Design, Synthesis, and Evaluation of Novel Ferroquine and Phenylequine Analogues as Potential Antiplasmodial Agents

ChemMedChem. 2015 Dec;10(12):2099-110. doi: 10.1002/cmdc.201500349. Epub 2015 Oct 8.

Abstract

7-Chloroquinoline-based antimalarial drugs are effective in the inhibition of hemozoin formation in the food vacuole of the Plasmodium parasite, the causative agent of malaria. We synthesized five series of ferroquine (FQ) and phenylequine (PQ) derivatives, which display good in vitro efficacy toward both the chloroquine-sensitive (CQS) NF54 (IC50 : 4.2 nm) and chloroquine-resistant (CQR) Dd2 (IC50 : 33.7 nm) strains of P. falciparum. Several compounds were found to have good inhibitory activity against β-hematin formation in an NP-40 detergent assay, with IC50 values ranging between 10.4 and 19.2 μm.

Keywords: ferroquine; malaria; oxalamide; phenylequine; β-hematin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoquinolines / chemistry*
  • Aminoquinolines / pharmacology
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Chloroquine / chemical synthesis
  • Chloroquine / chemistry*
  • Chloroquine / pharmacology
  • Crystallography, X-Ray
  • Drug Design*
  • Drug Resistance / drug effects
  • Ferrous Compounds / chemistry*
  • Ferrous Compounds / pharmacology
  • Hemeproteins / antagonists & inhibitors
  • Hemeproteins / metabolism
  • Inhibitory Concentration 50
  • Metallocenes
  • Microbial Sensitivity Tests
  • Molecular Conformation
  • Octoxynol
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / metabolism
  • Polyethylene Glycols / chemistry
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Aminoquinolines
  • Antimalarials
  • Ferrous Compounds
  • Hemeproteins
  • Metallocenes
  • hemozoin
  • Polyethylene Glycols
  • Chloroquine
  • ferroquine
  • Octoxynol
  • Nonidet P-40