title: Evaluation of bis-alkylamidoxime O-alkylsulfonates as orally available antimalarials.
abstract: The main threat to controlling malaria is the emerging multidrug resistance of Plasmodium sp. parasites. Bis-alkylamidines were developed as a potential new chemotherapy that targets plasmodial phospholipid metabolism. Unfortunately, these compounds are not orally available. To solve this absorption issue, we investigated a prodrug strategy based on sulfonate derivatives of alkylamidoximes. A total of 25 sulfonates were synthesized as prodrug candidates of one bis-N-alkylamidine and of six N-substituted bis-C-alkylamidines. Their antimalarial activities were evaluated in vitro against P. falciparum and in vivo against P. vinckei in mice to define structure-activity relationships. Small alkyl substituents on the sulfonate group of both C-alkyl- and N-alkylamidines led to the best oral antimalarial activities; alkylsulfonate derivatives are chemically transformed into the corresponding alkylamidines.
authors.affiliation: Institut des Biomolecules Max Mousseron, UMR 5247 CNRS-UMI-UMII, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Montpellier I, 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: Smitha
authors.initials: S
authors.lastname: Gouni
authors.forename: Christophe
authors.initials: C
authors.lastname: Tran Van Ba
authors.forename: Jean-Frédéric
authors.initials: JF
authors.lastname: Duckert
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; D000476:Alkanesulfonates / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D005260:Female; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000476:Alkanesulfonates; D000962:Antimalarials; D011355:Prodrugs