Made available in DSpace on 2015-05-14T13:21:06Z (GMT). No. of bitstreams: 1 parte1.pdf: 1561006 bytes, checksum: 92830d9ef59f992edaa0a7616cdb4412 (MD5) Previous issue date: 2011-03-30 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / This study was conducted in order to develop the synthesis of new Morita-Baylis-Hillman adducts of (MBHA) water soluble (29-34) with potential parasitic activity, using glycerol (1) as raw material. Two synthetic routes were carried out producing twelve new MBHA (23 - 34), six of which have hydrophilic characteristics 29-34 (main target of the work) and six more hydrophobic 23 28 (as synthesis intermediates), and these intermediaries are also important for comparative studies of structure and biological activity (SAR). Starting from glycerol (1), we synthesize the 2,2-dimethyl-1,3-dioxolan-4-yl)methyl acrylates (21, 94%) and from this, two synthetic routes were investigated to produce the 29- 34 adducts. On Route 1, the adducts 29-34 were produced in one-step (54 - 82%) from the Michael acceptor 2,3-dihydroxypropyl acrylate 22, which was prepared in 100% yield from 21. In route 2, MBHA intermediates 23 - 28 were prepared directly from 21 (90 - 100%) and these adducts were subsequently processed in adducts 29-34 (70 - 90%). In the synthesis of adduct 32 was observed the formation of the Michael addition product 47 and Indolizines unprecedented 48 as co-products of synthesis and characterized only by CGMS during the synthetic route 2. All syntheses in this work were developed in industry standards convenient. The activation reaction by microwave irradiation (MW) was widely used in most steps of this synthetic work, leading to high chemical yields and reduced reaction times. / Este trabalho foi realizado no intuito de desenvolver a síntese de novos adutos de Morita-Baylis-Hillman (AMBH) hidrossolúveis (29-34) com potenciais atividades antiparasitárias, usando o glicerol (1) como matéria-prima. Duas rotas sintéticas foram desenvolvidas conduzindo a doze AMBH inéditos (23 - 34), dos quais seis possuem as características hidrofílicas 29-34 (alvo principal do trabalho) e as outras seis mais hidrofóbicas 23 - 28 (como intermediários de síntese), sendo que estes intermediários são também importantes para estudos comparativos entre estrutura e atividades biológicas (SAR). Partindo do glicerol (1), sintetizamos o acrilato de 2,2-dimetil-1,3-dioxalila (21, 94%) e a partir deste, duas rotas sintéticas foram investigadas para os adutos-alvo 29- 34. Na rota 1, os adutos 29-34 foram produzidos em uma única etapa sintética (54 - 82%) a partir do aceptor de Michael acrilato de 2,3- dihidroxipropila 22, que foi preparado em 100% de rendimento a partir de 21. Na rota 2, os AMBH intermediários 23 28 foram preparados em 90 - 100% diretamente de 21 e estes adutos foram subseqüentemente transformados nos adutos 29-34 (70 - 90%). Na síntese do aduto 32 foi observado a formação do produto de adição de Michael 47 e da indolizina inédita 48 como co-produtos de síntese e caracterizados apenas por CGMS, durante a rota sintética 2. Todas as sínteses neste trabalho foram desenvolvidas em padrões convenientes a indústria. A ativação reacional por irradiação de microondas (MO) foi amplamente utilizada na maioria das etapas sintéticas deste trabalho, conduzindo aos altos rendimentos químicos e aos tempos reacionais reduzidos.

Neste trabalho investigou-se a oxidação de álcoois (etanol e glicerol) em meio alcalino empregando diferentes catalisadores de metais nobres suportados em carbono Vulcan preparados através da síntese de irradiação de micro-ondas, para aplicação em dispositivos de células a combustível. Neste âmbito, catalisadores suportados em carbono na razão metal:carbono de 40:60 % foram preparados com dois metais nobres: catalisadores a base de Pt(PtM/C, M=Sn, Ru e Ni); e catalisadores a base de Pd(PdM/C, M=Sn, Ru, Ni, Rh, Fe e Mn). Os resultados de EDX revelaram que todos os catalisadores apresentam composições experimentais próximas às nominais. Todos os catalisadores apresentaram características dos respectivos metais nobres; geometria cúbica de face-centrada. Catalisadores de Pd54Fe46/C, Pd71Ru29/C também apresentaram fases isoladas dos óxidos de rutênio e ferro,a fase de Pd2Sn também está presente nos catalisadores contendo Sn. Cristalitos e partículas na ordem de 2 a 7 nm foram observados. Dentre os diversos catalisadores estudados para a oxidação de etanol ([Etanol]=1,0 mol L-1 + [NaOH]=1,0 mol L-1), o catalisador Pt45Sn55/C apresentou maior atividade, formando ácido acético e acetaldeído em quantidade superiores aos demais catalisadores. Já para catalisadores a base de Pd, Pd54Fe46/C e Pd63Sn37/C apresentaram resultados eletroquímicos muito semelhantes, porém, em relação aos produtos formados durante a eletrólise, o catalisador Pd54Fe46/C formou 3 vezes mais ácido acético(4 elétrons). Para a eletro-oxidação de glicerol em meio alcalino ([Glicerol]=0,5 mol L-1 + [NaOH]=1,0 mol L-1), o catalisador Pt86Ru14/C foi o que apresentou os maiores valores de atividades catalíticas. Os principais produtos formados durante as eletrólises de glicerol foram ácido glicérico, ácido tartrônico, 1,3-dihidroxiacetona (DHA), a quantidade de produtos formados pelo catalisador Pt86Ru14/C foi, aproximadamente, três vezes superiorao catalisador Pt/C. A formação de um produto de maior valor agregado, 1,3-DHA, é interessante do ponto de vista eletrossíntético. A seguinte ordem de reatividade é observada para os catalisadores de Pd: PdRu/C >PdFe/C >PdMn/C >PdRh/C >PdSn/C. Dentre os produtos formados na oxidação de glicerol somente para os catalisadores PdRh/C e PdFe/Cidentificou-se ácido tartrônico (6 elétrons) e 1,3-DHA (2 elétrons) / In this thesis it was investigated ethanol and glycerol oxidation in alkaline medium using different noble metal catalysts supported on Vulcan carbon prepared by microwave irradiation synthesis, for application in fuel cell devices. In this context, catalysts in the ratio metal:carbon 40:60% were prepared using two noble metals: Pt-based catalysts (PtM/C, M = Sn, Ru and Ni); and Pd-based catalysts (PdM/C, M = Sn, Ru, Ni, Rh, Fe and Mn). The experimental compositions obtained by EDX were close to nominal values. All the catalysts exhibited cubic face-centered geometry characteristics of its respective noble metal. Catalysts Pd54Fe46/C and Pd71Ru29/C also presented of iron and ruthenium oxides phases, Pd2Sn phase is also observed for Pd61Sn39/C catalyst. Particles and crystallites around 2 to 7 nm were observed. Among all catalysts studied for ethanol electro-oxidation ([Ethanol]=1.0 mol L-1 + [NaOH]=1.0 mol L-1), Pt45Sn55/C catalyst was the most active, the yield of acetic acid and acetaldehyde are higher for this composition. Pd-based catalysts, Pd54Fe46/C and Pd61Sn39/C showed very similar electrochemical behavior; however, for Pd54Fe46/C catalyst the amount of acetic acid (4 electrons) formed are three times higher. Pt86Ru14/C catalyst presented the highest catalytic activities for glycerol electro-oxidation ([glycerol]=0.5 mol L-1 + [NaOH]=1.0 mol L-1). The main products formed during glycerol electrolysis were glyceric acid, tartronic acid, 1,3-dihydroxyacetone (DHA), the amount of products formed employing Pt86Ru14/C catalyst was almost three times higher than Pt/C catalyst. The formation of a product with higher added-value, 1,3-DHA, is interesting in electro-synthetic point of view. The reactivity order were observed for Pd catalysts are: PdRu/C > PdFe/C > PdMn/C > PdRh/C > PdSn/C. Tartronic acid (6 electrons) and 1,3-DHA (2 electrons) were only identified at PdRh/C and PdFe/C catalysts

Conselho Nacional de Desenvolvimento Científico e Tecnológico / The synthesis of a series of 1-aryl-4-[(dimethylamino)methylene] pyrrolidine- 2,3,5-trione from the cyclocondensation reaction between b-enaminodiketone [Cl3C(O)C(=CHNMe2)C(O)CO2Et] and aniline derivatives [R = Ph, 3-Me-C6H4, 3- MeO-C6H4, 3-HO-C6H4, 4-Me-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-O2N-C6H4, 4- MeCO-C6H4] was performed. The reaction conditions used to synthesize the pyrrolidine-2,3,5-triones involved environmentally benign techniques, as the use of microwave irradiation, employing the reactants b-enaminodiketone and amine in a molar ratio of 1:1.1, respectively, and a non-halogenated solvent. The reaction was carried out with short time (12-16 min) and the products were obtained in moderate to good yields (50- 76%). In addition, the advantages of using the microwave irradiation method in comparison to the conventional thermal heating were demonstrated. / A síntese de uma série de 4-(dimetilamino)metileno-1-aril-pirrolidino-2,3,5-triona foi realizada a partir da reação de ciclocondensação da b-enaminodicetona [Cl3C(O)C(=CHNMe2)C(O)CO2Et] com derivados da anilina [R = Ph, 3-Me-C6H4, 3- MeO-C6H4, 3-HO-C6H4, 4-Me-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-O2N-C6H4, 4- MeCO-C6H4]. As condições reacionais utilizadas para a síntese das pirrolidino-2,3,5- trionas envolveram técnicas ambientalmente corretas, como o uso de irradiação de micro-ondas, empregando uma relação molar da b-enaminodicetona e da amina de 1:1.1, respectivamente e solvente não halogenado. A reação foi realizada em curtos períodos de reação (12-16 min) e os produtos foram obtidos com rendimentos de moderados a bons (50-76%). Além disso, foram demonstradas as vantagens da utilização do método de irradiação de micro-ondas sobre o método convencional de aquecimento térmico.

The base-catalysed reaction of 4H-pyran-4-one with a range of nucleophiles, namely diethyl malonate, ethyl acetoacetate, nitromethane, acetylacetone and ethyl cyanoacetate, was developed as a reliable, high yielding method for the preparation of para-substituted phenols. The methodology was extended to include the use of the substituted pyranones, maltol, 2,6-dimethyl-4H-pyran-4-one and diethyl chelidonate. Reactions were studied using conventional heating methods and microwave irradiation. Microwave irradiation had definite beneficial effects, with improved yields, reduced reaction times and cleaner reaction profiles. The potential of this methodology was examined for the regioselective placement of ¹³C-atoms into benzene rings using ¹³C-labelled nucleophiles or ¹³C-labelled 4H-pyran-4-ones. [3,5-13C₂]4H-Pyran-4-one and [2,6-13C₂]4H-pyran-4-one were prepared from various ¹³C-labelled versions of triethyl orthoformate and acetone. This methodology was applied to the synthesis of [1,3,5-¹³C₃]gallic acid, via the base-catalysed reaction of [3,5-¹³C₂]4H-pyran-4-one with diethyl [2-¹³C]malonate, followed by subsequent transformations to yield [1,3,5-¹³C₃]gallic acid. The preparation of [2-¹³C]phloroglucinol was carried out via [2-¹³C]resorcinol, with regioselective placement of a single ¹³C-atom into the aromatic ring. This was accomplished from non-aromatic precursors, with the source of the ¹³C-atom being [¹³C]methyl iodide. The key step in this synthesis was the introduction of the third hydroxyl group, which was achieved using a modified iridium-catalysed C-H activation/borylation/oxidation procedure. The scope of an existing C-H activation/borylation reaction was modified and expanded to include a range of protected resorcinol derivatives. A catalyst system was developed which allowed high conversion to the intermediate arylboronic acids, followed by oxidation using aqueous Oxone® to yield the corresponding phenols. Finally, to demonstrate the potential of these new methods for application in the synthesis of isotopically labelled natural products and polyphenols, the syntheses of ¹³C-labelled anthocyanins were studied. A route was developed that could be applied to the synthesis of either cyanidin-3-glucoside or delphinidin-3-glucoside. Only the final coupling/cyclisation step to yield the desired anthocyanin targets remains to be carried out.

Le présent mémoire est subdivisé en deux principaux sujets. Le premier porte sur le développement d’une hydrolyse de thiazolidines assistée par micro-ondes en vue d’obtenir des cystéines a-substituées. Le second est axé sur le développement d’une méthodologie pour la synthèse catalytique énantiosélective d’alkylidènecyclopropanes 1,1-di-accepteurs. Dans un premier temps, les rôles et les utilités des acides aminés quaternaires, plus spécifiquement des cystéines a-substituées, seront abordés, puis une revue des différentes méthodes énantiosélectives pour accéder à ces unités sera effectuée. Par la suite, le développement d’une méthode rapide et efficace d’hydrolyse sous irradiation aux micro-ondes de thiazolines sera présenté. Finalement, les études menant à l’application de cette méthode à la synthèse de cystéines -substituées sur grande échelle au moyen de réacteurs en écoulement dynamique et à haut criblage seront détaillées. Dans la seconde partie, les applications ainsi que les synthèses générales des alkylidènecyclopropanes en synthèse organique seront décrites. Plus particulièrement, les applications spécifiques des alkylidènecyclopropanes 1,1-di-accepteurs ainsi que leurs synthèses seront traitées de manière exhaustive. Par la suite, le développement d’une méthodologie énantiosélective catalytique pour la synthèse d’alkylidènecyclopropanes 1,1-di-accepteurs sera présenté. L’extension de cette méthodologie à la synthèse de dérivés cyclopropanes et cyclopropènes, ainsi que l’application de réactions stéréospécifiques pour les alkylidènecyclopropanes 1,1-di-accepteurs seront brièvement discutées. / The present M.Sc. thesis will be divided into two main subjects. The first part will be focused on the development of an efficient microwave-assisted hydrolysis of thiazolidines for the synthesis of a-substituted cysteines. The second part will be on the development of methodology for the asymmetric synthesis of 1,1-di-acceptor alkylidenecyclopropanes. First, the role and the importance of quaternary amino acids, more specifically of a-substitued cysteines, will be described, then a review of the available enantioselective methods for their syntheses will be reported. Afterward, the development of a fast and efficient microwave-assisted hydrolysis of thiazolidines will be presented. Finally, the studies toward the applicability of the methodology for the multi-gram synthesis of -substituted cysteines using flow and high-throughput reactors will be detailed. In the second part, the general applications and syntheses of alkylidenecyclopropanes will be described. More specifically, the applications of 1,1-di-acceptor alkylidenecycloproanes as well as their syntheses will be exhaustively covered. Then, the development of a catalytic enantioselective methodology for the synthesis of di-acceptor alkylidenecyclopropanes will be presented. The extension of this methodology for the synthesis of cyclopropane and cyclopropene derivatives, as well as the applications of 1,1-diacceptor alkylidenecyclopropane in stereospecific derivatizations will be briefly discussed.

En aquesta tesi doctoral es va estudiar la preparació de pèptids biarílics en fase sòlida. En primer lloc, es varen borilar residus de fenilalanina o tirosina presents a la seqüència peptídica a través d’una reacció de Miyaura. A continuació, es varen arilar els boronats resultants a través d’una reacció de Suzuki-Miyaura sota irradiació de microones, utilitzant diversos halurs d’aril i haloaminoàcids. La metodologia trobada es va estendre a la preparació de pèptids biarílics cíclics. Aquesta aproximació presenta l’avantatge d’evitar la síntesi en dissolució i la purificació del boronoaminoàcid. A més, permet la preparació d’una àmplia diversitat de pèptids biarílics a partir d’un únic boronopèptid. L’avaluació de l’activitat biològica dels pèptids sintetitzats va permetre idenficar seqüències actives enfront dels bacteris Erwinia amylovora, Xanthomonas vesicatoria, i Pseudomonas syringae, que són responsables de malalties greus en plantes d’interès econòmic com pereres i pomeres, i que varen resultar ser molt poc tòxics enfront cèl•lules eucariotes. / The present PhD study was focused on the preparation of biaryl peptides on solid-phase. First, phenylalanine or tyrosine residues were borylated through a Miyaura reaction. Then, the resulting boronates were arylated via a Suzuki-Miyaura reaction under microwave irradiation, using a range of aryl halides and haloamino acids. This methodology was extended to the solid-phase synthesis of biaryl cyclic peptides. This strategy is advantageous because it avoids the synthesis and purification of amino acid boronates in solution. Moreover, it allows the preparation of a large diversity of biaryl peptides from a single boronopeptide intermediate. The evaluation of the biological activity allowed the identification of active sequences against the economically important plant pathogenic bacteria Erwinia amylovora, Xanthomonas vesicatoria, and Pseudomonas syringae, and moreover they were not toxic against eukaryotic cells.

Le présent mémoire est subdivisé en deux principaux sujets. Le premier porte sur le développement d’une hydrolyse de thiazolidines assistée par micro-ondes en vue d’obtenir des cystéines a-substituées. Le second est axé sur le développement d’une méthodologie pour la synthèse catalytique énantiosélective d’alkylidènecyclopropanes 1,1-di-accepteurs. Dans un premier temps, les rôles et les utilités des acides aminés quaternaires, plus spécifiquement des cystéines a-substituées, seront abordés, puis une revue des différentes méthodes énantiosélectives pour accéder à ces unités sera effectuée. Par la suite, le développement d’une méthode rapide et efficace d’hydrolyse sous irradiation aux micro-ondes de thiazolines sera présenté. Finalement, les études menant à l’application de cette méthode à la synthèse de cystéines -substituées sur grande échelle au moyen de réacteurs en écoulement dynamique et à haut criblage seront détaillées. Dans la seconde partie, les applications ainsi que les synthèses générales des alkylidènecyclopropanes en synthèse organique seront décrites. Plus particulièrement, les applications spécifiques des alkylidènecyclopropanes 1,1-di-accepteurs ainsi que leurs synthèses seront traitées de manière exhaustive. Par la suite, le développement d’une méthodologie énantiosélective catalytique pour la synthèse d’alkylidènecyclopropanes 1,1-di-accepteurs sera présenté. L’extension de cette méthodologie à la synthèse de dérivés cyclopropanes et cyclopropènes, ainsi que l’application de réactions stéréospécifiques pour les alkylidènecyclopropanes 1,1-di-accepteurs seront brièvement discutées. / The present M.Sc. thesis will be divided into two main subjects. The first part will be focused on the development of an efficient microwave-assisted hydrolysis of thiazolidines for the synthesis of a-substituted cysteines. The second part will be on the development of methodology for the asymmetric synthesis of 1,1-di-acceptor alkylidenecyclopropanes. First, the role and the importance of quaternary amino acids, more specifically of a-substitued cysteines, will be described, then a review of the available enantioselective methods for their syntheses will be reported. Afterward, the development of a fast and efficient microwave-assisted hydrolysis of thiazolidines will be presented. Finally, the studies toward the applicability of the methodology for the multi-gram synthesis of -substituted cysteines using flow and high-throughput reactors will be detailed. In the second part, the general applications and syntheses of alkylidenecyclopropanes will be described. More specifically, the applications of 1,1-di-acceptor alkylidenecycloproanes as well as their syntheses will be exhaustively covered. Then, the development of a catalytic enantioselective methodology for the synthesis of di-acceptor alkylidenecyclopropanes will be presented. The extension of this methodology for the synthesis of cyclopropane and cyclopropene derivatives, as well as the applications of 1,1-diacceptor alkylidenecyclopropane in stereospecific derivatizations will be briefly discussed.

Les phosphatases CDC25 sont des éléments-clé de la régulation du cycle cellulaire chez les eucaryotes; elles activent par une double déphosphorylation les complexes CDK/cyclines permettant ainsi la progression dans les différentes phases du cycle. Leur sur-expression, observée dans des cancers très fréquents, est corrélée à une forte agressivité des tumeurs et un mauvais pronostic ce qui en fait des cibles d’intérêt en cancérologie. Deux nouvelles séries d’inhibiteurs ont été développées à partir d’une thiazolopyrimidinone (TZP), capable d’inhiber l’activité des CDC25, et préalablement identifiée par l’équipe. La première série a été obtenue par dimérisation de deux noyaux thiazolones conduisant à des inhibiteurs avec des CI50 de l’ordre du micromolaire sur CDC25B plus actifs que les mono-thiazolones, ces composés étant sélectifs vs PTP1B et VHR. De plus, ces dimères semblent interagir avec le site actif et la poche de liaison des inhibiteurs. Une deuxième série d’analogues de thiazolidin-4-one a été obtenue par simplification de la structure TZP. Une réaction à quatre composants, utilisant l’énergie micro-onde, a été développée pour préparer rapidement des inhibiteurs de CDC25B avec des CI50 de l’ordre du micromolaire. Enfin, une approche originale pour inhiber CDC25 en ciblant l’interaction CDC25/CDK-Cycline a débutée. Un crible in silico/in vitro sera réalisé afin d’identifier de petites molécules inhibitrices de cette interaction. Des études préliminaires pour la mise en place d’outils permettant l’évaluation de l’affinité de ces molécules pour le site de reconnaissance de CDK2 ont été engagées. / CDC25 phosphatases are key regulators of the cell cycle and its checkpoints. Hence, they are required to dephosphorylate and thus activate the Cdk/Cyclin complexes triggering progression through the different phases. Over-expression of CDC25 has been demonstrated in a large number of human tumors and is often associated with aggressiveness and poor clinical prognosis. CDC25 phosphatases may therefore represent attractive targets for anti-cancer therapy. Starting from a thiazolopyrimidinone (TZP) structure, previously reported as CDC25 inhibitor in our laboratory, two series of new compounds have been developed. Dimerisation of the thiazolone scaffold led to bis-thiazolone derivatives with inhibitory activities in the micromolar range greater than that observed for the mono-thiazolones. Moreover, most of these compounds were selective CDC25 inhibitors. A second scaffold was designed by opening of the pyrimidine ring of the TZP, leading to thiazolidine-4-one derivatives that inhibit CDC25B activities with values of IC50 in the micromolar range. A four-component reaction, using micro-wave irradiation, was developed to rapidly prepare these compounds. Finally, an approach aiming at inhibiting the interactions between phosphatase CDC25 and its substrate CDK2 was engaged. Several virtual chemical libraries will be screened in silico, and the small molecules candidates selected will be assessed for their binding affinity using an in vitro assay, that we sought to develop.

Ce manuscrit de thèse concerne le développement d'une stratégie de synthèse multi-étapes de nouveaux composés comportant plusieurs plateformes hétérocycliques (rhodanine, benzimidazole, pyrazole et imidazole) à visée thérapeutique multiple contre la malaria, la leishmaniose, le cancer et les maladies neurodégénératives. Les pharmacomodulations de ces composés ont été élaborées sur la base du modèle de la pentamidine 35 comportant 2 motifs benzamidines (parties « Ouest » et « Est »). En effet, la substitution de sa partie « Ouest » par une plateforme rhodanine ou benzimidazole et de sa partie « Est » par un système aromatique plan ou système azole (pyrazole, imidazole) a permis d’accéder respectivement aux 5-arylidènes rhodanines (50, 58), aux dérivés ''aza'' (99,100) et aux dérivés ''aza azoles'' 174 qui sont des analogues de la pentamidine. Les rendements de ces composés sont respectivement compris entre 26 et 98%, 10 et 93% et 10 et 97%. L’ensemble des composés synthétisés dans les chapitres II, III et IV de ces travaux ont été l'objet d'évaluations pour leur activité antiproliférative sur les lignées cellulaires et pour leur activité inhibitrice sur les protéines kinases. / This thesis manuscript is focused on the development of multi-steps synthesis strategy of new compounds bearing several heterocyclic platforms (rhodanine, benzimidazole, pyrazole and imidazole) for multiple therapeutic use to fight malaria, leishmaniasis, cancer et neurodegenarative diseases. The pharmacomodulations of these compounds were developped from the design of pentamidine 35 which containins 2 fragments benzamidine (parts ''West'' and ''East''). Indeed, the substitution of its part ''West'' by a platform rhodanine or benzimidazole and its part ''East'' by an "azole" aromatic ring system (pyrazole, imidazole) lead respectively to 5-arylidene rhodanines (50, 58), to derivatives ''aza'' (99,100) and to derivatives ''aza azoles'' 174 which are pentamidine analogs. The chemical yields of these compounds are ranging respectively from 26 to 98%, 10 to 93% and 10 to 97%. All the compounds synthesized in the chapters II, III and IV of this research work were evaluated for their antiproliferative activity on tumoral cell lines and for their inhibitory activity on protein kinases.

Les effets du dérèglement de l’expression des protéines kinases DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) et plus particulièrement de DYRK1A sont étudiées dans le cas des maladies neurodégénératives (maladie d’Alzheimer, syndrome de Down) et celui de certains cancers. Ces travaux de thèse s’inscrivent dans la continuité des acquis du laboratoire et des résultats des évaluations de l’activité inhibitrice obtenus sur les thiazolo[5,4-f]quinazolines et les thiazolo[5,4-f]quinazolin-9(8H)-ones. L’objectif principal est la modulation du groupement en position C2 des thiazolo[5,4-f]quinazolin-9(8H)-ones en faisant varier la taille et la nature des substituants afin de former des inhibiteurs potentiels sélectifs de DYRK1A. Le premier chapitre de ce manuscrit concerne l’addition de nucléophiles originaux tels que des acides aminés sur la fonction nitrile en position C2 de la 8-benzylthiazolo[5,4-f]quinazolin-9(8H)-one. Le second chapitre décrit l’optimisation de la synthèse des thiazolo[5,4-f]quinazolin-9(8H)-ones ainsi que l’arylation directe ces motifs. La réaction de débenzylation des dérivés C2-arylés et la fonctionnalisation par C–H alcénylation de la 8-benzylthiazolo[5,4-f]quinazolin-9(8H)-one sont aussi décrites dans cette partie. Le troisième chapitre concerne l’évaluation de l’activité biologique de la plupart des composés synthétisés au cours de ces travaux, révélant le FC162 en tant qu’inhibiteur de DYRK1A. Ces résultats ont conduit à la modulation en position C2 de motifs plus simples : les benzo[d]thiazoles, permettant d’étudier la régiosélectivité du 6-aminobenzo[d]thiazole-2,7-dicarbonitrile et l’arylation directe de ces dérivés bicycliques. / The effects of expression modulation of protein kinases DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) and especially of DYRK1A are characterized in a variety of diseases including neurodegenerative diseases (Alzheimer’s disease or Down syndrome) and cancers. This thesis deals with our laboratory knowledge and previous results obtained with thiazolo[5,4-f]quinazolines and thiazolo[5,4-f]quinazolin-9(8H)-ones and their activity. The main part of this thesis is focused on the C2-modulation of thiazolo[5,4-f]quinazolin-9(8H)-ones to synthesize potent DYRK1A inhibitors. The first chapter of this manuscript describes the addition of nucleophiles such as amino acids at the C2-function of 8-benzylthiazolo[5,4-f]quinazolin-9(8H)-ones. The second chapter is focused on the optimization of the thiazolo[5,4-f]quinazolin-9(8H)-ones synthesis and their C–H arylation. Deprotection of C2-arylated products and C–H alkenylation approach of 8-benzylthiazolo[5,4-f]quinazolin-9(8H)-one are also described. The third chapter deals with the inhibitory activity evaluation of most of the compounds prepared along this work shown FC162 as DYRK1A inhibitor. These results led to C2 modulation of simpler structures such as benzo[d]thiazoles by studying the C–H arylation of these bicyclic derivatives.