Design, synthesis, and characterization of novel, nonquaternary reactivators of GF-inhibited human acetylcholinesterase

Bioorg Med Chem Lett. 2014 Apr 1;24(7):1711-4. doi: 10.1016/j.bmcl.2014.02.049. Epub 2014 Feb 28.

Abstract

The goal of this research was to identify structurally novel, non-quaternarypyridinium reactivators of GF (cyclosarin)-inhibited hAChE that possess the capacity to mediate in vitro reactivation of GF-inhibited human acetylcholinesterase (hAChE). New compounds were designed, synthesized and assessed in GF-inhibited hAChE assays. Structure activity relationships for AChE binding and reactivation of GF-inhibited hAChE were developed. Lead compounds from two different chemical series, represented by compounds 17 and 38, displayed proficient in vitro reactivation of GF-inhibited hAChE, while also possessing low inhibition of native enzyme.

Keywords: Acetylcholinesterase; Cyclosarin (GF); GF-inhibited hAChE; Heteroaryl keto-oximes; Reactivation; Structure–activity relationship.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Molecular Structure
  • Organophosphorus Compounds / chemical synthesis
  • Organophosphorus Compounds / chemistry
  • Organophosphorus Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • Cholinesterase Inhibitors
  • Organophosphorus Compounds
  • Acetylcholinesterase
  • cyclohexyl methylphosphonofluoridate