Organophosphorus compounds and oximes: a critical review

Abstract

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.

Understanding the Interaction Modes and Reactivity of Trimedoxime toward MmAChE Inhibited by Nerve Agents: Theoretical and Experimental Aspects

“…Among the major symptoms of the intoxication, we can cite excessive salivation, lacrimation, urination, sweating, broncho-constriction and neuromuscular block, leading to death in severe cases of poisoning [10][11][12]. The current treatment protocol for OP poisoning consists mainly of the employment of a reactivating agent, commonly an oxime compound [13][14][15][16], which is capable of restoring the AChE catalytic activity through a nucleophilic attack, thus remediating the intoxication effects and reestablishing the ACh levels [17][18][19]. The general reactivation mechanism through oximes is represented in Figure 1.…”

“…The current treatment protocol for OP poisoning consists mainly of the employment of a reactivating agent, commonly an oxime compound [13][14][15][16], which is capable of restoring the AChE catalytic activity through a nucleophilic attack, thus remediating the intoxication effects and reestablishing the ACh levels [17][18][19]. The general reactivation mechanism through oximes is represented in Figure 1.…”

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

“…[4] OPNAs are extremelyt oxic because they phosphorylate the catalytic serine residue of acetylcholinesterase (AChE), an enzymee ssential to humans and other species for neurotransmission. [5] They act as potent irreversible inhibitors of AChE and, consequently,l ead to cholinergic syndrome and, ultimately,t od eath. [5] Several reports and clinicals tudies mention that the current antidote treatmentb ased on pyridiniumaldoximes are not efficient enough.…”

“…[5] They act as potent irreversible inhibitors of AChE and, consequently,l ead to cholinergic syndrome and, ultimately,t od eath. [5] Several reports and clinicals tudies mention that the current antidote treatmentb ased on pyridiniumaldoximes are not efficient enough. [5] Apart from this limitation,t hey have al ow tendency to cross the blood-brain barrier (BBB) due to their permanent positive chargea nd exhibit limitedb ioavailability in the central nervous system (CNS).…”

Understand the interaction modes and reactivity of trimedoxime toward MmAChE inhibited by nerve agents: theoretical and experimental Aspects

“…The current treatment protocol for OP poisoning consists mainly of the employment of a reactivating agent, commonly an oxime compound [13][14][15][16], which is capable of restoring the AChE catalytic activity through a nucleophilic attack, thus remediating the intoxication effects and reestablishing the ACh levels [17][18][19]. The general reactivation mechanism through oximes is represented in gure 1.…”