Investigation into novel thiophene- and furan-based 4-amino-7-chloroquinolines afforded antimalarials that cure mice

Bioorg Med Chem. 2015 May 1;23(9):2176-86. doi: 10.1016/j.bmc.2015.02.061. Epub 2015 Mar 7.

Abstract

We herein report the design and synthesis of a novel series of thiophene- and furan-based aminoquinoline derivatives which were found to be potent antimalarials and inhibitors of β-hematin polymerization. Tested compounds were 3-71 times more potent in vitro than CQ against chloroquine-resistant (CQR) W2 strain with benzonitrile 30 being as active as mefloquine (MFQ), and almost all synthesized aminoquinolines (22/27) were more potent than MFQ against multidrug-resistant (MDR) strain C235. In vivo experiments revealed that compound 28 showed clearance with recrudescence at 40 mg/kg/day, while 5/5 mice survived in Thompson test at 160 mg/kg/day.

Keywords: Aminoquinoline inhibitors; Chemotherapy; Cytotoxicity; Furan; Malaria; P. berghei; Thiophene; β-Hematin polymerization inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoquinolines / chemical synthesis
  • Aminoquinolines / chemistry
  • Aminoquinolines / pharmacology*
  • Animals
  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Furans / chemistry
  • Furans / pharmacology*
  • Hep G2 Cells
  • Humans
  • Macrophages / drug effects
  • Mice
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Plasmodium berghei / drug effects*
  • Structure-Activity Relationship
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*

Substances

  • Aminoquinolines
  • Antimalarials
  • Furans
  • Thiophenes
  • furan