Imidazole aldoximes effective in assisting butyrylcholinesterase catalysis of organophosphate detoxification

Rakesh K. Sit, Valery V. Fokin, Gabriel Amitai, K. Barry Sharpless, Palmer Taylor, Zoran Radić

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Intoxication by organophosphate (OP) nerve agents and pesticides should be addressed by efficient, quickly deployable countermeasures such as antidotes reactivating acetylcholinesterase or scavenging the parent OP. We present here synthesis and initial in vitro characterization of 14 imidazole aldoximes and their structural refinement into three efficient reactivators of human butyrylcholinesterase (hBChE) inhibited covalently by nerve agent OPs, sarin, cyclosarin, VX, and the OP pesticide metabolite, paraoxon. Rapid reactivation of OP-hBChE conjugates by uncharged and nonprotonated tertiary imidazole aldoximes allows the design of a new OP countermeasure by conversion of hBChE from a stoichiometric to catalytic OP bioscavenger with the prospect of oral bioavailability and central nervous system penetration. The enhanced in vitro reactivation efficacy determined for tertiary imidazole aldoximes compared to that of their quaternary N-methyl imidazolium analogues is attributed to ion pairing of the cationic imidazolium with Asp 70, altering a reactive alignment of the aldoxime with the phosphorus in the OP-hBChE conjugate.

Original languageEnglish
Pages (from-to)1378-1389
Number of pages12
JournalJournal of Medicinal Chemistry
Volume57
Issue number4
DOIs
Publication statusPublished - 27 Feb 2014
Externally publishedYes

Fingerprint

Butyrylcholinesterase
Oximes
Organophosphates
Catalysis
Pesticides
Sarin
Paraoxon
Antidotes
Acetylcholinesterase
imidazole
Phosphorus
Biological Availability
Central Nervous System
Ions

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Imidazole aldoximes effective in assisting butyrylcholinesterase catalysis of organophosphate detoxification. / Sit, Rakesh K.; Fokin, Valery V.; Amitai, Gabriel; Sharpless, K. Barry; Taylor, Palmer; Radić, Zoran.

In: Journal of Medicinal Chemistry, Vol. 57, No. 4, 27.02.2014, p. 1378-1389.

Research output: Contribution to journalArticle

Sit, Rakesh K. ; Fokin, Valery V. ; Amitai, Gabriel ; Sharpless, K. Barry ; Taylor, Palmer ; Radić, Zoran. / Imidazole aldoximes effective in assisting butyrylcholinesterase catalysis of organophosphate detoxification. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 4. pp. 1378-1389.
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