N10,N11-di-alkylamine indolo[3,2-b]quinolines as hemozoin inhibitors: design, synthesis and antiplasmodial activity

Bioorg Med Chem. 2015 Apr 1;23(7):1530-9. doi: 10.1016/j.bmc.2015.02.007. Epub 2015 Feb 13.


We recently reported that potent N10,O11-bis-alkylamine indolo[3,2-b]quinoline antimalarials act as hemozoin (Hz) growth inhibitors. To improve access and binding to the target we have now designed novel N10,N11-di-alkylamine bioisosteres. 3-Chloro derivatives (10a-f) showed selectivity for malaria parasite compared to human cells, high activity against Plasmodium falciparum chloroquine (CQ)-resistant strain W2 (IC50s between 20 and 158nM), good correlation with β-hematin inhibition and improved vacuolar accumulation ratios, thus suggesting inhibition of Hz growth as one possible mechanism of action for these compounds. Moreover, our studies show that Hz is a valid target for the development of new antimalarials able to overcome CQ resistance.

Keywords: Hemozoin; Indolo[3,2-b]quinolines; Malaria; Resistance; Vacuolar accumulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / chemical synthesis*
  • Antimalarials / pharmacology
  • Cryptolepis
  • Drug Design*
  • Hemeproteins / antagonists & inhibitors*
  • Hemeproteins / metabolism
  • Humans
  • Plasmodium falciparum / drug effects*
  • Quinolines / chemical synthesis*
  • Quinolines / pharmacology


  • Antimalarials
  • Hemeproteins
  • Quinolines
  • hemozoin