Monooxime reactivators of acetylcholinesterase with (E)-but-2-ene linker – Preparation and reactivation of tabun and paraoxon-inhibited

K Musilek, O Holas, D Jun, Francis James Gunn-Moore, V Dohnal, V Opletalova, M Dolezala, K Kuca

Research output: Contribution to journalArticlepeer-review

55 Citations (Scopus)

Abstract

Acetylcholinesterase reactivators are crucial antidotes for the treatment of organophosphate intoxication. Fifteen new monooxime reactivators of acetyleholinesterase with a (E)-but-2-ene linker were developed in an effort to extend the properties of K-oxime (E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide (K203). The known reactivators (pralidoxime, HI-6, obidoxime, K075, K203) and the new compounds were tested in vitro on a model of tabun- and paraoxon-inhibited AChE. Monooxime reactivators were not able to exceed the best known compounds for tabun poisoning, but some of them did show reactivation comparable with known compounds for paraoxon poisoning. However, extensive differences were found by a SAR study for various substitutions on the non-oxime part of the reactivator molecule. (C) 2007 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)6733-6741
Number of pages9
JournalBioorganic & Medicinal Chemistry
Volume15
DOIs
Publication statusPublished - 1 Nov 2007

Keywords

  • acetylcholinesterase
  • reactivation
  • nerve agent
  • tabun pesticide
  • paraoxon
  • reactivator
  • oxime
  • BISPYRIDINIUM COMPOUNDS BEARING
  • PYRIDINIUM OXIMES
  • CHOLINESTERASE REACTIVATORS
  • CRYSTAL-STRUCTURES
  • SERIES
  • POTENCY
  • AGENT

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