Structure-Based Optimization of Nonquaternary Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Nerve Agents

Santoni, Gianluca; Sousa, Julien de; Mora, E. De la; Dias, José; Jean, Ludovic; Sussman, Joel L.; Silman, Israel; Renard, Pierre; Brown, Richard C. D.; Weik, Martin H.; Baati, Rachid; Nachon, Florian

doi:10.1021/acs.jmedchem.8b00592

Cited by 48 publications

(39 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In fact, much effort has been made at finding ways to restoret he activity of AChE. [150,153,154] The proposed mechanism of enzyme inhibition and enzyme reactivation is summarized in Scheme 9.…”

Section: Phosphorus-containing Drugs As Transitionstate Inhibitorsmentioning

confidence: 99%

The Role of the Phosphorus Atom in Drug Design

2019

View full text Add to dashboard Cite

Although the phosphorus atom is found in a variety of oxidation states, most of the phosphorus‐containing molecules of pharmacological importance possess phosphorus in the form of phosphonate or phosphinate functional groups, or in a major oxidation state as a phosphate group. The most common occurrence of phosphorus in drugs is either in prodrugs or in compounds for which the phosphorus atom plays a role in the biological activity, such as in modified nucleotides, in metabolically stable analogues of metabolites bearing phosphate groups, and as bioisosteric analogues of carboxyl groups.

show abstract

Section: Phosphorus-containing Drugs As Transitionstate Inhibitorsmentioning

confidence: 99%

The Role of the Phosphorus Atom in Drug Design

2019

View full text Add to dashboard Cite

show abstract

“…Chemical structure of selected novel oxime and non-oxime reactivators according to de Koning et al (2011a, b, 2018), Mercey et al (2011), Radic et al (2012), Kalisiak et al (2011),Katz et al (2015),Santoni et al (2018) …”

mentioning

confidence: 99%

Organophosphorus compounds and oximes: a critical review

Worek¹,

2020

View full text Add to dashboard Cite

Organophosphorus (OP) pesticides and nerve agents still pose a threat to the population. Treatment of OP poisoning is an ongoing challenge and burden for medical services. Standard drug treatment consists of atropine and an oxime as reactivator of OP-inhibited acetylcholinesterase and is virtually unchanged since more than six decades. Established oximes, i.e. pralidoxime, obidoxime, TMB-4, HI-6 and MMB-4, are of insufficient effectiveness in some poisonings and often cover only a limited spectrum of the different nerve agents and pesticides. Moreover, the value of oximes in human OP pesticide poisoning is still disputed. Long-lasting research efforts resulted in the preparation of countless experimental oximes, and more recently non-oxime reactivators, intended to replace or supplement the established and licensed oximes. The progress of this development is slow and none of the novel compounds appears to be suitable for transfer into advanced development or into clinical use. This situation calls for a critical analysis of the value of oximes as mainstay of treatment as well as the potential and limitations of established and novel reactivators. Requirements for a straightforward identification of superior reactivators and their development to licensed drugs need to be addressed as well as options for interim solutions as a chance to improve the therapy of OP poisoning in a foreseeable time frame.

show abstract

“…KM297 is an uncharged reactivator of OP-inhibited AChE based on tetrahydroacridine pyridine-aldoxime hybrids [9,33]. Its tacrine scaffold has been recently identified as relevant against an OP pesticide poisoning [34].…”

Section: Discussionmentioning

confidence: 99%

Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime

Calas¹,

Hanak²,

Jaffré³

et al. 2020

Biomolecules

Self Cite

View full text Add to dashboard Cite

(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.

show abstract

Structure-Based Optimization of Nonquaternary Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Nerve Agents

Cited by 48 publications

References 41 publications

The Role of the Phosphorus Atom in Drug Design

The Role of the Phosphorus Atom in Drug Design

Organophosphorus compounds and oximes: a critical review

Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime

Contact Info

Product

Resources

About