Novel oximes as blood–brain barrier penetrating cholinesterase reactivators

Abstract

The US Army utilizes pralidoxime (2-PAM) for the reactivation of OP-inhibited AChE. While 2-PAM effectively reactivates acetylcholinesterase (AChE) in the body, it does not cross the blood–brain barrier (BBB) at therapeutically relevant levels. To address this problem of central nervous system AChE reactivation, novel sugar–oxime conjugates were utilized. These ‘sugar–oximes’ would potentially be transported across the BBB because they contain a sugar moiety which would be recognized by the facilitative glucose transporters. Eight previously reported, but understudied sugar–oximes, as well as six novel sugar–oximes were synthesized, and their ability to reactivate both human red blood cell AChE and plasma butyrylcholinesterase poisoned with DFP, paraoxon, sarin and VX were tested. The results show that the novel sugar–oxime 13c was more active than the other compounds with a reactivation potential similar to 2-PAM. The sugar–oxime 8b had low toxicity with a LD 50 of 1590 mg/kg from a single IM dose in the guinea pig and >2000 mg/kg IP in the mouse. Histopathological analysis showed that there were no apparent differences in hippocampus, heart, liver, kidney sciatic nerve, or skeletal muscle between treated and untreated animals. These results show that sugar–oximes can be effective reactivators and suggest that high treatment doses may be possible.