N-Cinnamoylation of Antimalarial Classics: Effects of Using Acyl Groups Other than Cinnamoyl toward Dual-Stage Antimalarials

ChemMedChem. 2015 Aug;10(8):1344-9. doi: 10.1002/cmdc.201500164. Epub 2015 Jun 2.

Abstract

In a follow-up study to our reports of N-cinnamoylated chloroquine and quinacrine analogues as promising dual-stage antimalarial leads with high in vitro potency against both blood-stage Plasmodium falciparum and liver-stage Plasmodium berghei, we decided to investigate the effect of replacing the cinnamoyl moiety with other acyl groups. Thus, a series of N-acylated analogues were synthesized, and their activities against blood- and liver-stage Plasmodium spp. were assessed along with their in vitro cytotoxicities. Although the new N-acylated analogues were found to be somewhat less active and more cytotoxic than their N-cinnamoylated counterparts, they equally displayed nanomolar activities in vitro against blood-stage drug-sensitive and drug-resistant P. falciparum, and significant in vitro liver-stage activity against P. berghei. Therefore, it is demonstrated that simple N-acylated surrogates of classical antimalarial drugs are promising dual-stage antimalarial leads.

Keywords: antimalarial drugs; chloroquine; cinnamic acid; malaria; quinacrine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry*
  • Antimalarials / pharmacology
  • Cell Survival / drug effects
  • Chloroquine / analogs & derivatives
  • Chloroquine / chemical synthesis
  • Chloroquine / pharmacology
  • Cinnamates / chemistry*
  • Hep G2 Cells
  • Humans
  • Life Cycle Stages / drug effects
  • Plasmodium berghei / drug effects
  • Plasmodium berghei / growth & development
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / growth & development
  • Quinacrine / analogs & derivatives
  • Quinacrine / chemical synthesis
  • Quinacrine / pharmacology
  • Structure-Activity Relationship

Substances

  • Antimalarials
  • Cinnamates
  • cinnamoyl chloride
  • Chloroquine
  • Quinacrine