Evaluation of Bis-Alkylamidoxime O-Alkylsulfonates as Orally Available Antimalarials - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue ChemMedChem Année : 2012

Evaluation of Bis-Alkylamidoxime O-Alkylsulfonates as Orally Available Antimalarials

Résumé

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.

Domaines

Chimie organique

Dates et versions

hal-00712957 , version 1 (28-06-2012)

Identifiants

Citer

Melissa Degardin, Sharon Wein, Smitha Gouni, Christophe Tran van Ba, Jean-Frédéric Duckert, et al.. Evaluation of Bis-Alkylamidoxime O-Alkylsulfonates as Orally Available Antimalarials. ChemMedChem, 2012, 7, pp.991-1001. ⟨10.1002/cmdc.201200112⟩. ⟨hal-00712957⟩
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