Ces travaux de thèse ont porté sur la conversion catalytique de l'acide aconitique (un co-produit de la filière canne à sucre) en molécules d'intérêt industriel. Par deux voies catalytiques. 1) Par catalyse homogène, hydrogénation de l'acide en polyols, a été étudiée dans un réacteur Batch à l'aide d'un complexe catalytique actif à base de Ru [Ru(acac)3/Triphos]. L'optimisation des différents paramètres réactionnels a été effectuée sur une réaction modèle, l'hydrogénation de l'acide succinique en 1,4-butanediol. Ultérieurement, ces conditions réactionnelles optimales ont été utilisées pour l'hydrogénation de l'acide aconitique et ont permis l'obtention d'un produit majoritaire, le 2-méthyl 1,4-butanediol. 2) Par catalyse hétérogène, la réaction d'hydro-cyclisation de l'acide aconitique en MTHF ou en lactones, a été réalisée en réacteur continue en présence de catalyseurs à base de cuivre en partant de solutions d'acide aconitique dans l'éthanol. Les conditions de test catalytiques et la synthèse du catalyseur ont été optimisées. Les caractéristiques des différents catalyseurs testés ont été réalisées en faisant recours à des techniques analytiques complémentaires (SBET, Analyse chimique, DRX, XPS et MET) afin de corréler les propriétés de surface à l'activité catalytique / This thesis is focused on the catalytic conversion of aconitic acid (a co-product of sugarcane industry) into molecules of industrial interest, by two catalytic ways. 1) By homogeneous catalysis, the acid hydrogenation into polyols, was carried out in a batch reactor using a Ru complex [Ru(acac)3/Triphos]. The various reaction parameters was optimized in the model reaction of hydrogenation of succinic acid into 1.4-butanediol. Subsequently, these optimal reaction conditions were used for the hydrogenation of aconitic acid and resulted to a predominant formation of 2-methyl 1,4-butanediol. 2) By heterogeneous catalysis, the hydro-cyclization reaction of aconitic acid into MTHF or lactones, was performed in a continuous reactor in the presence of copper catalysts, using aconitic acid solutions in ethanol as substrate. The different conditions of the catalytic test and catalyst synthesis was optimized. Furthermore, the different catalysts tested in this thesis work was characterized using complementary techniques (BET, Elementary analysis, XRD, XPS and TEM) in order to correlate the superficial properties to the catalytic activity

Thymidylate synthase (TS), encoded by the ThyA gene, is essential for the growth and survival of Mycobacterium tuberculosis and therefore is a potential drug target. Thymidylate synthase binds both a substrate, 2'-deoxyuridine-5'monophosphate (dUMP) as well as a cofactor, (6R,S)-5,10-methylenetetrahydrofolate (mTHF), providing the ability to inhibit a single target by two separate classes of molecules. 5'-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) is a very tight binding mechanism based inhibitor, shown to have a Ki of 2nM for Mtb TS. Pemetrexed and Raltitrexed are both anti-folates, targeting the cofactor binding site of thymidylate synthase. The x-ray crystal structures of Mycobacterium tuberculosis thymidylate synthase were solved in the binary complexes ThyA-dUMP and ThyA-FdUMP at 2.5 A and 2.4 A resolutions, respectively. The ternary complex, ThyA-dUMP-Pemetrexed was solved to a resolution of 1.7 A. The enzyme is comprised of 8 alpha-helices as well as 23% of the protein formed by beta-sheets, including the dimer interface which is a beta-sandwich. Examination of the dUMP binding site allowed the identification of key conserved residues that play a role in ligand binding and catalysis. Comparison of the dUMP-Pemetrexed ternary complex with that of the human crystal structure shows two fewer interactions in the Mtb enzyme. One is due to the replacement of a Met with a Val which doesn't allow hydrophobic interactions with the ring system of Pemetrexed, and the other is the replacement of an Asn with a Trp, depriving the Mtb protein of a hydrogen bond at the N7 of the pyrrolo ring. A spectrophotometric assay that monitored DHF formation was used to determine the inhibition of Pemetrexed and Raltitrexed on Mtb TS. Both were verified as noncompetitive inhibitors, and Pemetrexed was found to have an IC50 of 17muM and a Ki of 16.8muM, while Raltitrexed had an IC50 of 3.5muM and a Ki of 3.2muM.