Synthesis, evaluation and molecular dynamics study of some new 4-aminopyridine semicarbazones as an antiamnesic and cognition enhancing agents

Bioorg Med Chem. 2013 Sep 1;21(17):5451-60. doi: 10.1016/j.bmc.2013.06.003. Epub 2013 Jun 11.

Abstract

Some new semicarbazones of 4-aminopyridine were synthesized and evaluated for antiamnesic, cognition enhancing and anticholinesterase activities. The results illustrated a significant cognition enhancing effect on elevated plus maze model with a significant reversal of scopolamine-induced amnesia. A significant inhibition in acetycholinesterase (AChE) activity by all the synthesized compounds in specific brain regions that is, prefrontal cortex, hippocampus and hypothalamus was observed. Compound 4APi exhibited significant antiamnesic and cognition enhancing activity which was comparable with standard drug donepezil. Its enzyme kinetic study revealed a non-competitive inhibition of AChE and a competitive inhibition of butyrylcholinesterase (BChE). Docking studies predicted the binding modes of these compounds in AChE active site, which were further processed for molecular dynamics simulation for calculating binding free energies using Molecular Mechanics-Generalized Born Surface Area (MM/GBSA). All the computational study confirmed their consensual interaction with AChE justifying the experimental outcome.

Keywords: 4-Aminopyridine; AZVZKBWWICYDKQ-UHFFFAOYSA-N; Antiamnesic; Anticholinesterase; BUYKIHNWCJPNLT-UHFFFAOYSA-N; Enzyme kinetic study; GYGIBXHJGSWTKF-UHFFFAOYSA-N; ICJVRPQWEPOSOL-UHFFFAOYSA-N; JOPUUEPBDBDCNF-UHFFFAOYSA-N; KODLYXQOPZUKPJ-LICLKQGHSA-N; KYHXKWDXJRGIMV-UHFFFAOYSA-N; MJTBMALRTPNOQB-UHFFFAOYSA-N; Molecular dynamics; Nootropic; UCDUYUHBSRPAQF-UHFFFAOYSA-N; ZZYHSQUEYLZWSM-UHFFFAOYSA-N.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism
  • Aminopyridines / chemistry*
  • Amnesia / chemically induced
  • Amnesia / drug therapy
  • Animals
  • Behavior, Animal / drug effects
  • Binding Sites
  • Brain / enzymology
  • Butyrylcholinesterase / chemistry
  • Butyrylcholinesterase / metabolism
  • Catalytic Domain
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Inhibitors / therapeutic use
  • Kinetics
  • Molecular Docking Simulation
  • Rats
  • Semicarbazones / chemistry*
  • Semicarbazones / pharmacology
  • Semicarbazones / therapeutic use

Substances

  • Aminopyridines
  • Cholinesterase Inhibitors
  • Semicarbazones
  • Acetylcholinesterase
  • Butyrylcholinesterase