title: Design, synthesis and antimalarial activity of a new class of iron chelators.
abstract: Iron is crucial for many biochemical reactions involved in the growth and multiplication of the malaria parasite Plasmodium falciparum. There are many reports indicating that the iron chelators have antimalarial activity in vitro, in vivo and in human studies. However, these compounds suffer from a number of serious problems such as limited membrane permeability, short half-life and require long subcutaneous infusions. To circumvent these drawbacks we have designed a new class of iron chelators, wherein EDTA is tethered to 4-aminoquinoline. Here 4-aminoquinoline scaffold is used as a carrier to penetrate biological membrane and facilitate targetting the compounds to acidic food vacuole of the parasite. This study describes the synthesis of novel iron chelators and their in vitro antimalarial activity against P. falciparum strain of NF-54. The calculated LogP values of these compounds suggest the importance of lipophilicity for the antimalarial activity. The EDTA esters are more active than the corresponding acids. The biophysical studies suggest that these compounds may inhibit the parasite growth by iron chelation mechanism.
authors.affiliation: Division of Medicinal & Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India.
authors.forename: V Raja
authors.initials: VR
authors.lastname: Solomon
authors.forename: W
authors.initials: W
authors.lastname: Haq
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Puri
authors.forename: Kumkum
authors.initials: K
authors.lastname: Srivastava
authors.forename: S B
authors.initials: SB
authors.lastname: Katti
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D004492:Edetic Acid / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D007502:Iron Chelating Agents; D004492:Edetic Acid; C001920:4-aminoquinoline