Reactivation of VX-inhibited AChE by novel oximes having two oxygen atoms in the linker.

Two newly developed AChE reactivators possessing two oxime groups in 4-position of the pyridinium rings with linkers CH(2)O(CH(2))(2)OCH(2) and CH(2)O(CH(2))(4)OCH(2) were tested for their potency to reactivate VX-inhibited AChE. Their reactivation potency was compared with currently available oximes such as pralidoxime, obidoxime and HI-6. Appropriate constants (affinity towards the intact and inhibited enzyme, reactivation rate) characterizing the reactivation process were determined.

Reactivation of DFP- and paraoxon-inhibited acetylcholinesterases by pyridinium oximes.

Exposure to the organophosphorus nerve agents such as sarin, soman, cyclosarin, and VX causes acute intoxication by inhibiting acetylcholinesterase (AChE), where the serine residue of the active site can attack the phosphorous atom of the organophosphorus agents to form a strong P-O bond. The purpose of the present study was to evaluate new oxime antidotes to reactivate the inhibited AChE. We have designed and synthesized several new oximes, and have evaluated the substances that differ from the currently used oximes in linker between the two pyridinium rings.

New oxime reactivators connected with CH2O(CH2)nOCH2 linker and their reactivation potency for organophosphorus agents-inhibited acetylcholinesterase.

New bis-pyridinium oxime reactivators 6 with CH(2)O(CH(2))(2)OCH(2) and CH(2)O(CH(2))(4)OCH(2) linkers between the two pyridinium rings were designed and synthesized. In the in vitro test of their potency to reactivate AChE inhibited by organophosphorus agents at 5 x 10(-3)M concentration, the reactivation ability of 1,2-dimethoxy-ethylene-bis-N,N'-4-pyridiumaldoxime dichloride (6a) was 63% for housefly (HF) AChE inhibited by diisopropyl fluorophosphates (DFP), 51% for bovine red blood cell (RBC) AChE inhibited by DFP, 67% for HF-AChE inhibited by paraoxon, and 81% for RBC-AChE inhibited by paraoxon. Except in the case of DFP-inhibited HF AChE test of 2-PAM, the activities of 6a are much higher than the activities of 2-PAM and HI-6 which are AChE reactivators currently in use.

Bis-pyridiumaldoxime reactivators connected with CH2O(CH2)n OCH2 linkers between pyridinium rings and their reactivity against VX.

New bis-pyridinium oxime reactivators connected with CH2O(CH2)n OCH2 linkers between two pyridinium rings were designed and synthesized, and their reactivation potency was evaluated for AChE inhibited by organophosphorus VX agent. Among the prepared compounds, 1,2-dimethoxy-ethylene-bis-N,N'-4-pyridiumaldoxime dichloride 5a was the most potent and appeared to be the most promising compound as a potential reactivator for AChE inhibited by organophosphorus VX agent.