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ChemMedChem. 2012 Jun;7(6):991-1001. doi: 10.1002/cmdc.201200112. Epub 2012 Apr 27.

Evaluation of bis-alkylamidoxime O-alkylsulfonates as orally available antimalarials.

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  • 1Institut 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.


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.

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