Nonquaternary cholinesterase reactivators. 3. 3(5)-Substituted 1,2,4-oxadiazol-5(3)-aldoximes and 1,2,4-oxadiazole-5(3)-thiocarbohydroximates as reactivators of organophosphonate-inhibited eel and human acetylcholinesterase in vitro

Abstract

As an extension of an earlier investigation (J. Med. Chem. 1984, 27, 1431), we prepared a series of 3-substituted 5-[(hydroxyimino)methyl]-1,2,4-oxadiazoles and the corresponding 5-thiocarbohydroximic acid 2-(N,N-dialkylamino)ethyl S-esters. The compounds were evaluated in vitro as reactivators of phosphonylated electric eel and human erythrocyte (RBC) acetylcholinesterases (AChE). The compounds were characterized with respect to (hydroxyimino)methyl acid dissociation constant, nucleophilicity, octanol/buffer partition coefficient, reversible AChE inhibition, and kinetics of reactivating ethyl methylphosphonylated AChE. One compound was also tested for effectiveness in preventing AChE phosphonylation. All of the tested compounds significantly reactivate ethyl methylphosphonylated AChE: the 3-n-octyl- and 3-(1-naphthyl)-substituted aldoximes are as reactive (within a factor of 5-10) toward the inhibited enzymes as the benchmark pyridinium reactivators, 2-PAM and HI-6. All of the substituted thiocarbohydroximic acid S-esters are powerful reversible inhibitors of AChE's: the 3-n-octyl- and 3-(1-naphthyl)-substituted thiocarbohydroximates inhibit eel AChE to 50% initial activity at concentrations less than 5 microM. When added to an eel AChE solution at concentrations between 5 and 50 microM, the 3-phenyl-substituted thiocarbohydroximate effectively antagonizes AChE inhibition by ethyl p-nitrophenyl methylphosphonate (EPMP), suggesting the potential utility of this compound for preventing anti-AChE-agent poisoning.

Positron emission tomography evaluation of oxime countermeasures in live rats using the tracer O‐(2‐[18F]fluoroethyl)‐O‐(p‐nitrophenyl)methylphosphonate [18F]‐VXS

“…2), are widely used despite poor penetration into the brain, whereas a neutral oxime like monoisonitrosoacetone (MINA) and ionizable oxime like RS194b (Fig. 2) can penetrate the CNS more easily 27–29 but may not form a strong ionic attraction to AChE.…”

Organophosphate Exposure

“…6.6A). Although there are a few noncharged oximes developed that can cross the BBB, they have not been developed further because of their poor in vivo efficacy [80,81]. 4.1.2 2-Pyridine aldoxime methyl chloride, HI-6 (oximes) 2-PAM (2-pyridine aldoxime methyl chloride or pralidoxime) is a quaternary charged oxime that can bind to inactivated ChE and reactivate its functional activity (Fig.…”

Oximes of five-membered heterocyclic compounds with three and four heteroatoms 2. Synthesis of derivatives, reactions, and biological activity (Review)

“…Triazole [231], oxadiazole [232], and thiadiazole [233] oximes have been investigated as antidotes for poisoning by organophosphorus compounds.…”