Synthesis and in vitro reactivation study of isonicotinamide derivatives of 2-(hydroxyimino)-N-(pyridin-3-yl)acetamide as reactivators of Sarin and VX inhibited human acetylcholinesterase (hAChE)

Bioorg Med Chem. 2016 Sep 15;24(18):4171-4176. doi: 10.1016/j.bmc.2016.07.005. Epub 2016 Jul 6.

Abstract

Previously (Karade et al., 2014), we have reported the synthesis and in vitro evaluation of bis-pyridinium derivatives of pyridine-3-yl-(2-hydroxyimino acetamide), as reactivators of sarin and VX inhibited hAChE. Few of the molecules showed superior in vivo protection efficacy (mice model) (Kumar et al., 2014; Swami et al., 2016) in comparison to 2-PAM against DFP and sarin poisoning. Encouraged by these results, herein we report the synthesis and in vitro evaluation of isonicotinamide derivatives of pyridine-3-yl-(2-hydroxyimino acetamide) (4a-4d) against sarin and VX inhibited erythrocyte ghost hAChE. Reactivation kinetics of these compounds was studied and the determined kinetic parameters were compared with that of commercial reactivators viz. 2-PAM and obidoxime. In comparison to 2-PAM and obidoxime, oxime 4a and 4b exhibited enhanced reactivation efficacy toward sarin inhibited hAChE while oxime 4c showed far greater reactivation efficacy toward VX inhibited hAChE. The acid dissociation constant and IC50 values of these oximes were determined and correlated with the observed reactivation potential.

Keywords: 2-(Hydroxyimino)-N-(pyridin-3-yl)acetamide; Acetylcholinesterase; Isonicotinamide; Nerve agents; Organophosphorus.

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry*
  • Aminopyridines / chemical synthesis
  • Aminopyridines / chemistry*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Reactivators / chemical synthesis
  • Cholinesterase Reactivators / chemistry*
  • Erythrocyte Membrane / enzymology
  • Humans
  • Kinetics
  • Niacinamide / analogs & derivatives*
  • Niacinamide / chemical synthesis
  • Niacinamide / chemistry*
  • Obidoxime Chloride / chemistry
  • Organothiophosphorus Compounds / chemistry
  • Oximes / chemical synthesis
  • Oximes / chemistry*
  • Pralidoxime Compounds / chemistry
  • Sarin / chemistry

Substances

  • Acetamides
  • Aminopyridines
  • Cholinesterase Inhibitors
  • Cholinesterase Reactivators
  • Organothiophosphorus Compounds
  • Oximes
  • Pralidoxime Compounds
  • Niacinamide
  • Obidoxime Chloride
  • VX
  • Sarin
  • pralidoxime