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.

Parmi la vingtaine de pathologies neurodégénératives recensées à ce jour, il a été retrouvé des caractéristiques communes telles que des lésions neuronales. Dans le cas de la Maladie d’Alzheimer, une dégénérescence neurofibrillaire a notamment été mise en évidence, ce qui se traduit par l’agrégation de protéines Tau anormalement modifiées. Bien que les mécanismes moléculaires impliqués demeurent encore mal compris, nous nous sommes intéressés, au cours de cette thèse, à la synthèse puis à l’évaluation biologique de nouveaux inhibiteurs de l’agrégation de la protéine TAU impliquée dans la Maladie d’Alzheimer. Les deux premières parties de ce travail sont basées sur la conception de dérivés imidazo[2,1-b]thiazoliques, sur lesquels sont greffés un ou plusieurs groupements (hétéro)aryles. La troisième partie est, quant à elle, consacrée à la formation d’entités thiazolo[3,2-b]triazoliques di- ou trisubstituées. Le choix de ces bicycles fusionnés à cinq chainons [5,5] découle de leurs propriétés biologiques dans des domaines très variés. L’obtention de ces composés a notamment été l’occasion de mettre en oeuvre de nouvelles méthodologies de synthèses. Ainsi, sur le motif imidazo[2,1-b]thiazolique, ont été développées des réactions de couplages de Suzuki-Miyaura, des réactions multicomposants, ainsi qu’une séquence réactionnelle de condensation d’électrophiles. Sur le bicycle thiazolo[3,2-b]triazole, un travail de CH activation a également été mise au point. Une collection de deux cents moléculesoriginales a ainsi pu être constituée, et plus de la moitié des nouveaux produits ont été évalués in vitro. Unetechnique de fluorescence permettant de déterminer l’inhibition de l’agrégation des protéines TAU a été miseau point, utilisant notamment la protéine K18 comme modèle tronqué de protéine TAU. / TAU pathology is a brain lesion common to more than twenty neurodegeneratives diseases. It consists of the abnormal aggregation of the microtubule-associated protein TAU into neurofibrillary tangles. While mechanisms underlying TAU aggregation are not fully understood yet, we have been investigated the synthesis and the biological evaluations of novel class of TAU aggregation inhibitors involved in Alzheimer’s disease. The first two parts of this work reports the synthesis of various imidazo[2,1-b]thiazoles molecules, on which are substituted (het)aryles groups. The third and last part is devoted to the formation of some di-/trisubstituted novel N-fused ring system such as thiazolo[3,2-b]triazoles. In order to provide a functional diversity and generate a therapeutic effect, the peaks C-2, C-3, C-5 and C-6 were functionalized on the imidazo[2,1-b]thiazole ring. It was also the opportunity to develop news synthetic methodologies such as a new Suzuki-Miyaura reaction, a multicomponent reaction, and an electrophilic condensation. On the thiazolotriazole core, an effective procedure of CH activation was performed. More than two hundred original molecules were synthesized, and more than half were evaluated in vitro. A fluorescence technique allowed us to determine the inhibition of TAU aggregation, using the particular K18 protein as a truncated model of normal TAU protein.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / This work describes the synthesis of a number of polyaza heterocycles and the mechanistic study to obtain these products. Furthermore, the characterization was performed by spectroscopic method and the structural study by X-ray diffraction and theoretical calculations of molecular orbitals. The synthesis of polyaza heterocyclic compounds began from the cyclocondensation reaction between a β- enaminodiketone and 2-aminopyridine, 2-aminothiazole or 2-aminobenzoimidazole in order to achieve pyrido[1,2-a]pyrimidin-4-one, thiazole[3,2-a]pyrimidin-5-one or 2- oxo-pyrimido[1,2-a]benzimidazole, respectively, with a α-keto ester substituent, in high regioselectivity. The mechanistic proposal developed in this step is based on the semi-empirical theoretical calculations by the PM3 method. From these data it was possible to say that the reaction was controlled by frontier molecular orbital, according to values of HOMO/LUMO coefficient obtained for the reactants. In the next step, the α-keto esters previously obtained, were reacted with ethylenediamine and derivatives ledding to the pyrazinones formation and the reaction with 1,2- phenylenediamine and derivatives led to the formation quinoxalinones. The same reaction of α-keto esters with amidines did not lead to the formation of imidazolonas as expected, since only the formation of the substitution product in the ester group occurred. The reaction mechanisms proposed in these steps are also based in theoretical calculations, where it was possible to infer that the reaction was thermodynamically controlled, since the reactivity sites were less important than the stability of the intermediates. The compounds were characterized by 1D nuclear magnetic resonance experiments of such as 1H and 13C and 2D such as COSY, HETCOR and HMBC, besides of mass spectrometry. The molecular structural studies by X-ray diffraction (for the compounds that could be measured) revealed that polyaza heterocycles pyrido[1,2-a]pyrimidin-4-one, thiazole[3,2-a]pyrimidin-5-one and 2-oxo-pyrimido[1,2-a]benzimidazole are essentially plane. All these compounds showed as pattern at least one intramolecular interaction between a carbonyl oxygen atom and a carbonyl carbon via π-hole, forming a five membered pseudo-ring, which stabilizes the position of a carbonyl group. The study revealed that all structural supramolecular compounds exhibit a large number of weak hydrogen bonds of the type CH···X (where X = O, N) and the compounds which exhibited a NH group in its structure or water in the asymmetric unit formed additionally strong hydrogen bonds of the type X-H···X (where X = O, N). Since the structures studied are aromatic heterocycles, all compounds showed interactions involving π systems in their interactions like π···π and/or lone-pair···π in their crystal packing. Only one intermolecular interaction via σ-hole (C=O···S) and another via π-hole (C=O···C=O) were found. / Neste trabalho é descrita a síntese de uma série de poliaza heterociclos e o estudo mecanístico para a obtenção destes produtos. Além disso, é realizada sua caracterização utilizando métodos espectroscópicos e o estudo estrutural por difração de Raios-X e cálculos teóricos de orbitais moleculares. A síntese dos compostos poliaza heterocíclicos teve inicio a partir de reações de ciclocondensação entre uma β-enaminodicetona e 2-aminopiridina, 2-aminotiazol ou 2-aminobenzoimidazol para obter pirido[1,2-a]pirimidin-4-ona, tiazolo[3,2-a]pirimidin-5- ona e 2-oxo-pirimido[1,2-a]benzoimidazol, respectivamente, com um substituinte α- ceto éster, de maneira altamente regiosseletiva. A proposta mecanística elaborada nesta etapa está embasada em cálculos teóricos semi-empíricos pelo método PM3. A partir destes dados é possível afirmar que a reação é controlada por orbital molecular de fronteira, conforme os valores de coeficiente de HOMO/LUMO obtidos para os reagentes. Na etapa seguinte, os α-ceto ésteres, previamente obtidos, ao reagirem com etilenodiamino e derivados levaram a formação de pirazinonas, bem como, a reação com 1,2-fenilenodiamino e derivados levou a formação de quinoxalinonas como produto. A reação dos mesmos α-ceto ésteres com amidinas não levou a formação de imidazolonas como desejado, pois ocorreu apenas a formação do produto de substituição no grupo éster. Os mecanismos de reação propostos nestas etapas também estão embasados em cálculos teóricos, onde foi possível inferir que a reação foi termodinamicamente controlada, já que, a reatividade dos sítios foi menos importante que a estabilidade dos intermediários. Os compostos foram caracterizados utilizando ressonância magnética nuclear em experimentos de 1D como 1H e 13C, e 2D como COSY, HETCOR e HMBC, além de espectrometria de massas. O estudo estrutural molecular por difração de Raios-x (referente aos compostos que puderam ser medidos) revelou que os poliaza heterociclos pirido[1,2- a]pirimidin-4-ona, tiazolo[3,2-a]pirimidin-5-ona e 2-oxo-pirimido[1,2-a]benzoimidazol são essencialmente planos. Um padrão observado nestes compostos é que todos apresentam, pelo menos, uma interação intramolecular entre um átomo de oxigênio carbonílico e um carbono carbonílico via π-hole, formando um pseudo-anel de cinco membros, que estabiliza a posição de uma carbonila. O estudo estrutural supramolecular revelou que todos os compostos apresentam um amplo número de ligações de hidrogênio fracas do tipo C-H· · ·X (quando, X = O, N) e os compostos que apresentaram um grupo N-H em sua estrutura ou água na unidade assimétrica formam, adicionalmente, ligações de hidrogênio fortes do tipo X-H···X (quando, X = O, N). Como as estruturas estudadas apresentam heterociclos aromáticos, todos os compostos mostraram interações envolvendo seus sistemas π em interações do tipo π· · ·π e/ou lone-pair· · ·π em seus empacotamentos cristalinos. Apenas uma interação intermolecular via σ-hole (C=O· · ·S) e uma via π-hole (C=O· · ·C=O) foram encontradas.