Novel series of tacrine-tianeptine hybrids: Synthesis, cholinesterase inhibitory activity, S100B secretion and a molecular modeling approach

Eur J Med Chem. 2016 Oct 4:121:758-772. doi: 10.1016/j.ejmech.2016.06.025. Epub 2016 Jun 23.

Abstract

Tianeptine was linked to various 9-aminoalkylamino-1,2,3,4-tetrahydroacridines using EDC·HCl/HOBt to afford a series of tacrine-tianeptine hybrids. The hybrids were tested for their ability to inhibit AChE and BuChE and IC50 values in the nanomolar concentration scale were obtained. AChE molecular modeling studies of these hybrids indicated that tacrine moiety interacts in the bottom of the gorge with the catalytic active site (CAS) while tianeptine binds to peripheral anionic site (PAS). Furthermore, the compounds 2g and 2e were able to reduce the in vitro basal secretion of S100B, suggesting its therapeutic action in some cases or stages of Alzheimer's disease.

Keywords: AChE; BuChE; Coupling reaction; Molecular modeling; S100B secretion; Tacrine; Tianeptine.

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism
  • Animals
  • Brain / drug effects
  • Brain / enzymology
  • Butyrylcholinesterase / chemistry
  • Butyrylcholinesterase / metabolism
  • Catalytic Domain
  • Chemistry Techniques, Synthetic
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / pharmacology*
  • Electrophorus
  • Humans
  • L-Lactate Dehydrogenase / metabolism
  • Models, Molecular
  • S100 Calcium Binding Protein beta Subunit / metabolism
  • Tacrine / chemistry*
  • Thiazepines / chemical synthesis
  • Thiazepines / chemistry*
  • Thiazepines / pharmacology*

Substances

  • Cholinesterase Inhibitors
  • S100 Calcium Binding Protein beta Subunit
  • Thiazepines
  • tianeptine
  • Tacrine
  • L-Lactate Dehydrogenase
  • Acetylcholinesterase
  • Butyrylcholinesterase