Publications by authors named "Jean-Frederic Duckert"

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.

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We report herein the design, synthesis, and biological screening of a series of 15 disulfide prodrugs as precursors of albitiazolium bromide (T3/SAR97276, compound 1), a choline analogue which is currently being evaluated in clinical trials (phase II) for severe malaria. The corresponding prodrugs are expected to revert back to the active bis-thiazolium salt through an enzymatic reduction of the disulfide bond. To enhance aqueous solubility of these prodrugs, an amino acid residue (valine or lysine) or a phosphate group was introduced on the thiazolium side chain.

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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.

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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.

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An innovative therapeutic approach based on the use of dicationic derivatives was previously designed to inhibit the biosynthesis of phosphatidylcholine in Plasmodium spp. Among these, bis-thiazolium salts were shown to block proliferation of the malaria parasite at concentrations in the low nanomolar range. However, due to unsuitable molecular properties such as the presence of the two polar heads and flexibility in the linker, these compounds have low oral bioavailability.

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Interactions involving phosphorylated Ser/Thr-Pro motifs in proteins play a key role in numerous regulatory processes in the cell. Here, we investigate potential ligands of the WW binding domain of Pin1 in order to inhibit protein-protein interactions between Pin1 and phosphopeptides. Our structure-based strategy implies the synthesis of analogues of the Ac-Thr(PO(3)H(2))-Pro-NH(2) dipeptide and relies on high resolution NMR spectroscopy to accurately measure the affinity constants even in the high micromolar range.

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