Structure-activity relationships of the antimalarial agent artemisinin. 4. Effect of substitution at C-3

J Med Chem. 1996 Jul 19;39(15):2900-6. doi: 10.1021/jm960200e.

Abstract

Novel antimalarial artemisinin analogs, 3-alkylartemisinins as well as 3-(arylalkyl)- and 3-(carboxyalkyl)artemisinins, were prepared via the synthetic intermediate 2. Formation of the N,N-dimethylhydrazones 5 and 24 and then regio- and chemoselective deprotonation followed by alkylation provided initially alkylated hydrazones that upon chromatography gave ketones 6-13 and 25-30. Direct ozonolysis of the ketones followed by in situ acidification lead directly to the formation of title compounds 14-21 and 31-36. The analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum and found to be in some cases much more active than the natural product (+)-artemisinin. The results were included in structure-activity relationship (CoMFA) studies for further analog design.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antimalarials* / chemistry
  • Antimalarials* / pharmacology
  • Artemisinins*
  • Drug Resistance
  • Hemin / chemistry
  • Hydrogen Bonding
  • Hydrogen-Ion Concentration
  • Ketones / chemistry
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Structure
  • Ozone / chemistry
  • Plasmodium falciparum / drug effects
  • Sesquiterpenes / chemical synthesis*
  • Sesquiterpenes / chemistry*
  • Sesquiterpenes / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antimalarials
  • Artemisinins
  • Ketones
  • Sesquiterpenes
  • octahydro-3-(3-ethoxypropionyl)-6-methyl-9-butyl-3,12-epoxy-12H-pyrano(4,3-j)-1,2-benzodioxepin-10(3H)-one
  • Ozone
  • Hemin
  • artemisinin