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

• Published in: ChemMedChem 2012-06, Vol.7 (6), p.991-1001
• Main Authors: Degardin, Mélissa, Wein, Sharon, Gouni, Smitha, Tran Van Ba, Christophe, Duckert, Jean-Frédéric, Durand, Thierry, Escale, Roger, Vial, Henri, Vo-Hoang, Yen
• Format: Article
• Language: English
• Subjects: Administration, Oral; Alkanesulfonates - chemistry; Alkanesulfonates - pharmacology; Alkanesulfonates - therapeutic use; Animals; antimalarial activity; Antimalarials - chemistry; Antimalarials - pharmacology; Antimalarials - therapeutic use; Chemical Sciences; Drug Evaluation, Preclinical; Female; Malaria; Malaria - drug therapy; Mice; Organic chemistry; parasitemia; phospholipids; Plasmodium falciparum - drug effects; prodrugs; Prodrugs - chemistry; Prodrugs - pharmacology; Prodrugs - therapeutic use; Structure-Activity Relationship; structure-activity relationships
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201200112

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. Improved bioavailability: Bis‐alkylamidines were originally developed as potential new antimalarial agents that target phospholipid metabolism, but these compounds are not orally bioavailable. To solve this issue, 25 sulfonates were investigated as prodrug candidates. Their antimalarial activities were evaluated in vitro and in vivo to define structure–activity relationships.