Antitrypanosomatid Pharmacomodulation at Position 3 of the 8-Nitroquinolin-2(1H)-one Scaffold Using Palladium-Catalysed Cross-Coupling Reactions

ChemMedChem. 2018 Oct 22;13(20):2217-2228. doi: 10.1002/cmdc.201800456. Epub 2018 Sep 17.

Abstract

An antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3-bromo-8-nitroquinolin-2(1H)-one was conducted. Twenty-four derivatives were synthesised using the Suzuki-Miyaura cross-coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para-carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3-(4-carboxyphenyl)-8-nitroquinolin-2(1H)-one (21) with a lower reduction potential (-0.56 V) than the initial hit (-0.45 V). Compound 21 displays micromolar antitrypanosomal activity (IC50 =1.5 μm) and low cytotoxicity on the human HepG2 cell line (CC50 =120 μm), having a higher selectivity index (SI=80) than the reference drug eflornithine. Contrary to results previously obtained in this series, hit compound 21 is inactive toward L. infantum and is not efficiently bioactivated by T. brucei brucei type I nitroreductase, which suggests the existence of an alternative mechanism of action.

Keywords: 8-nitroquinolin-2(1H)-ones; antikinetoplastid pharmacomodulation; palladium-catalysed cross-coupling; parasitic nitroreductases; trypanosomatids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalysis
  • Hep G2 Cells
  • Humans
  • Leishmania donovani / drug effects
  • Leishmania infantum / drug effects
  • Molecular Structure
  • Nitroquinolines / chemical synthesis
  • Nitroquinolines / chemistry
  • Nitroquinolines / pharmacology*
  • Nitroquinolines / toxicity
  • Palladium / chemistry
  • Parasitic Sensitivity Tests
  • Quinolones / chemical synthesis
  • Quinolones / chemistry
  • Quinolones / pharmacology*
  • Quinolones / toxicity
  • Trypanocidal Agents / chemical synthesis
  • Trypanocidal Agents / chemistry
  • Trypanocidal Agents / pharmacology*
  • Trypanocidal Agents / toxicity
  • Trypanosoma brucei brucei / drug effects

Substances

  • Nitroquinolines
  • Quinolones
  • Trypanocidal Agents
  • Palladium