Evaluation of amidoxime derivatives as prodrug candidates of potent bis-cationic antimalarials.

Plasmodium falciparum is responsible for most of the cases of malaria and its resistance to established antimalarial drugs is a major issue. Thus, new chemotherapies are needed to fight the emerging multi-drug resistance of P. falciparum malaria, like choline analogues targeting plasmodial phospholipidic metabolism.

Development of the first oral bioprecursors of bis-alkylguanidine antimalarial drugs.

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.

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

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.

Symmetrical choline-derived dications display strong anti-kinetoplastid activity.

Objectives: to investigate the anti-kinetoplastid activity of choline-derived analogues with previously reported antimalarial efficacy.

Methods: from an existing choline analogue library, seven antimalarial compounds, representative of the first-, second- and third-generation analogues previously developed, were assessed for activity against Trypanosoma and Leishmania spp. Using a variety of techniques, the effects of choline analogue exposure on the parasites were documented and a preliminary investigation of their mode of action was performed.

Pharmacokinetic properties and metabolism of a new potent antimalarial N-alkylamidine compound, M64, and its corresponding bioprecursors.

Antimalarial activities and pharmacokinetics of the bis-alkylamidine, M64, and its amidoxime, M64-AH, and O-methylsulfonate, M64-S-Me, derivatives were investigated. M64 and M64-S-Me had the most potent activity against the Plasmodium falciparum growth (IC(50)<12nM). The three compounds can clear the Plasmodium vinckei infection in mice (ED(50)<10mg/kg).

Reverse-benzamidine antimalarial agents: design, synthesis, and biological evaluation.

In the frame of the development of bis-cationic choline analogs, the RSA of bis-N-alkylamidines were studied and a new series of reverse-benzamidine derivatives was designed. Contrary to the lipophilicity, the basicity of alkylamidine compounds directly influences their antimalarial potencies.

N-substituted bis-C-alkyloxadiazolones as dual effectors: efficient intermediates to amidoximes or amidines and prodrug candidates of potent antimalarials.

A convenient route to N-substituted bis-C-alkylamidines possessing antiplasmodial activity and their oxadiazolone and amidoxime prodrug candidates, is described. These three families of compounds were available after a key N-alkylation step of the parent oxadiazolone 1a. Testing of the three compound classes in vitro and in vivo is also presented.

Design and synthesis of amidoxime derivatives for orally potent C-alkylamidine-based antimalarial agents.

Within the frame of the design of prodrug candidates to deliver a C-alkylamidine antimalarial agent, we showed that specific O-substitutions were needed on the alkylamidoxime structure. Among the newly synthesized molecules, bis-oxadiazolone and bis-O-methylsulfonylamidoxime derivatives induced a complete clearance of parasitemia in mice after oral administration.

Potent antimalarial activity of 2-aminopyridinium salts, amidines, and guanidines.

We describe the design, synthesis, and antimalarial activity of 60 bis-tertiary amine, bis-2(1 H)-imino-heterocycle, bis-amidine, and bis-guanidine series. Bis-tertiary amines with a linker from 12 to 16 methylene groups were active against the in vitro growth of Plasmodium falciparum within the 10 (-6)-10 (-7) M concentration range. IC 50 decreased by 2 orders of magnitude for bis-2-aminopyridinium salts, bis-amidines, and bis-guanidines (27 compounds with IC 50 < 10 nM).

Synthesis and antimalarial activity of new 1,12-bis(N,N'-acetamidinyl)dodecane derivatives.

Amidoxime and O-substituted derivatives of the bis-alkylamidine 1,12-bis(N,N'-acetamidinyl)dodecane were synthesized and evaluated as in vitro and in vivo antimalarial prodrugs. The bis-O-methylsulfonylamidoxime 8 and the bis-oxadiazolone 9 derivatives show relatively potent antimalarial activity after oral administration.