Design, synthesis, and development of novel guaianolide-endoperoxides as potential antimalarial agents

J Med Chem. 2010 Nov 11;53(21):7864-8. doi: 10.1021/jm1006462.

Abstract

Design and synthesis of a guaianolide-endoperoxide (thaperoxide) 3 was pursued as a new antimalarial lead which was found to be noncytotoxic as compared to the natural product lead thapsigargin 2. Several analogues of 3 were successfully synthesized and found to be comparable to derivatives of artemisinin 1 in in vitro antimalarial assay. Among the synthesized compounds, 22 showed excellent in vitro potency against the cultured parasites (W2 IC(50) = 13 nM) without apparent cytotoxicity. Furthermore, SAR trends in thaperoxide analogues are presented and explained with the help of docking studies in the homology model of PfSERCA(PfATP6).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Artemisinins / pharmacology
  • Chlorocebus aethiops
  • Drug Design
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Parasitic Sensitivity Tests
  • Peroxides / chemical synthesis*
  • Peroxides / chemistry
  • Peroxides / pharmacology
  • Plasmodium falciparum / drug effects*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / chemistry
  • Sesquiterpenes, Guaiane / chemical synthesis*
  • Sesquiterpenes, Guaiane / chemistry
  • Sesquiterpenes, Guaiane / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thapsigargin / chemical synthesis
  • Thapsigargin / chemistry
  • Thapsigargin / pharmacology
  • Vero Cells

Substances

  • Antimalarials
  • Artemisinins
  • Peroxides
  • Sesquiterpenes, Guaiane
  • Thapsigargin
  • artemisinin
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases