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.