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 (pK(a)). The pK(a) 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.
Acharya
Jyotiranjan
J
Process Technology Development Division, Defence Research and Development Establishment, Gwalior, India. jracharya@rediffmail.com
Dubey
Devendra Kumar
DK
Raza
Syed Kalbey
SK
D000328:Adult; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D004910:Erythrocyte Membrane / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009768:Obidoxime Chloride / Q000494:pharmacology*; D011220:Pralidoxime Compounds / Q000494:pharmacology*; D012524:Sarin / Q000633:toxicity*
D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D011220:Pralidoxime Compounds; D009768:Obidoxime Chloride; D012524:Sarin; C028797:pralidoxime