N-ferrocenylpyridazinones and new organic analogues: Synthesis, cyclic voltammetry, DFT analysis and in vitro antiproliferative activity associated with ROS-generation

Tamás Jernei, Szilvia Bősze, Rita Szabó, Ferenc Hudecz, Katalin Majrik, Antal Csámpai

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Employing an optimized Pd-catalyzed cross-coupling reaction promoted by CuI, novel N-ferrocenylpyridazinones along with N-phenyl- and N-(2-pyridyl) analogues were synthesized from readily available heterocyclic precursors, iodoferrocene, iodobenzene and 2-bromopyridine. With exception of the ferrocenylation of 6-ferrocenylpyridazin-3(2H)-one yielding both N- and O-substituted products, the studied reactions exclusively afforded N-aryl lactams. The novel compounds exhibited cytotoxicity towards HEPG2 and HT-29 human malignant cells under in vitro conditions. The measured IC50 values supplemented with the results of cyclic voltammetry and DFT calculations suggest that the cytotoxic activity of the N- and O-ferrocenyl-substituted derivatives and the decreased effect of the N-phenyl analogues seem to be at least partly associated with the potential to generate reactive oxygen species (ROS). This interpretation, allowing the prediction of characteristic substituent-dependent SAR, was supported by the results of related studies on the practically inactive N-(2-pyridyl)pyridazinones assumed to be present in protonated chelate forms with highly a decreased propensity to undergo ionization.

Original languageEnglish
Pages (from-to)6181-6192
Number of pages12
JournalTetrahedron
Volume73
Issue number43
DOIs
Publication statusPublished - Jan 1 2017

Keywords

  • Cyclic voltammetry
  • Cytotoxicity
  • Ferrocene
  • HOMO energy
  • Ionization energy
  • Lactams
  • N-arylation
  • Pyridazine
  • SAR

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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