title: Synthesis and antimalarial activity of ethylene glycol oligomeric ethers of artemisinin.
abstract: OBJECTIVE
  The aim of this study was to synthesize a series of ethylene glycol ether derivatives of the antimalarial drug artemisinin, determine their values for selected physicochemical properties and evaluate their antimalarial activity in vitro against Plasmodium falciparum strains.
  
  
  METHODS
  The ethers were synthesized in a one-step process by coupling ethylene glycol moieties of various chain lengths to carbon C-10 of artemisinin. The aqueous solubility and log D values were determined in phosphate buffered saline (pH 7.4). The derivatives were screened for antimalarial activity alongside artemether and chloroquine against chloroquine-sensitive (D10) and moderately chloroquine-resistant (Dd2) strains of P. falciparum.
  
  
  RESULTS
  The aqueous solubility within each series increased as the ethylene glycol chain lengthened. The IC50 values revealed that all the derivatives were active against both D10 and Dd2 strains. All were less potent than artemether irrespective of the strain. However, they proved to be more potent than chloroquine against the resistant strain. Compound 8, featuring three ethylene oxide units, was the most active of all the synthesized ethers.
  
  
  CONCLUSIONS
  The conjugation of dihydroartemisinin to ethylene glycol units of various chain lengths through etheral linkage led to water-soluble derivatives. The strategy did not result in an increase of antimalarial activity compared with artemether. It is nevertheless a promising approach to further investigate and synthesize water-soluble derivatives of artemisinin that may be more active than artemether by increasing the ethylene glycol chain length.
authors.affiliation: Pharmaceutical Chemistry, North-West University, Potchefstroom, South Africa.
authors.forename: Minette
authors.initials: M
authors.lastname: Steyn
authors.forename: David D
authors.initials: DD
authors.lastname: N'Da
authors.forename: Jaco C
authors.initials: JC
authors.lastname: Breytenbach
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.forename: Sandra
authors.initials: S
authors.lastname: Meredith
authors.forename: Wilma J
authors.initials: WJ
authors.lastname: Breytenbach
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000077549:Artemether; D037621:Artemisinins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005026:Ethylene Glycols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D012995:Solubility
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004987:Ethers; D005026:Ethylene Glycols; D002738:Chloroquine; D000077549:Artemether