In vitro reactivation kinetics of paraoxon- and DFP-inhibited electric eel AChE using mono- and bis-pyridinium oximes.
Oxime-assisted reactivation of organophosphate (OP)-inhibited acetylcholinesterase (AChE) is a crucial step in the post-inhibitory treatment of OP intoxication. The limited efficacy of oxime reactivators for all OP nerve agents and pesticides led to the development of various novel oximes and their thorough kinetic investigations. Hence, in the present investigation, we have tested 10 structurally different pyridinium oxime-based reactivators for their in vitro potency to reactivate paraoxon- and DFP-inhibited electric eel AChE. From structure activity relationship point of view, various oximes such as mono-quaternary (2-PAM, K100, K024) and bis-quaternary symmetric (obidoxime, TMB-4) and asymmetric (K027, K048, K203, K618, K628) oximes bearing different connecting linkers (oxybismethylene, trimethylene, propane, butane, butene, and xylene) have been studied. The observed kinetic data demonstrate that not only the position of oxime group is decisive for the increased reactivation ability of oximes, but the role of connecting linker is also significant. Oximes with aliphatic linkers are superior reactivators than the oximes with unsaturated and aromatic linkers. The optimal chain length for plausible reactivation ability for paraoxon- and DFP-inhibited AChE is 3 or 4 carbon-carbon connecting linker between prydinium rings.
School of Studies in Chemistry, Pt. Ravishankar Shukla University, Raipur, 492010, CG, India.
Bhanushree
B
Gupta
Rahul
R
Sharma
Namrata
N
Singh
Kamil
K
Kuca
J R
JR
Acharya
Kallol K
KK
Ghosh
D000110:Acetylcholinesterase / Q000378:metabolism; D000475:Alkenes / Q000737:chemistry; D000818:Animals; D002073:Butanes / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004593:Electrophorus; D007531:Isoflurophate / Q000633:toxicity*; D007700:Kinetics; D009768:Obidoxime Chloride / Q000737:chemistry / Q000494:pharmacology; D010261:Paraoxon / Q000633:toxicity*; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014289:Trimedoxime / Q000737:chemistry / Q000494:pharmacology
D000475:Alkenes; D002073:Butanes; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D011726:Pyridinium Compounds; D007531:Isoflurophate; C558934:butylene; D009768:Obidoxime Chloride; D014289:Trimedoxime; C046888:butane; D000110:Acetylcholinesterase; D010261:Paraoxon