title: In vitro activities of novel catecholate siderophores against Plasmodium falciparum.
abstract: The activities of novel iron chelators, alone and in combination with chloroquine, quinine, or artemether, were evaluated in vitro against susceptible and resistant clones of Plasmodium falciparum with a semimicroassay system. N4-nonyl,N1,N8-bis(2,3-dihydroxybenzoyl) spermidine hydrobromide (compound 7) demonstrated the highest level of activity: 170 nM against a chloroquine-susceptible clone and 1 microM against a chloroquine-resistant clone (50% inhibitory concentrations). Compounds 6, 8, and 10 showed antimalarial activity with 50% inhibitory concentrations of about 1 microM. Compound 7 had no effect on the activities of chloroquine, quinine, and artemether against either clone, and compound 8 did not enhance the schizontocidal action of either chloroquine or quinine against the chloroquine-resistant clone. The incubation of compound 7 with FeCI3 suppressed or decreased the in vitro antimalarial activity of compound 7, while no effect was observed with incubation of compound 7 with CuSO4 and ZnSO4. These results suggest that iron deprivation may be the main mechanism of action of compound 7 against the malarial parasites. Chelator compounds 7 and 8 primarily affected trophozoite stages, probably by influencing the activity of ribonucleotide reductase, and thus inhibiting DNA synthesis.
authors.affiliation: Laboratoire de Parasitologie, Hôpital Bichat-Claude Bernard, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Pradines
authors.forename: F
authors.initials: F
authors.lastname: Ramiandrasoa
authors.forename: L K
authors.initials: LK
authors.lastname: Basco
authors.forename: L
authors.initials: L
authors.lastname: Bricard
authors.forename: G
authors.initials: G
authors.lastname: Kunesch
authors.forename: J
authors.initials: J
authors.lastname: Le Bras
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002396:Catechols / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D017262:Siderophores / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D002396:Catechols; D007502:Iron Chelating Agents; D017262:Siderophores; D002738:Chloroquine; D007501:Iron