Finally, the therapeutic potential against OPs poisoning was determined through the assessment of protective indices. For JDS364. HCl, the NOAEL dose corresponds to the smallest dose inducing the most significant therapeutic effect without causing any abnormality in ChE activity. In contrast, for HI-6 DMS, its therapeutic benefit was observed at doses higher than its NOAEL, leading to alterations in respiratory function. These alterations could not be directly correlated with ChE inhibition and had no adverse effects on survival. They are potentially attributed to the stimulation of non-enzymatic cholinergic targets by HI-6 DMS. Thus, the NOAEL appears to be an optimal dose for evaluating the efficacy of oximes, particularly when it can be linked to respiratory alterations effectively resulting from ChE inhibition.
ESTHER : Trancart_2024_Chem.Biol.Interact__110929
PubMedSearch : Trancart_2024_Chem.Biol.Interact__110929
PubMedID: 38417730

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 : Long-Term Anxiety-like Behavior and Microbiota Changes Induced in Mice by Sublethal Doses of Acute Sarin Surrogate Exposure - Francois_2022_Biomedicines_10_
Author(s) : Francois S , Mondot S , Gerard Q , Bel R , Knoertzer J , Berriche A , Cavallero S , Baati R , Orset C , Dal Bo G , Thibault K
Ref : Biomedicines , 10 : , 2022
Abstract : Anxiety disorder is one of the most reported complications following organophosphorus (OP) nerve agent (NA) exposure. The goal of this study was to characterize the long-term behavioral impact of a single low dose exposure to 4-nitrophenyl isopropyl methylphosphonate (NIMP), a sarin surrogate. We chose two different sublethal doses of NIMP, each corresponding to a fraction of the median lethal dose (one mild and one convulsive), and evaluated behavioral changes over a 6-month period following exposure. Mice exposed to both doses showed anxious behavior which persisted for six-months post-exposure. A longitudinal magnetic resonance imaging examination did not reveal any anatomical changes in the amygdala throughout the 6-month period. While no cholinesterase activity change or neuroinflammation could be observed at the latest timepoint in the amygdala of NIMP-exposed mice, important modifications in white blood cell counts were noted, reflecting a perturbation of the systemic immune system. Furthermore, intestinal inflammation and microbiota changes were observed at 6-months in NIMP-exposed animals regardless of the dose received. This is the first study to identify long-term behavioral impairment, systemic homeostasis disorganization and gut microbiota alterations following OP sublethal exposure. Our findings highlight the importance of long-term care for victims of NA exposure, even in asymptomatic cases.
ESTHER : Francois_2022_Biomedicines_10_
PubMedSearch : Francois_2022_Biomedicines_10_
PubMedID: 35625901

Title : A New Class of Bi- and Trifunctional Sugar Oximes as Antidotes against Organophosphorus Poisoning - Da Silva_2022_J.Med.Chem_65_4649
Author(s) : Da Silva O , Probst N , Landry C , Hanak AS , Warnault P , Coisne C , Calas AG , Gosselet F , Courageux C , Gastellier AJ , Trancart M , Baati R , Dehouck MP , Jean L , Nachon F , Renard PY , Dias J
Ref : Journal of Medicinal Chemistry , 65 :4649 , 2022
Abstract : Recent events demonstrated that organophosphorus nerve agents are a serious threat for civilian and military populations. The current therapy includes a pyridinium aldoxime reactivator to restore the enzymatic activity of acetylcholinesterase located in the central nervous system and neuro-muscular junctions. One major drawback of these charged acetylcholinesterase reactivators is their poor ability to cross the blood-brain barrier. In this study, we propose to evaluate glucoconjugated oximes devoid of permanent charge as potential central nervous system reactivators. We determined their in vitro reactivation efficacy on inhibited human acetylcholinesterase, the crystal structure of two compounds in complex with the enzyme, their protective index on intoxicated mice, and their pharmacokinetics. We then evaluated their endothelial permeability coefficients with a human in vitro model. This study shed light on the structural restrains of new sugar oximes designed to reach the central nervous system through the glucose transporter located at the blood-brain barrier.
ESTHER : Da Silva_2022_J.Med.Chem_65_4649
PubMedSearch : Da Silva_2022_J.Med.Chem_65_4649
PubMedID: 35255209
Gene_locus related to this paper: human-ACHE

Title : An Antidote Screening System for Organophosphorus Poisoning Using Zebrafish Larvae - Dubrana_2021_ACS.Chem.Neurosci__
Author(s) : Dubrana LE , Knoll-Gellida A , Bourcier LM , Merce T , Pedemay S , Nachon F , Calas AG , Baati R , Soares M , Babin PJ
Ref : ACS Chem Neurosci , : , 2021
Abstract : Organophosphorus (OP) cholinesterase inhibitors, which include insecticides and chemical warfare nerve agents, are very potent neurotoxicants. Given that the actual treatment has several limitations, the present study provides a general method, called the zebrafish-OP-antidote test (ZOAT), and basic scientific data, to identify new antidotes that are more effective than the reference pyridinium oximes after acute OP poisoning. The reactivation capacity of a chemical compound can be measured using in vivo and ex vivo acetylcholinesterase (AChE) assays. We demonstrated that it is possible to differentiate between chemical compound protective efficacies in the central and peripheral nervous system via the visual motor response and electric field pulse motor response tests, respectively. Moreover, the ability to cross the brain-blood barrier can be estimated in a physiological context by combining an AChE assay on the head and trunk-tail fractions and the cellular and tissue localization of AChE activity in the whole-mount animal. ZOAT is an innovative method suitable for the screening and rapid identification of chemicals and mixtures used as antidote for OP poisoning. The method will make it easier to identify more effective medical countermeasures for chemical threat agents, including combinatorial therapies.
ESTHER : Dubrana_2021_ACS.Chem.Neurosci__
PubMedSearch : Dubrana_2021_ACS.Chem.Neurosci__
PubMedID: 34284583

Title : Persistent brainwave disruption and cognitive impairment induced by acute sarin surrogate sub-lethal dose exposure - Angrand_2021_Toxicology__152787
Author(s) : Angrand L , Takillah S , Malissin I , Berriche A , Cervera C , Bel R , Gerard Q , Knoertzer J , Baati R , Kononchik JP , Megarbane B , Thibault K , Dal Bo G
Ref : Toxicology , :152787 , 2021
Abstract : Warfare neurotoxicants such as sarin, soman or VX, are organophosphorus compounds which irreversibly inhibit cholinesterase. High-dose exposure with nerve agents (NA) is known to produce seizure activity and related brain damage, while less is known about the effects of acute sub-lethal dose exposure. The aim of this study was to characterize behavioral, brain activity and neuroinflammatory modifications at different time points after exposure to 4-nitrophenyl isopropyl methylphosphonate (NIMP), a sarin surrogate. In order to decipher the impacts of sub-lethal exposure, we chose 4 different doses of NIMP each corresponding to a fraction of the median lethal dose (LD(50)). First, we conducted a behavioral analysis of symptoms during the first hour following NIMP challenge and established a specific scoring scale for the intoxication severity. The intensity of intoxication signs was dose-dependent and proportional to the cholinesterase activity inhibition evaluated in mice brain. The lowest dose (0.3 LD(50)) did not induce significant behavioral, electrocorticographic (ECoG) nor cholinesterase activity changes. Animals exposed to one of the other doses (0.5, 0.7 and 0.9 LD(50)) exhibited substantial changes in behavior, significant cholinesterase activity inhibition, and a disruption of brainwave distribution that persisted in a dose-dependent manner. To evaluate long lasting changes, we conducted ECoG recording for 30 days on mice exposed to 0.5 or 0.9 LD(50) of NIMP. Mice in both groups showed long-lasting impairment of theta rhythms, and a lack of restoration in hippocampal ChE activity after 1-month post-exposure. In addition, an increase in neuroinflammatory markers (IBA-1, TNF-alpha, NF-kappaB) and edema were transiently observed in mice hippocampus. Furthermore, a novel object recognition test showed an alteration of short-term memory in both groups, 1-month post-NIMP intoxication. Our findings identified both transient and long-term ECoG alterations and some long term cognitive impairments following exposure to sub-lethal doses of NIMP. These may further impact morphopathological alterations in the brain.
ESTHER : Angrand_2021_Toxicology__152787
PubMedSearch : Angrand_2021_Toxicology__152787
PubMedID: 33887375

Title : Chemoselective Hydrogenation of 6-Alkynyl-3-fluoro-2-pyridinaldoximes: Access to First-in-Class 6-Alkyl-3-Fluoro-2-pyridinaldoxime Scaffolds as New Reactivators of Sarin-Inhibited Human Acetylcholinesterase with Increased Blood-Brain Barrier Permeability - Yerri_2020_Chemistry_26_15035
Author(s) : Yerri J , Dias J , Nimmakayala MR , Razafindrainibe F , Courageux C , Gastellier AJ , Jegoux J , Coisne C , Landry C , Gosselet F , Hachani J , Goossens JF , Dehouck MP , Nachon F , Baati R
Ref : Chemistry , 26 :15035 , 2020
Abstract : Novel 6-alkyl- and 6-alkenyl-3-fluoro-2-pyridinaldoximes have been synthesised by using a mild and efficient chemoselective hydrogenation of 6-alkynyl-3-fluoro-2-pyridinaldoxime scaffolds, without altering the reducible, unprotected, sensitive oxime functionality and the C-F bond. These novel 6-alkyl-3-fluoro-2-pyridinaldoximes may find medicinal application as antidotes to organophosphate poisoning. Indeed, one low-molecular-weight compound exhibited increased affinity for sarin-inhibited acetylcholinesterase (hAChE) and greater reactivation efficiency or resurrection for sarin-inhibited hAChE, compared with those of 2-pyridinaldoxime (2-PAM) and 1-({[4-(aminocarbonyl)pyridinio]methoxy}methyl)-2-[(hydroxyimino)methyl]pyridinium chloride (HI-6), two pyridinium salts currently used as antidote by several countries. In addition, the uncharged 3-fluorinated bifunctional hybrid showed increased in vitro blood-brain barrier permeability compared with those of 2-PAM, HI-6 and obidoxime. These promising features of novel low-molecular-weight alkylfluoropyridinaldoxime open up a new era for the design, synthesis and discovery of central non-quaternary broad spectrum reactivators for organophosphate-inhibited cholinesterases.
ESTHER : Yerri_2020_Chemistry_26_15035
PubMedSearch : Yerri_2020_Chemistry_26_15035
PubMedID: 32633095

Title : Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime - Calas_2020_Biomolecules_10_
Author(s) : Calas AG , Hanak AS , Jaffre N , Nervo A , Dias J , Rousseau C , Courageux C , Brazzolotto X , Villa P , Obrecht A , Goossens JF , Landry C , Hachani J , Gosselet F , Dehouck MP , Yerri J , Kliachyna M , Baati R , Nachon F
Ref : Biomolecules , 10 : , 2020
Abstract : (1) Background: Human exposure to organophosphorus compounds employed as pesticides or as chemical warfare agents induces deleterious effects due to cholinesterase inhibition. One therapeutic approach is the reactivation of inhibited acetylcholinesterase by oximes. While currently available oximes are unable to reach the central nervous system to reactivate cholinesterases or to display a wide spectrum of action against the variety of organophosphorus compounds, we aim to identify new reactivators without such drawbacks. (2) Methods: This study gathers an exhaustive work to assess in vitro and in vivo efficacy, and toxicity of a hybrid tetrahydroacridine pyridinaldoxime reactivator, KM297, compared to pralidoxime. (3) Results: Blood-brain barrier crossing assay carried out on a human in vitro model established that KM297 has an endothelial permeability coefficient twice that of pralidoxime. It also presents higher cytotoxicity, particularly on bone marrow-derived cells. Its strong cholinesterase inhibition potency seems to be correlated to its low protective efficacy in mice exposed to paraoxon. Ventilatory monitoring of KM297-treated mice by double-chamber plethysmography shows toxic effects at the selected therapeutic dose. This breathing assessment could help define the No Observed Adverse Effect Level (NOAEL) dose of new oximes which would have a maximum therapeutic effect without any toxic side effects.
ESTHER : Calas_2020_Biomolecules_10_
PubMedSearch : Calas_2020_Biomolecules_10_
PubMedID: 32512884

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 : Potent 3-Hydroxy-2-Pyridine Aldoxime Reactivators of Organophosphate-Inhibited Cholinesterases with Predicted Blood-Brain Barrier Penetration - Zorbaz_2018_Chemistry_24_9675
Author(s) : Zorbaz T , Braiki A , Marakovic N , Renou J , De la Mora E , Macek Hrvat N , Katalinic M , Silman I , Sussman JL , Mercey G , Gomez C , Mougeot R , Perez B , Baati R , Nachon F , Weik M , Jean L , Kovarik Z , Renard PY
Ref : Chemistry , 24 :9675 , 2018
Abstract : A new series of 3-hydroxy-2-pyridine aldoxime compounds have been designed, synthesised and tested in vitro, in silico, and ex vivo as reactivators of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibited by organophosphates (OPs), for example, VX, sarin, cyclosarin, tabun, and paraoxon. The reactivation rates of three oximes (16-18) were determined to be greater than that of 2-PAM and comparable to that of HI-6, two pyridinium aldoximes currently used by the armies of several countries. The interactions important for a productive orientation of the oxime group within the OP-inhibited enzyme have been clarified by molecular-modelling studies, and by the resolution of the crystal structure of the complex of oxime 17 with Torpedo californica AChE. Blood-brain barrier penetration was predicted for oximes 15-18 based on their physicochemical properties and an in vitro brain membrane permeation assay. Among the evaluated compounds, two morpholine-3-hydroxypyridine aldoxime conjugates proved to be promising reactivators of OP-inhibited cholinesterases. Moreover, efficient ex vivo reactivation of phosphylated native cholinesterases by selected oximes enabled significant hydrolysis of VX, sarin, paraoxon, and cyclosarin in whole human blood, which indicates that the oximes have scavenging potential.
ESTHER : Zorbaz_2018_Chemistry_24_9675
PubMedSearch : Zorbaz_2018_Chemistry_24_9675
PubMedID: 29672968
Gene_locus related to this paper: torca-ACHE

Title : Tryptoline-3-hydroxypyridinaldoxime conjugates as efficient reactivators of phosphylated human acetyl and butyrylcholinesterases - Renou_2014_Chem.Commun.(Camb)_50_3947
Author(s) : Renou J , Loiodice M , Arboleas M , Baati R , Jean L , Nachon F , Renard PY
Ref : Chem Commun (Camb) , 50 :3947 , 2014
Abstract : Two promising uncharged reactivators for inhibited human BChE and AChE have been described. These compounds show an ability to reactivate VX-inhibited BChE largely superior to those of known pyridinium aldoximes. Moreover, these oximes also exhibit a good ability to reactivate VX-, tabun- and paraoxon-inhibited human AChE.
ESTHER : Renou_2014_Chem.Commun.(Camb)_50_3947
PubMedSearch : Renou_2014_Chem.Commun.(Camb)_50_3947
PubMedID: 24599312

Title : Design, synthesis and biological evaluation of novel tetrahydroacridine pyridine- aldoxime and -amidoxime hybrids as efficient uncharged reactivators of nerve agent-inhibited human acetylcholinesterase - Kliachyna_2014_Eur.J.Med.Chem_78C_455
Author(s) : Kliachyna M , Santoni G , Nussbaum V , Renou J , Sanson B , Colletier JP , Arboleas M , Loiodice M , Weik M , Jean L , Renard PY , Nachon F , Baati R
Ref : Eur Journal of Medicinal Chemistry , 78C :455 , 2014
Abstract : A series of new uncharged functional acetylcholinesterase (AChE) reactivators including heterodimers of tetrahydroacridine with 3-hydroxy-2-pyridine aldoximes and amidoximes has been synthesized. These novel molecules display in vitro reactivation potencies towards VX-, tabun- and paraoxon-inhibited human AChE that are superior to those of the mono- and bis-pyridinium aldoximes currently used against nerve agent and pesticide poisoning. Furthermore, these uncharged compounds exhibit a broader reactivity spectrum compared to currently approved remediation drugs.
ESTHER : Kliachyna_2014_Eur.J.Med.Chem_78C_455
PubMedSearch : Kliachyna_2014_Eur.J.Med.Chem_78C_455
PubMedID: 24704618

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

Title : Syntheses and in vitro evaluations of uncharged reactivators for human acetylcholinesterase inhibited by organophosphorus nerve agents - Renou_2013_Chem.Biol.Interact_203_81
Author(s) : Renou J , Mercey G , Verdelet T , Paunescu E , Gillon E , Arboleas M , Loiodice M , Kliachyna M , Baati R , Nachon F , Jean L , Renard PY
Ref : Chemico-Biological Interactions , 203 :81 , 2013
Abstract : Organophosphorus nerve agents (OPNAs) are highly toxic compounds that represent a threat to both military and civilian populations. They cause an irreversible inhibition of acetylcholinesterase (AChE), by the formation of a covalent P-O bond with the catalytic serine. Among the present treatment of nerve agents poisoning, pyridinium and bis-pyridinium aldoximes are used to reactivate this inhibited enzyme but these compounds do not readily cross the blood brain barrier (BBB) due to their permanent cationic charge and thus cannot efficiently reactivate cholinesterases in the central nervous system (CNS). In this study, a series of seven new uncharged oximes reactivators have been synthesized and their in vitro ability to reactivate VX and tabun-inhibited human acetylcholinesterase (hAChE) has been evaluated. The dissociation constant K(D) of inhibited enzyme-oxime complex, the reactivity rate constant kr and the second order reactivation rate constant k(r2) have been determined and have been compared to reference oximes HI-6, Obidoxime and 2-Pralidoxime (2-PAM). Regarding the reactivation of VX-inhibited hAChE, all compounds show a better reactivation potency than those of 2-PAM, nevertheless they are less efficient than obidoxime and HI-6. Moreover, one of seven described compounds presents an ability to reactivate tabun-inhibited hAChE equivalent to those of 2-PAM.
ESTHER : Renou_2013_Chem.Biol.Interact_203_81
PubMedSearch : Renou_2013_Chem.Biol.Interact_203_81
PubMedID: 23111374

Title : Phenyltetrahydroisoquinoline-pyridinaldoxime conjugates as efficient uncharged reactivators for the dephosphylation of inhibited human acetylcholinesterase - Mercey_2012_J.Med.Chem_55_10791
Author(s) : Mercey G , Renou J , Verdelet T , Kliachyna M , Baati R , Gillon E , Arboleas M , Loiodice M , Nachon F , Jean L , Renard PY
Ref : Journal of Medicinal Chemistry , 55 :10791 , 2012
Abstract : Pyridinium and bis-pyridinium aldoximes are used as antidotes to reactivate acetylcholinesterase (AChE) inhibited by organophosphorus nerve agents. Herein, we described a series of nine nonquaternary phenyltetrahydroisoquinoline-pyridinaldoxime conjugates more efficient than or as efficient as pyridinium oximes to reactivate VX-, tabun- and ethyl paraoxon-inhibited human AChE. This study explores the structure-activity relationships of this new family of reactivators and shows that 1b-d are uncharged hAChE reactivators with a broad spectrum.
ESTHER : Mercey_2012_J.Med.Chem_55_10791
PubMedSearch : Mercey_2012_J.Med.Chem_55_10791
PubMedID: 23148598

Title : Reactivators of acetylcholinesterase inhibited by organophosphorus nerve agents - Mercey_2012_Acc.Chem.Res_45_756
Author(s) : Mercey G , Verdelet T , Renou J , Kliachyna M , Baati R , Nachon F , Jean L , Renard PY
Ref : Acc Chem Res , 45 :756 , 2012
Abstract : Since the September 11, 2001, terrorist attacks in the United States, the specter of a chemical threat against civilian populations has renewed research interest in chemical warfare agents, their mechanisms of action, and treatments that reverse their effects. In this Account, we focus specifically on organophosphorus nerve agents (OPNAs). Although some OPNAs are used as pest control, the most toxic chemicals in this class are used as chemical warfare agents in armed conflicts. The acute toxicity of OPNAs results from the irreversible inhibition of acetylcholinesterase (AChE, EC via the formation of a covalent P-O bond at the serine hydroxyl group in the enzyme active site. AChE breaks down the neurotransmitter acetylcholine at neuronal synapses and neuromuscular junctions. The irreversible inhibition of AChE causes the neurotransmitter to accumulate in the synaptic cleft, leading to overstimulation of cholinergic receptors, seizures, respiratory arrest, and death. The current treatment for OPNA poisoning combines an antimuscarinic drug (e.g., atropine), an anticonvulsant drug (e.g., diazepam), and an AChE reactivator of the pyridinium aldoxime family (pralidoxime, trimedoxime, obidoxime, HI-6, HLo-7). Because of their high nucleophilicity, oximes can displace the phosphyl group from the catalytic serine, thus restoring the enzyme's catalytic activity. During 50 years of research in the reactivator field, researchers have synthesized and tested numerous structural modifications of monopyridinium oximes and bispyridinium oximes. In the past decade, medicinal chemists have focused their research on the more efficient bispyridinium reactivators, but all known reactivators have several drawbacks. First, due to their permanent positive charge, they do not cross the blood-brain barrier (BBB) efficiently and do not readily reactivate AChE in the central nervous system. Second, no single oxime is efficient against a wide variety of OPNAs. Third, oximes cannot reactivate "aged" AChE. This Account summarizes recent strategies for the development of AChE reactivators capable of crossing the BBB. The use of nanoparticulate transport and inhibition of P-glycoprotein efflux pumps improves BBB transport of these AChE reactivators. Chemical modifications that increased the lipophilicity of the pyridinium aldoximes, the addition of a fluorine atom and the replacement of a pyridyl ring with a dihydropyridyl moiety, enhances BBB permeability. The glycosylation of pyridine aldoximes facilitates increased BBB penetration via the GLUT-1 transport system. The development of novel uncharged reactivators that can move efficiently across the BBB represents one of the most promising of these new strategies.
ESTHER : Mercey_2012_Acc.Chem.Res_45_756
PubMedSearch : Mercey_2012_Acc.Chem.Res_45_756
PubMedID: 22360473

Title : First efficient uncharged reactivators for the dephosphylation of poisoned human acetylcholinesterase - Mercey_2011_Chem.Commun.(Camb)_47_5295
Author(s) : Mercey G , Verdelet T , Saint-Andre G , Gillon E , Wagner A , Baati R , Jean L , Nachon F , Renard PY
Ref : Chem Commun (Camb) , 47 :5295 , 2011
Abstract : Nerve agents are highly toxic organophosphorus compounds with strong inhibition potency against acetylcholinesterase (AChE). Herein, we describe two first extremely promising uncharged reactivators for poisoned human AChE with a superior or similar in vitro ability to reactivate the enzyme as compared to that of HI-6, obidoxime, TMB-4 and HLo-7.
ESTHER : Mercey_2011_Chem.Commun.(Camb)_47_5295
PubMedSearch : Mercey_2011_Chem.Commun.(Camb)_47_5295
PubMedID: 21451868

Title : A HTS assay for the detection of organophosphorus nerve agent scavengers - Louise-Leriche_2010_Chemistry_16_3510
Author(s) : Louise-Leriche L , Paunescu E , Saint-Andre G , Baati R , Romieu A , Wagner A , Renard PY
Ref : Chemistry , 16 :3510 , 2010
Abstract : A new pro-fluorescent probe aimed at a HTS assay of scavengers is able to selectively and efficiently cleave the P-S bond of organophosphorus nerve agents and by this provides non-toxic phosphonic acid has been designed and synthesised. The previously described pro-fluorescent probes were based on a conventional activated P-Oaryl bond cleavage, whereas our approach uses a self-immolative linker strategy that allows the detection of phosphonothioase activity with respect to a non-activated P-Salkyl bond. Further, we have also developed and optimised a high-throughput screening assay for the selection of decontaminants (chemical or biochemical scavengers) that could efficiently hydrolyse highly toxic V-type nerve agents. A preliminary screening, realised on a small alpha-nucleophile library, allowed us to identify some preliminary "hits", among which pyridinealdoximes, alpha-oxo oximes, hydroxamic acids and, less active but more original, amidoximes were the most promising. Their selective phosphonothioase activity has been further confirmed by using PhX as the substrate, and thus they offer new perspectives for the synthesis of more potent V nerve agent scavengers.
ESTHER : Louise-Leriche_2010_Chemistry_16_3510
PubMedSearch : Louise-Leriche_2010_Chemistry_16_3510
PubMedID: 20143367