title: Potent inhibitors of Plasmodium phospholipid metabolism with a broad spectrum of in vitro antimalarial activities.
abstract: We characterized the potent in vitro antimalarial activity and biologic assessment of 13 phospholipid polar head analogs on a comparative basis. There was a positive relationship between the abilities of the drugs to inhibit parasite growth in culture and their abilities to specifically inhibit phosphatidylcholine biosynthesis of Plasmodium falciparum-infected erythrocytes. Maximal activity of G25 was observed for the trophozoite stage of the 48-h erythrocytic cycle (50% inhibitory concentration, 0.75 nM), whereas the schizont and ring stages were 12- and 213-fold less susceptible. The compounds exerted a rapid nonreversible cytotoxic effect, with complete clearance of parasitemia after 5 h of contact with the mature stages. The compounds were highly specific against P. falciparum, with much lower toxicity against three other mammalian cell lines, and the in vitro therapeutic indices ranged from 300 to 2,500,000. Finally, the monoquaternary ammonium E10 and two bis-ammonium salts, G5 and G25, were similarly active against multiresistant strains and fresh isolates of P. falciparum. This impressive selective in vitro toxicity against P. falciparum strongly highlights the clinical potential of these quaternary ammonium salts for malarial chemotherapy.
authors.affiliation: UMR 5539, CNRS, Université Montpellier II, 34095 Montpellier Cedex 5, France.
authors.forename: Marie L
authors.initials: ML
authors.lastname: Ancelin
authors.forename: Michèle
authors.initials: M
authors.lastname: Calas
authors.forename: Valérie
authors.initials: V
authors.lastname: Vidal-Sailhan
authors.forename: Serge
authors.initials: S
authors.lastname: Herbuté
authors.forename: Pascal
authors.initials: P
authors.lastname: Ringwald
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Vial
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D018432:Drug Resistance, Multiple; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D019169:Jurkat Cells; D008264:Macrophages / Q000187:drug effects; D008533:Megakaryocytes / Q000187:drug effects; D010743:Phospholipids / Q000096:biosynthesis / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology
chemical_list: C448986:1,16-hexadecamethylenebis(N-methylpyrrolidinyl); D000962:Antimalarials; D010743:Phospholipids; D011759:Pyrrolidines; D000644:Quaternary Ammonium Compounds