title: Novel ferrocenic artemisinin derivatives: synthesis, in vitro antimalarial activity and affinity of binding with ferroprotoporphyrin IX.
abstract: Following our search for novel compounds with high antimalarial activity, a series of artemisinin (QHS) derivatives containing a ferrocenic nucleus was prepared and tested in vitro against Plasmodium falciparum strains. Two new metallocenic derivatives (1 and 3) were found as potent as QHS. All compounds showed a capacity to bind with ferroprotoporphyrin IX. A decrease in the Soret band absorbance of ferroprotoporphyrin IX, resulting from the addition of different drugs concentrations, was shown. The association stoichiometry of compounds to ferroprotoporphyrin IX appears to be 1:2 at equilibrium, with an intermediate 1:1 complexation. These results appear to strengthen the role of adducts between artemisinin derivatives and heme in generation of artemisinin radicals. Such interaction of artemisinin ferrocenyl derivatives with ferroprotoporphyrin IX and its biological significance could form a basis in future drug development.
authors.affiliation: INSERM U.42, Villeneuve d'Ascq, France.
authors.forename: L
authors.initials: L
authors.lastname: Delhaes
authors.forename: C
authors.initials: C
authors.lastname: Blot
authors.forename: L
authors.initials: L
authors.lastname: Berry
authors.forename: L A
authors.initials: LA
authors.lastname: Maciejewski
authors.forename: D
authors.initials: D
authors.lastname: Camus
authors.forename: J S
authors.initials: JS
authors.lastname: Brocard
authors.forename: D
authors.initials: D
authors.lastname: Dive
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D037621:Artemisinins; D015195:Drug Design; D006418:Heme / Q000378:metabolism; D066298:In Vitro Techniques; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D007783:Lactones; D012717:Sesquiterpenes; D006418:Heme; C075875:artemisin