Interactions between xylene-linked carbamoyl bis-pyridinium mono-oximes and organophosphates inhibited-AChE: a kinetic study.

Reactivation of organophosphate (OP) inhibited acetylcholinesterase (AChE) by oximes is inadequate against various OP nerve agents known till date owing to their diverse structural features. As a consequence, in the past decades widespread research programs have been undertaken independently throughout the world to develop and identify more effective oxime reactivators. The efficacy of oxime reactivators is estimated through different in vitro and in vivo models using AChE from various sources against structurally different OPs. In the present study, reactivation kinetics of OP (paraoxon, DFP, sarin and VX) inhibited AChE by xylene linked carbamoyl bis-pyridinum mono-oximes have been described. It was found that the reactivation potency of tested oximes varied with the inhibitors used as 5l (4-carbamoyl-2' hydroxyiminomethyl-1-1'-(1,3-phenylenedimethyl)-bis-pyridinium dibromide) was found to be the most effective reactivator against paraoxon. In case of DFP, 5k (3-carbamoyl-2' hydroxyiminomethyl-1-1'-(1,3-phenylenedimethyl)-bis-pyridinium dibromide) showed best reactivation while in case of sarin 5e (3-carbamoyl-2' hydroxyiminomethyl-1-1'-(1,4-phenylenedimethyl)-bis-pyridinium dibromide) exhibited outstanding reactivation ability in comparison to standard oximes (2-PAM, obidoxime and TMB-4) as indicated by its highest value of second order reactivation rate constant (k(r2)) 3.26 mM⁻¹ min⁻¹. The enhanced reactivation efficacy of oximes may be attributed to the optimal length of xylene linker which facilitates appropriate positioning of carbamoyl function to the peripheral anionic site (PAS) and extending the oxime moiety to the active site of AChE.