Synthesis and evaluation of antimalarial properties of novel 4-aminoquinoline hybrid compounds

Chem Biol Drug Des. 2014 Oct;84(4):462-72. doi: 10.1111/cbdd.12335. Epub 2014 Jun 3.


Pharmacophore hybridization has recently been employed in the search for antimalarial lead compounds. This approach chemically links two pharmacophores, each with their own antimalarial activity and ideally with different modes of action, into a single hybrid molecule with the goal to improve therapeutic properties. In this paper, we report the synthesis of novel 7-chloro-4-aminoquinoline/primary sulfonamide hybrid compounds. The chlorinated 4-aminoquinoline scaffold is the core structure of chloroquine, an established antimalarial drug, while the primary sulfonamide functional group has a proven track record of efficacy and safety in many clinically used drugs and was recently shown to exhibit some antimalarial activity. The activity of the hybrid compounds was determined against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains. While the hybrid compounds had lower antimalarial activity when compared to chloroquine, they demonstrated a number of interesting structure-activity relationship (SAR) trends including the potential to overcome the resistance profile of chloroquine.

Keywords: Plasmodium falciparum; antimalarial; carbonic anhydrase; chloroquine; click chemistry; hybrid; primary sulfonamide; sulfonamide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoquinolines / chemistry*
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Cell Line
  • Cell Survival / drug effects
  • Click Chemistry
  • Drug Design
  • Drug Resistance / drug effects
  • Humans
  • Plasmodium falciparum / drug effects
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*


  • Aminoquinolines
  • Antimalarials
  • Sulfonamides
  • 4-aminoquinoline