Novel ferrocenic artemisinin derivatives: Synthesis, in vitro antimalarialactivity and affinity of binding with ferroprotoporphyrin IX

Following our search for novel compounds with high antimalarial activity, a series of artemisinin (QHS) derivatives containing a ferrocenic nucleus wa s prepared and tested in vitro against Plasmodium falciparum strains. Two n ew metallocenic derivatives (1 and 3) were found as potent as QHS. All comp ounds showed a capacity to bind with ferroprotoporphyrin IX. A decrease in the Soret band absorbance of ferroprotoporphyrin IX, resulting from the add ition of different drugs concentrations, was shown. The association stoichi ometry of compounds to ferroprotoporphyrin IX appears to be 1:2 at equilibr ium, with an intermediate 1:1 complexation. These results appear to strengt hen the role of adducts between artemisinin derivatives and heme in generat ion of artemisinin radicals. Such interaction of artemisinin ferrocenyl der ivatives with ferroprotoporphyrin IX and its biological significance could form a basis in future drug development. (C) 2000 Elsevier Science Ltd. All rights reserved.