In vitro reactivation of sarin-inhibited human acetylcholinesterase (AChE) by bis-pyridinium oximes connected by xylene linkers.
A series of bis-pyridinium oximes connected by xylene linkers were synthesized and their in vitro reactivation potential was evaluated against human acetylcholinesterase (hAChE) inhibited by nerve agent sarin and the data were compared with 2-PAM and obidoxime. Among the synthesized compounds, N,N'-p-xylene-bis-[(2,2'-hydroxyiminomethyl)pyridinium] dibromide (3c) was found to be the most potent reactivator for hAChE inhibited by sarin. The oxime 3c exhibited 45% regeneration of inhibited hAChE, in comparison to 34% and 24% regeneration by 2-PAM and obidoxime, respectively, at a concentration of 10(-3) M within 10 min. The higher reactivation efficacies of these oximes were attributed to their acid dissociation constants (pKa). The pKa values of all the oximes were determined spectrophotometrically and correlated with their observed reactivation potential. This method involving the in vitro reactivation of inhibited hAChE may be useful for the screening of new oximes as reactivators.
Acharya
Jyotiranjan
J
Process Technology Development Division, Defence Research and Development Establishment, Gwalior, India. jracharya@rediffmail.com
Dubey
Devendra Kumar
DK
Srivastava
Ashish Kumar
AK
Raza
Syed Kalbey
SK
D000110:Acetylcholinesterase / Q000378:metabolism; D000328:Adult; D000465:Algorithms; D002619:Chemical Warfare Agents / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000737:chemistry / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000737:chemistry; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004910:Erythrocyte Membrane / Q000201:enzymology; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008297:Male; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology*; D012524:Sarin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D014992:Xylenes / Q000737:chemistry / Q000494:pharmacology
D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D003432:Cross-Linking Reagents; D058851:GPI-Linked Proteins; C558050:N,N'-p-xylene-bis-((2,2'-hydroxyiminomethyl)pyridinium) dibromide; D010091:Oximes; D011726:Pyridinium Compounds; D014992:Xylenes; D012524:Sarin; C548244:ACHE protein, human; D000110:Acetylcholinesterase