Monooxime-monocarbamoyl Bispyridinium Xylene-Linked Reactivators of Acetylcholinesterase-Synthesis, In vitro and Toxicity Evaluation, and Docking Studies

ChemMedChem. 2010 Feb 1;5(2):247-54. doi: 10.1002/cmdc.200900455.

Abstract

Acetylcholinesterase (AChE) reactivators are crucial antidotes to organophosphate intoxication. A new series of 26 monooxime-monocarbamoyl xylene-linked bispyridinium compounds was prepared and tested in vitro, along with known reactivators (pralidoxime, HI-6, obidoxime, trimedoxime, methoxime, K107, K108 and K203), on a model of tabun- and paraoxon-, methylparaoxon- and DFP-inhibited human erythrocyte AChE. Although their ability to reactivate tabun-inhibited AChE did not exceed that of the previously known compounds, some newly prepared compounds showed promising reactivation of pesticide-inhibited AChE. The acute toxicity of the novel compounds was also determined. Docking studies using tabun-inhibited AChE were performed for three compounds of interest. The structure-activity relationship (SAR) study confirmed the apparent influence of the xylene linkage and carbamoyl moiety on the reactivation ability and toxicity of the agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Animals
  • Binding Sites
  • Carbamates / chemistry*
  • Cholinesterase Reactivators / chemical synthesis*
  • Cholinesterase Reactivators / toxicity
  • Computer Simulation
  • Drug Design
  • Erythrocytes / enzymology
  • Humans
  • Mice
  • Oximes / chemistry*
  • Pyridinium Compounds / chemistry*
  • Structure-Activity Relationship
  • Xylenes / chemistry*

Substances

  • Carbamates
  • Cholinesterase Reactivators
  • Oximes
  • Pyridinium Compounds
  • Xylenes
  • Acetylcholinesterase