L'objectif de ce travail consiste en la synthèse et l'évaluation antiparasitaire in vitro de nouveaux dérivés du thiazole et apparentés. Plusieurs stratégies de synthèse visant à une pharmacomodulation en séries mono- et polycycliques ont été étudiées : en série 2-méthyl-5-nitrothiazole, la pharmacomodulation anti-Trichomonas de la position 4 par stratégie SRN1 n'a pas permis d'améliorer l'activité déjà démontrée en série 2-méthyl-5-nitroimidazole, mais a conduit à des dérivés à activité antiproliférative in vitro, spécifique de la lignée HepG2. En série 4-arylsulfonylméthyl-2-méthylthiazole, la pharmacomodulation de la position 5, par couplage de Suzuki-Miyaura d'une part, et par arylation directe et réaction de Knoevenagel intramoléculaire d'autre part, a conduit à des dérivés mono- et polycycliques dont certains ont démontré une activité antiplasmodiale in vitro encourageante. En série 5H-thiazolo[3,2-a]pyrimidin-5-one, la réaction de double couplage de Suzuki-Miyaura a révélé l'importance du groupement phényle en position 6 pour l'activité antiplasmodiale de ces dérivés. Enfin, l'évaluation biologique in vitro de thiéno[3,2-d]pyrimidin-4(3H)-ones a permis de caractériser le pharmacophore responsable de l'activité antiplasmodiale significative de cette série. Les résultats préliminaires encourageants d'une étude mécanistique antiplasmodiale présentent l'inhibition spécifique des kinases plasmodiales comme un mécanisme d'action potentiel de ces composés. / The objective of this work consists of the synthesis and the antiparasitic in vitro evaluation of new thiazole derivatives and related structures. Several synthetic strategies aiming at the pharmacomodulation on mono- and polycyclic series have been studied: in 2-methyl-5-nitrothiazole series, the anti-Trichomonas pharmacomodulation on position 4 by SRN1 strategy did not improve the activity previously demonstrated in 2-methyl-5-nitroimidazole series, but led to derivatives displaying a selective in vitro antiproliferative activity toward the HepG2 cell line. In 4-arylsulfonylmethyl-2-methylthiazole series, the pharmacomodulation on position 5, by Suzuki-Miyaura cross-coupling reaction on the one hand, and by direct arylation and intramolecular Knoevenagel reaction on the other hand, led to mono- and polycyclic derivatives among which some displayed an encouraging in vitro antiplasmodial activity. In 5H-thiazolo[3,2-a]pyrimidin-5-one series, a double Suzuki-Miyaura cross-coupling reaction revealed that the phenyl group on position 6 contributes to the antiplasmodial effect of this series. Finally, the in vitro biological evaluation of the thieno[3,2-d]pyrimidin-4(3H)-one scaffold let to characterize the pharmacophore responsible for the significant antiplasmodial activity. Some preliminary encouraging results regarding a mechanistic antiplasmodial study show the specific inhibition of plasmodial kinases, as a potential mechanism of action of some of these compounds.

L'objectif de ce travail consiste en la synthèse de nouveaux 5-nitroimidazoles fonctionnalisés à visée thérapeutique. Dans un premier temps, l'étude de la réactivité du 4-bromo-1,2-diméthyl-5-nitro-1H-imidazole vis-à-vis du couplage de Suzuki-Miyaura sous irradiation micro-ondes a permis la synthèse de nouveaux produits substitués en position 4 par différents groupements aryle ou styryle. Dans un second temps, la réactivité LD-SRN1 a été étudiée entre le 4-[4-(chlorométhyl)phényl]-1,2-diméthyl-5-nitro-1H-imidazole et différents nucléophiles centrés sur l'atome de carbone ou de soufre. Cette étude a révélé l'importance de la température dans l'activation de la réaction par transfert monoélectronique. De nouveaux dérivés substitués en position 4 par divers groupements sulfonyles ont ensuite été synthétisés, par réactions SN2 et SNAr entre des dérivés 5-nitroimidazolés et différents anions sulfinates. Cette synthèse a été suivie par la mise au point de tests biologiques sur Trichomonas vaginalis. L'activité trichomonacide a été évaluée sur certaines de ces molécules, à l'origine de relations structure-activité montrant l'influence de la position du groupement sulfonyle substituant le noyau 5-nitroimidazole. La dernière partie de ce travail décrit une réaction de O-arylation pallado-catalysée inattendue et originale, d'un dérivé fluoré en série nitro(o-nitrophényl)imidazole impliquant des acides arylboroniques dans les conditions opératoires de la réaction de Suzuki-Miyaura. / The aim of this work consists of the synthesis of new potentially bioactive functionalized 5-nitroimidazoles. Initially, the reactivity study of the 4-bromo-1,2-dimethyl-5-nitro-1H-imidazole under microwave-assisted Suzuki-Miyaura cross-coupling conditions gave new derivatives substituted by various aryl or styryl groups in 4-position. In a second step the 4-[4-(chloromethyl)phenyl]-1,2-dimethyl-5-nitro-1H-imidazole was prepared in order to study LD-SRN1 reactivity with different carbon and sulphur centered nucleophiles. This study pointed the role of the temperature for the electron transfer reactions. Then, new 4-position sulfonyl substituted derivatives were synthesized by SN2 and SNAr reactions between sulfinate anions and three substrates in 5-nitroimidazole series. This synthesis was followed by the development of biological assays on Trichomonas vaginalis. This assay was performed on some of these molecules, which revealed a relation between the structure and the position of the sulfonyl group and the antitrichomonas activity. The last part of this work describes an unexpected and original palladium-catalyzed O-arylation in fluorinated nitro(o-nitrophenyl)imidazole series involving arylboronic acids under Suzuki-Miyaura cross-coupling reaction conditions.

L’accès à de nouveaux composés hétérocycliques originaux biologiquement actifs nécessite la mise au point de nouvelles méthodes de synthèse rapides et efficaces. Dans ce contexte, nous nous sommes intéressés à la réactivité des indazoles. Dans la première partie, nous avons étudié la sélectivité des couplages de type Suzuki, pour fonctionnaliser la position 3 d’indazoles possédant la fonction NH libre. Par la suite, un nouveau procédé d’(hétéro)arylation direct pallado-catalysé régiosélectif a été mis à profit pour synthétiser des indazoles fonctionnalisés tant sur la position 3 que sur le sommet 7. Nous avons ensuite montré la possibilité d’accéder à des entités disubstituées indazoliques en une seule étape, via une procédure "one-pot". Afin d’accroître la diversité autour du noyau indazole, nous avons mis au point une réaction d’alcénylation oxydative pallado-catalysée, des (2H)- et (1H)-indazoles sur les sommets C-3 et C-7. Pour exemplifier cette méthodologie, nous avons développé une synthèse en trois étapes du Gamendazole, composé actuellement en phase clinique pour la contraception masculine et ce, en utilisant l’alcénylation directe en C3 d’(1H)-indazoles convenablement fonctionnalisés. Le dernier volet de ce mémoire a été consacré à la préparation de composés à structure indazolique contenant une fonction sulfonamide afin de générer des librairies de dérivés substitués par un tel motif, dans le but de les tester biologiquement dans le domaine des anticancéreux. / Access to new biologically active compounds requires the development of new rapid and efficient methods for the synthesis of original heterocyclic scaffolds. In this context, we decided to focus particularly on the reactivity of indazoles. First, we studied the selectivity of Suzuki cross-coupling reaction to functionalize position 3 of the indazole with the free NH function. Indeed, we have described the first example of the direct and regioselective palladium-catalyzed (hetero)arylation of indazoles, the reaction may be induced to occur at either in position 3 and 7. We then showed the possibility of "one-pot" synthesis of disubstituted indazolic entities. Moreover, in order to increase diversity around the indazole scaffold, we developed a direct and regioselective alkenylation of (2H)- and (1H)-indazoles by oxidative palladium catalyzed at the C-3 and C-7, then we envisaged a three staps synthesis of Gamendazole, molecule currently in clinical phase for male contraception, by using the direct alkenylation at C3 of the suitably functionalized (1H)-indazoles. The last part of this report was dedicated to the preparation of indazoles containing a sulphonamide function, with the aim of biological testing them as potentially anti-cancer candidates.

The 2-aryl-6,8-dibromoquinazolin-4(3H)-ones were prepared in a single-pot operation by condensing 6,8-dibromoanthranilamide and aryl aldehydes in the presence of molecular iodine in ethanol. Treatment of the 2-aryl-6,8-dibromoquinazolin-4(3H)-ones with thionylchloride in the presence of dimethylformamide afforded the corresponding 2-aryl-4-chloro-6,8-dibromoquinazolines. Palladium(0)-copper iodide catalysed Sonogashira cross-coupling reaction of 2-aryl-4-chloro-6,8-dibromoquinazolines with terminal alkynes at room temperature afforded series of 2-aryl-6,8-dibromo-4-(alkynyl)quinazolines. Further transformation of the 2-aryl-6,8-dibromo-4-(phenylethynyl)quinazolines via Suzuki-Miyaura cross-coupling with arylboronic acids occurred without selectivity to afford the corresponding 2,6,8-triaryl-4-(phenylethynyl)quinazolines. The compounds were characterized using a combination of NMR (1H and 13C) and IR spectroscopic techniques as well as mass spectrometry. The absorption and emission properties of 2,6,8-triaryl-4-(phenylethynyl)quinazolines were determined in solution. / Chemistry / M.Sc. (Chemistry)

3,5-Dibromo-2-aminobenzamide was reacted with 1,3-cyclohexanedione derivatives in the presence of iodine as catalyst in toluene under reflux to afford novel 6,8-dibromo-2-[3-(2´-alkyl-1´,2´,3´,4´-tetrahydro-6´,8´-dibromo-4´-oxoquinazoline-2yl)propyl]quinazolin-4(3H)-ones in high yields. Suzuki-Miyaura cross-coupling of the latter with arylboronic acids in the presence of Pd(PPh3)2Cl2–Xphos catalyst complex and K2CO3 as a base in dioxane-water mixture (3:1, v/v) afforded the corresponding polyaryl-substituted bis-heterocycles in a single step operation. The resultant compounds were characterized using a combination of NMR (1H and 13C) and IR spectroscopic techniques, as well as mass spectrometry. The electronic absorption and emission properties of these polyaryl-substituted bis-heterocycles comprising 2,3-dihydroquinazolin-4(1H)-one and quinazolin-4(3H)-one moieties linked by a flexible carbon chain were measured in dimethylsulfoxide (DMSO) and acetic acid by means of UV-Vis and fluorescence spectroscopic techniques. The absorption spectra of the resultant polyaryl-substituted bis-heterocycles showed blue-shift in acetic acid and red-shift in DMSO, while their emission spectra are blue-shifted in DMSO and red-shifted in acetic acid. The 4-methoxy groups on aryl-substituents caused red shift on π‒π* transition of the aryl-substituents. Moreover, it was also observed that as the propyl linkage becomes more substituted, the absorption and emission intensities decrease. / Chemistry / M. Sc. (Chemistry)

3,5-Dibromo-2-aminobenzamide was reacted with 1,3-cyclohexanedione derivatives in the presence of iodine as catalyst in toluene under reflux to afford novel 6,8-dibromo-2-[3-(2´-alkyl-1´,2´,3´,4´-tetrahydro-6´,8´-dibromo-4´-oxoquinazoline-2yl)propyl]quinazolin-4(3H)-ones in high yields. Suzuki-Miyaura cross-coupling of the latter with arylboronic acids in the presence of Pd(PPh3)2Cl2–Xphos catalyst complex and K2CO3 as a base in dioxane-water mixture (3:1, v/v) afforded the corresponding polyaryl-substituted bis-heterocycles in a single step operation. The resultant compounds were characterized using a combination of NMR (1H and 13C) and IR spectroscopic techniques, as well as mass spectrometry. The electronic absorption and emission properties of these polyaryl-substituted bis-heterocycles comprising 2,3-dihydroquinazolin-4(1H)-one and quinazolin-4(3H)-one moieties linked by a flexible carbon chain were measured in dimethylsulfoxide (DMSO) and acetic acid by means of UV-Vis and fluorescence spectroscopic techniques. The absorption spectra of the resultant polyaryl-substituted bis-heterocycles showed blue-shift in acetic acid and red-shift in DMSO, while their emission spectra are blue-shifted in DMSO and red-shifted in acetic acid. The 4-methoxy groups on aryl-substituents caused red shift on π‒π* transition of the aryl-substituents. Moreover, it was also observed that as the propyl linkage becomes more substituted, the absorption and emission intensities decrease. / Chemistry / M. Sc. (Chemistry)

The 2-aryl-6,8-dibromoquinazolin-4(3H)-ones were prepared in a single-pot operation by condensing 6,8-dibromoanthranilamide and aryl aldehydes in the presence of molecular iodine in ethanol. Treatment of the 2-aryl-6,8-dibromoquinazolin-4(3H)-ones with thionylchloride in the presence of dimethylformamide afforded the corresponding 2-aryl-4-chloro-6,8-dibromoquinazolines. Palladium(0)-copper iodide catalysed Sonogashira cross-coupling reaction of 2-aryl-4-chloro-6,8-dibromoquinazolines with terminal alkynes at room temperature afforded series of 2-aryl-6,8-dibromo-4-(alkynyl)quinazolines. Further transformation of the 2-aryl-6,8-dibromo-4-(phenylethynyl)quinazolines via Suzuki-Miyaura cross-coupling with arylboronic acids occurred without selectivity to afford the corresponding 2,6,8-triaryl-4-(phenylethynyl)quinazolines. The compounds were characterized using a combination of NMR (1H and 13C) and IR spectroscopic techniques as well as mass spectrometry. The absorption and emission properties of 2,6,8-triaryl-4-(phenylethynyl)quinazolines were determined in solution. / Chemistry / M.Sc. (Chemistry)

The known 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones 122 were dehydrogenated using thallium(III) p-tolylsulfonate in dimethoxyethane under reflux to afford the 2-aryl-6,8-dibromoquinolin-4(1H)-ones 136. Palladium-catalyzed Sonogashira cross-coupling of the 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones with terminal alkynes in the presence of PdCl2(PPh3)2-CuI (as homogeneous catalyst source) and 10% Pd/C-PPh3-CuI (as heterogeneous catalyst source) catalyst mixture and NEt3 as a base and co-solvent in ethanol under reflux afforded the corresponding 6,8-dialkynyl-2-aryl-2,3-dihydroquinolin-4(1H)-ones 138 and 8-alkynyl-2-aryl-6-bromo-2,3-dihydroquinolin-4(1H)-ones 137, respectively. PdCl2-catalyzed electrophilic cyclization of the 8-alkynyl-2-aryl-6-bromo-2,3-dihydroquinolin-4(1H)-ones in acetonitrile under reflux afforded the 4-aryl-8-bromo-2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 139 or the 2-aryl-6-bromo-8-(4-hydroxybutanoyl)-2,3-dihydroquinolin-4(1H)-ones 140 from the 4-phenylethynyl-substituted or 4-alkylethynyl-substituted precursors, respectively. The 2-aryl-6,8-dibromoquinolin-4(1H)-ones 136 wturn, subjected to similar homogeneous and heterogeneous palladium catalyst sources using NEt3 as a base in DMF-water mixture under reflux and K2CO3 as a base in dioxane under reflux afforded 2,8-disubstituted 4-aryl-6-oxopyrrolo[3,2,1-ij]quinolines 143 and 2-substituted 4-aryl-8-bromo-6-oxopyrrolo[3,2,1-ij]quinolines 142, respectively. The monoalkynylated 4-aryl-8-bromo-2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 139 and 2-substituted 4-aryl-8-bromo-6-oxopyrrolo[3,2,1-ij]quinolines 142 were subsequently transformed using palladium-catalyzed Suzuki-Miyaura cross-coupling with arylboronic acids in the presence of PdCl2(PPh3)2-PCy3 catalyst mixture and K2CO3 as a base in dioxane-water mixture to afford the corresponding novel 8-substituted 2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 141 and 2,8-disubstituted 4-aryl-6-oxopyrrolo[3,2,1-ij]quinolines 144, respectively. All the new compounds were characterized using a combination of 1H NMR, 13C NMR, IR, mass spectroscopic techniques and X-ray crystallography. / Chemistry / D. Phil. (Chemistry)