Novel multipotent phenylthiazole-tacrine hybrids for the inhibition of cholinesterase activity, β-amyloid aggregation and Ca²⁺ overload

Bioorg Med Chem. 2012 Nov 1;20(21):6513-22. doi: 10.1016/j.bmc.2012.08.040. Epub 2012 Aug 30.

Abstract

In this study, a series of multipotent phenylthiazole-tacrine hybrids (7a-7e, 8, and 9a-9m) were synthesized and biologically evaluated. Screening results showed that phenylthiazole-tacrine hybrids were potent cholinesterase inhibitors with pIC(50) (-logIC(50)) value ranging from 5.78 ± 0.05 to 7.14 ± 0.01 for acetylcholinesterase (AChE), and from 5.75 ± 0.03 to 10.35 ± 0.15 for butyrylcholinesterase (BuChE). The second series of phenylthiazole-tacrine hybrids (9a-9m) could efficiently prevent Aβ(1-42) self-aggregation. The structure-activity relationship revealed that their inhibitory potency relied on the type of middle linker and substitutions at 4'-position of 4-phenyl-2-aminothiazole. In addition, 7a and 7c also displayed the Ca(2+) overload blockade effect in the primary cultured cortical neurons. Consequently, these compounds emerged as promising molecules for the therapy of Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Calcium / metabolism*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Cholinesterases / metabolism*
  • Dose-Response Relationship, Drug
  • Molecular Structure
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Peptide Fragments / antagonists & inhibitors*
  • Peptide Fragments / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Tacrine / chemistry
  • Tacrine / pharmacology*
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*

Substances

  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Peptide Fragments
  • Thiazoles
  • amyloid beta-protein (1-42)
  • Tacrine
  • Cholinesterases
  • Calcium