title: In vivo antimalarial activities of mono- and bis quaternary ammonium salts interfering with Plasmodium phospholipid metabolism.
abstract: We previously showed that quaternary ammonium salts have potent antimalarial activities against the blood stage of drug-resistant Plasmodium falciparum. In the present study, 13 compounds of this series were comparatively assessed in murine in vivo malarial models. Mice infected with Plasmodium berghei were successfully treated with 11 quaternary ammonium salts in a 4-day suppressive test with a once-daily intraperitoneal administration. The dose required to decrease parasitemia by 50% (ED(50)) ranged from 0.04 to 4.5 mg/kg of body weight. For six mono- and three bis-quaternary ammonium salts, the therapeutic indices (i.e., 50% lethal dose and ED(50)) were higher than 5, and at best, around 20 to 30 for five of them (E6, E8, F4, G5, and G25), which is comparable to that of chloroquine under the same conditions. Plasmodium chabaudi was significantly more susceptible to G5, G15, and G25 compounds than P. berghei. Similar therapeutic indices were obtained, regardless of the administration mode or initial parasitemia (up to 11.2%). Parasitemia clearance was complete without recrudescence. Subcutaneously administered radioactive compounds had a short elimination half-life in mice (3.5 h) with low bioavailability (17.3%), which was likely due to the permanent cationic charge of the molecule. The high in vivo therapeutic index in the P. chabaudi-infected mouse model and the absence of recrudescence highlight the enormous potential of these quaternary ammonium salts for clinical malarial treatment.
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: Anne
authors.initials: A
authors.lastname: Bonhoure
authors.forename: Serge
authors.initials: S
authors.lastname: Herbute
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Vial
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006207:Half-Life; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007928:Lethal Dose 50; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D051379:Mice; D010743:Phospholipids / Q000378:metabolism*; D010961:Plasmodium / Q000187:drug effects* / Q000378:metabolism*; D010962:Plasmodium berghei / Q000187:drug effects; D016788:Plasmodium chabaudi / Q000187:drug effects; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D000644:Quaternary Ammonium Compounds / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity
chemical_list: C448986:1,16-hexadecamethylenebis(N-methylpyrrolidinyl); D000962:Antimalarials; D010743:Phospholipids; D011759:Pyrrolidines; D000644:Quaternary Ammonium Compounds