In vitro evaluation of bis-pyridinium oximes bearing methoxy alkane linker as reactivators of sarin inhibited human acetylcholinesterase

A series of bis-pyridinium oximes connected by methoxy alkane linkers were synthesized and their in vitro reactivation efficacy was evaluated against sarin-inhibited human AChE, and data were compared with 2-PAM and obidoxime. Among the synthesized compounds, 1,2-dimethoxy ethylene bis-[4,4′-(hydroxyiminomethyl) pyridinium] dichloride (4P-2) and 1,2-dimethoxy ethylene bis-[3,3′-(hydroxyiminomethyl) pyridinium] dichloride (3P-2) were found to be the most potent reactivators of human AChE inhibited by nerve agent sarin. The oximes 4P-2 and 3P-2 exhibited 41% and 36% regeneration of sarin-inhibited AChE, respectively, whereas 2-PAM showed 32% regeneration. The higher reactivation efficacy of the oximes was attributed to their acid dissociation constants (pKa). The pKa values of all the oximes were determined by UV–vis spectrophotometric method and correlated with their observed reactivation potential. Overall, the study reveals that the oxime 4P-2 may have therapeutic potential in the reactivation of human AChE inhibited by sarin.