Odile Dechy-Cabaret

Trioxaquines Are New Antimalarial Agents Active on All Erythrocytic Forms, Including Gametocytes

ABSTRACT Malaria is the third most significant cause of infectious disease in the world. The search for new antimalarial chemotherapy has become increasingly urgent due to parasite resistance to classical drugs. Trioxaquines are synthetic hybrid molecules containing a trioxane motif (which is responsible for the antimalarial activity of artemisinin) linked to an aminoquinoline entity (which is responsible for the antiplasmodial properties of chloroquine). These trioxaquines are highly potent against young erythrocytic stages of Plasmodium falciparum and exhibit efficient activity in vitro against chloroquine-sensitive and -resistant strains of P. falciparum (50% inhibitory concentration, 4 to 32 nM) and are also active in vivo against P. vinckei petteri and P. yoelii nigeriensis in suppressive and curative murine tests. The trioxaquine DU1302 is one of these promising antimalarial agents. The present study confirms the absence of toxicity of this drug on cell lines and in a mice model. Moreover, DU1302 exhibits potent activity against gametocytes, the form transmitted by mosquitoes, as killing of the gametocytes is essential to limit the spread of malaria. The ease of chemical synthesis of this trioxaquine prototype should be considered an additional advantage and would make these drugs affordable without perturbations of the drug supply.

Preparation and Antimalarial Activities of “Trioxaquines”, New Modular Molecules with a Trioxane Skeleton Linked to a 4‐Aminoquinoline

Trioxaquines are new antimalarial drugs which combine two active fragments (an aminoquinoline and a trioxane) with independant modes of action covalently linked within a single molecule. This strategy, which can be characterized as a “covalent bitherapy”, allowed us to obtain modular molecules with high antimalarial activity in vitro either on chloroquine sensitive or on chloroquine resistant Plasmodium falciparum strains.

In Vitro Activities of DU-1102, a New Trioxaquine Derivative, against Plasmodium falciparum Isolates

ABSTRACT The antimalarial trioxaquine derivative DU-1102, synthesized by covalent linkage between aminoquinoline and trioxane moieties, was highly active against Cameroonian isolates (mean 50% inhibitory concentration of 43 nmol/liter) of Plasmodium falciparum. There was no correlation between the responses to DU-1102 and chloroquine and only a low correlation between the responses to DU-1102 and pyrimethamine, suggesting an independent mode of action of the trioxaquine against the parasites.

Effects of antimalarial molecules on the gametocyte stage of Plasmodium falciparum: the debate.

Although the illness malaria is caused by the asexual blood stages, the presence of gametocytes is directly responsible for the infection of the vector Anopheles, thus perpetuating the plasmodial cycle. Fight against malaria is more than ever a current problem, and the solution will probably go through the development of efficient molecules against gametocytes. Knowledge of the pharmacological properties of antiplasmodials is helpful in term of using relevant molecules to treat malaria and to eradicate this dramatic public health problem. The effects of the major antiplasmodial drugs including artemisinin-based combination therapies on gametocyte load are thus reviewed herein, making the difference whenever possible between the effects on gametocytogenesis and the gametocytocidal activity. Current status on the portfolio of the most promising anti-gametocytes compounds is also presented. A close analysis of the relationship between chemical structure and antiplasmodial activity should help the design of novel antimalarial drugs targeting Plasmodium sexual stages.

Predicting the substrate specificity of a glycosyltransferase implicated in the production of phenolic volatiles in tomato fruit

The volatile compounds that constitute the fruit aroma of ripe tomato (Solanum lycopersicum) are often sequestered in glycosylated form. A homology‐based screen was used to identify the gene SlUGT5, which is a member of UDP‐glycosyltransferase 72 family and shows specificity towards a range of substrates, including flavonoid, flavanols, hydroquinone, xenobiotics and chlorinated pollutants. SlUGT5 was shown to be expressed primarily in ripening fruit and flowers, and mapped to chromosome I in a region containing a QTL that affected the content of guaiacol and eugenol in tomato crosses. Recombinant SlUGT5 protein demonstrated significant activity towards guaiacol and eugenol, as well as benzyl alcohol and methyl salicylate; however, the highest in vitro activity and affinity was shown for hydroquinone and salicyl alcohol. NMR analysis identified isosalicin as the only product of salicyl alcohol glycosylation. Protein modelling and substrate docking analysis were used to assess the basis for the substrate specificity of SlUGT5. The analysis correctly predicted the interactions with SlUGT5 substrates, and also indicated that increased hydrogen bonding, due to the presence of a second hydrophilic group in methyl salicylate, guaiacol and hydroquinone, appeared to more favourably anchor these acceptors within the glycosylation site, leading to increased stability, higher activities and higher substrate affinities.

Phosphole-based ligands in catalysis

This review provides an overview of phosphole-based ligand families (monophospholes, multidentate hybrid phosphole ligands, diphospholes and 2,2′-biphosphole-based ligands) and their potential in metal- and organo-catalyzed reactions (asymmetric reactions included).

Accurate Measurement of the Photon Flux Received Inside Two Continuous Flow Microphotoreactors by Actinometry

Abstract In this study, the photon flux received in two continuous flow microphotoreactors was measured by actinometry (potassium ferrioxalate). The microphotoreactors had two different geometries and were irradiated by either a polychromatic or a monochromatic light source. A model considering the partial absorption of photons through the reactor depth and, if required, the polychromatic character of the light source and the dependence of the actinometer properties on the wavelength were formulated to describe the variation of the actinometer conversion with the irradiation time. The photon flux received in the microphotoreactors could be thus accurately calculated as a function of the emitted wavelength. The same methodology was then applied to measure the photon flux received in a batch immersion well photoreactor. The radiant power received in each photoreactor was compared to that emitted by the lamp and major differences were found, thus confirming the need for this kind of in situ measurement. Finally, some guidelines based on a knowledge of the photon flux were proposed to compare various photoreactors. They revealed in particular that the choice of the most efficient photoreactor depended on the criteria chosen to evaluate the performances (i.e. productivity, Space Time Yield).

Probing the stereo‐electronic properties of cationic rhodium complexes bearing chiral diphosphine ligands by 103Rh NMR

103Rh NMR represents a powerful tool to assess the global electronic and steric contribution of diphosphine ligands on [Rh(COD)(diphosphine)]+ complexes. In the case of DIOP, BINAP and MeDUPHOS, this approach proved to be more informative than classical CO‐stretching frequency measurements. After validation, this method has been extended to a set of seven diphosphines. 103Rh NMR measurements on [Rh(COD)(diphosphine)]PF6 lead to the following order of donor properties: dppe > MeBPE > MeDUPHOS > dppb > DIOP > BINAP > Tol‐BINAP. This trend has been validated by DFT in the case of DIOP, BINAP and MeDUPHOS. In conjunction, 31P NMR chemical shift has been shown to reflect the ring constraints of the Rh‐diphosphine scaffold. This contribution is a step towards a mechanistic investigation of the catalytic hydrogenation of unsaturated substrates by 103Rh NMR and DFT. Copyright

Synthesis and biological evaluation of a new trioxaquine containing a trioxane moiety obtained by halogenocyclisation of a hemiperoxyacetal

Abstract The preparation and the biological evaluation of a new antimalarial modular drug, named trioxaquine are reported. The trioxane moiety of this trioxaquine is prepared through the halogenocyclisation of a hemiperoxyacetal derived from the allylic hydroperoxide of 2,3-dimethyl-2-butene.

Synthesis and stereochemical study of a trioxaquine prepared from cis-bicyclo〚3.3.0〛octane-3,7-dione

Abstract The preparation of a modular antimalarial drug named trioxaquine containing a cis-bicyclo〚3.3.0〛octane-3,7-dione is reported. Two diastereomeric racemates have been separated and characterised by NMR.