Synthesis and cytoprotective characterization of 8-hydroxyquinoline Betti products

Iván Kanizsai, Ramóna Madácsi, László Hackler, Márió Gyuris, Gábor J. Szebeni, Orsolya Huzián, L. Puskás

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The 8-hydroxyquinoline pharmacophore scaffold has been shown to possess a range of activities as metal chelation, enzyme inhibition, cytotoxicity, and cytoprotection. Based on our previous findings we set out to optimize the scaffold for cytoprotective activity for its potential application in central nervous system related diseases. A 48-membered Betti-library was constructed by the utilization of formic acid mediated industrial-compatible coupling with sets of aromatic primary amines such as anilines, oxazoles, pyridines, and pyrimidines, with (hetero)aromatic aldehydes and 8-hydroxiquinoline derivatives. After column chromatography and re-crystallization, the corresponding analogues were obtained in yields of 13–90%. The synthesized analogs were optimized with the utilization of a cytoprotection assay with chemically induced oxidative stress, and the most active compounds were further tested in orthogonal assays, a real time cell viability method, a fluorescence-activated cell sorting (FACS)-based assay measuring mitochondrial membrane potential changes, and gene expression analysis. The best candidates showed potent, nanomolar activity in all test systems and support the need for future studies in animal models of central nervous system (CNS) disorders.

Original languageEnglish
Article number1934
JournalMolecules
Volume23
Issue number8
DOIs
Publication statusPublished - Jan 1 2018

    Fingerprint

Keywords

  • 8-HQ
  • 8-hydroxyquinoline
  • Betti-reaction
  • Cytoprotection
  • HIF1A
  • Mannich-reaction
  • Mitochondrial membrane potential
  • Multicomponent reaction
  • Multitarget directed ligand
  • Neurodegeneration
  • Phenotypic screening

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Kanizsai, I., Madácsi, R., Hackler, L., Gyuris, M., Szebeni, G. J., Huzián, O., & Puskás, L. (2018). Synthesis and cytoprotective characterization of 8-hydroxyquinoline Betti products. Molecules, 23(8), [1934]. https://doi.org/10.3390/molecules23081934