title: Development of the first oral bioprecursors of bis-alkylguanidine antimalarial drugs.
abstract: Plasmodium falciparum is responsible of the most severe form of malaria, and new targets and novel chemotherapeutic scaffolds are needed to fight emerging multidrug-resistant strains of this parasite. Bis-alkylguanidines have been designed to mimic choline, resulting in the inhibition of plasmodial de novo phosphatidylcholine biosynthesis. Despite potent in vitro antiplasmodial and in vivo antimalarial activities, a major drawback of these compounds for further clinical development is their low oral bioavailability. To solve this issue, various modulations were performed on bis-alkylguanidines. The introduction of N-disubstituents on the guanidino motif improved both in vitro and in vivo activities. On the other hand, in vivo pharmacological evaluation in a mouse model showed that the N-hydroxylated derivatives constitute the first oral bioprecursors in bis-alkylguanidine series. This study paves the way for bis-alkylguanidine-based oral antimalarial agents targeting plasmodial phospholipid metabolism.
authors.affiliation: UMR 5247 CNRS-UMI-UMII-ENSCM, Institut des Biomolecules Max Mousseron (IBMM), Faculté des Sciences Pharmaceutiques et Biologiques, Université de Montpellier I/II, 15 Avenue Charles Flahault, 34093 Montpellier (France).
authors.forename: Mélissa
authors.initials: M
authors.lastname: Degardin
authors.forename: Sharon
authors.initials: S
authors.lastname: Wein
authors.forename: Jean-Frédéric
authors.initials: JF
authors.lastname: Duckert
authors.forename: Marjorie
authors.initials: M
authors.lastname: Maynadier
authors.forename: Alexandre
authors.initials: A
authors.lastname: Guy
authors.forename: Thierry
authors.initials: T
authors.lastname: Durand
authors.forename: Roger
authors.initials: R
authors.lastname: Escale
authors.forename: Henri
authors.initials: H
authors.lastname: Vial
authors.forename: Yen
authors.initials: Y
authors.lastname: Vo-Hoang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D019791:Guanidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D010961:Plasmodium / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D019791:Guanidine
keywords: antimalarial agents; antiplasmodial activity; bioavailability; guanidines; malaria; prodrug strategies