Structure-activity relationships of the antimalarial agent artemisinin. 2. Effect of heteroatom substitution at O-11: synthesis and bioassay of N-alkyl-11-aza-9-desmethylartemisinins

J Med Chem. 1995 Dec 22;38(26):5038-44. doi: 10.1021/jm00026a011.

Abstract

A novel class of artemisinin analogs, N-alkyl-11-aza-9-desmethylartemisinins 17-29, were synthesized via ozonolysis and acid-catalyzed cyclization of precursor amides 5-16. These amides were prepared through condensation of an activated ester of the known intermediate acid 2 with the corresponding primary amine. The analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum and found in some cases to be more active than artemisinin. A comparison of the in vitro testing methods of Milhous and Makler was conducted and gave similar relative antimalarial activities for these artemisinin analogs. Log P values were determined for most of the compounds, but no apparent correlation between log P and in vitro activity was found.

MeSH terms

  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Artemisinins*
  • Drug Evaluation, Preclinical
  • Drugs, Chinese Herbal / chemical synthesis
  • Drugs, Chinese Herbal / chemistry
  • Drugs, Chinese Herbal / pharmacology*
  • Erythrocytes / parasitology
  • Humans
  • Molecular Structure
  • Plasmodium falciparum / drug effects*
  • Sesquiterpenes / chemistry
  • Sesquiterpenes / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antimalarials
  • Artemisinins
  • Drugs, Chinese Herbal
  • Sesquiterpenes
  • artenimol
  • deoxyartemisinin
  • artemisinin