Over fifty structurally diverse, novel fluorinated heteroarenes, have been successfully synthesised by SNAr reaction of a range of fluorinated arenes including pentafluoropyridine, hexafluorobenzene, and methyl pentafluorobenzoate by introduction of a range of groups such as imidazole, triazole, benzimidazole, benzotriazole, and carbazole. Different water solubilising side chains were introduced to some of the successfully synthesised fluorinated heteroarenes to improve water solubility and potential biological activity. X-ray crystal structures of over 10 compounds were obtained including those of two macrocyclic compounds containing 21- and 24-membered rings. The synthesised compounds have been characterized by elemental analysis, IR, 1H and 19F spectroscopy and high resolution mass spectrometry. These compounds have been screened for their biological activities and possible interaction with DNA by methods including UV-visible spectroscopy, fluorescence spectroscopy, co-crystallization for X-ray diffraction analysis, and antimicrobial activity. A number of the fluoroaryl benzimidazole derivatives have been tested against K-562 and MCF-7 cell lines and G361 and HOS cell lines. From the all tested compounds three tethered fluoroaryl benzimidazole derivatives demonstrated micromolar inhibition against K-562 and MCF-7 cell lines. These compounds, in addition to 1-tetrafluoropyrid-4-yl-2-tetrafluoropyrid-4-ylsulfanyl-1H-benzimidazole, also demonstrated micromolar inhibition against G361 and HOS cell lines. Two of the compounds were found to activate caspases leading to apoptosis.

Made available in DSpace on 2014-06-11T19:30:18Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-07-27Bitstream added on 2014-06-13T18:06:41Z : No. of bitstreams: 1 goncalves_rs_me_bauru.pdf: 4669388 bytes, checksum: b30004cd2539c06798b6a06a2acbec15 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Amino ésteres lactâmicos derivados do PABA e que podem ser potencialmente bioativos, por exemplo, como anestésicos locais, foram sintetizados com bons rendimentos por uma reação seletiva de SnAr de ácidos benzóicos com n-(3-aminopropil)-lactamas seguida por esterificação com aminoálcoois terciários. Produtos da N-arilação do N, N-dimetilformamida foram também obtidos através da esterificação direta do ácido 4-cloro-3-nitrobenzóico / Lactamic amino esters PABA-related, and can potentially bioactive, for exemple, as local anesthetics were synthesized in good yields by a selective 'S IND. n'Ar reactions of benzoic acids with N-(3-aminopropyl)lactams followed by esteterification with tertiary aminoalcohols. Products of the N-arylation with N,N-dimethylformamide are also obtained through of direct esterification of 4-chloro3-nitrobenzoic acid

Despite the unfavorable pharmacokinetic properties associated with peptides, they are still of great interest in drug development due to a multitude of interesting biological functions. The development of peptidomimetics strives to maintain or improve the biological activity of a peptide concurrently with removing the unwanted properties. This thesis describes two synthetic approaches to peptidomimetics with particular emphasis on secondary structure mimetics. First the design, synthesis and evaluation of two beta-turn mimetics incorporated in the endorphin Leu-enkephalin is presented. The beta-turn mimetics were stabilized by replacement of the intramolecular hydrogen bond with an ethylene bridge, and the amide bond between Tyr and Gly was replaced with an ether linkage. Linear analogues of the two mimetics were also synthesized. The peptidomimetics and their linear analogues were evaluated in a competitive binding assay at two opiate receptors, my and delta. One of the cyclized beta-turn mimetics was found to be a delta receptor antagonist with an IC50 value of 160 nM. Second a synthetic strategy to a beta-strand mimetic using 2-fluoro-4-iodopyridine as scaffold is described. The synthesis involved a Grignard exchange reaction on the pyridine scaffold using an amino acid derivative as electrophile followed by an SNAr reaction using an amine as nucleophile. The synthesis of a tripeptidomimetic of Leu-Gly-Gly and attempts to introduce chiral building blocks at the C-terminal, as well as studies towards elongated mimetics are presented. Two additional studies deal with the synthesis of two classes of potential thrombin inhibitors based on the pyridine scaffold. The first class contain pyridine as central fragment (P2 residue) substituted with a para-amidinobenzylamine group as P1 residue and various benzoyl groups as P3 residues. Three potential thrombin inhibitors were synthesized and found to be microM inhibitors in an enzymatic assay. In the second class, the pyridine ring serves as P3 residue. This class also lacks a strongly basic group in the P1 position. A small library of eight compounds were synthesized and evaluated in the enzymatic assay. Unfortunately, these compounds lacked inhibitory activity.

Orientador: Eduardo René Pérez Gonzáles / Banca: Alvicler Magalhães / Banca: Wanda Pereira Almeida / O Programa de Pós-Graduação em Ciência e Tecnologia de Materiais, PosMat, tem caráter institucional e integra as atividades de pesquisa em materiais de diversos campi da Unesp / Resumo: Amino ésteres lactâmicos derivados do PABA e que podem ser potencialmente bioativos, por exemplo, como anestésicos locais, foram sintetizados com bons rendimentos por uma reação seletiva de SnAr de ácidos benzóicos com n-(3-aminopropil)-lactamas seguida por esterificação com aminoálcoois terciários. Produtos da N-arilação do N, N-dimetilformamida foram também obtidos através da esterificação direta do ácido 4-cloro-3-nitrobenzóico / Abstract: Lactamic amino esters PABA-related, and can potentially bioactive, for exemple, as local anesthetics were synthesized in good yields by a selective 'S IND. n'Ar reactions of benzoic acids with N-(3-aminopropyl)lactams followed by esteterification with tertiary aminoalcohols. Products of the N-arylation with N,N-dimethylformamide are also obtained through of direct esterification of 4-chloro3-nitrobenzoic acid / Mestre

Le paludisme et la leishmaniose sont les deux plus importantes infections parasitaires au monde, en termes de mortalité. La recherche de nouvelles molécules actives contre les protozoaires responsables de ces « maladies tropicales négligées », Plasmodium sp et Leishmania sp, est un enjeu majeur de santé publique. Après une première partie dressant un état des lieux des connaissances disponibles en matière de chimiothérapie antiplasmodiale, une seconde partie s’est intéressée à l’étude des propriétés anti-infectieuses du noyau 2-trichlorométhyl-quinazoline, en introduisant en position 4 des motifs alcynyles par couplage de Sonogashira, optimisés par LC/MS. Une troisième partie a porté sur la pharmacomodulation en positions 2 et 4 du même noyau, notamment par réactions de SNAr. Une quatrième partie a consisté à rechercher le mécanisme d'action des meilleures quinazolines antiplasmodiales, via une approche de chromatographie d'affinité sur inhibiteur immobilisé. La fonctionnalisation multi-étapes des molécules les plus puissantes, par un bras espaceur, a été suivie de leur ancrage sur divers supports solides, pour constituer des matrices biocompatibles spécifiques. L’une d’entre-elles a permis la mise en évidence de 2 cibles plasmodiales protéiques originales : la GTPase Pfrab6 et la pyruvate-kinase PfpyrK1. Enfin, une cinquième partie relate la pharmacomodulation antileishmanienne du noyau 8-nitroquinoléin-2(1H)-one. Les travaux se sont intéressés à l'étude de la substitution de la position 4 de ce noyau par des réactions de SNAr, ainsi que des réactions de couplages pallado-catalysés optimisées à l’aide de la technologie micro-ondes. / Malaria and leishmaniasis are the two most important parasitic infections worldwide, in terms of mortality. Thus, the research for new molecules targeting the protozoa parasites responsible for these “neglected tropical diseases”, Plasmodium sp and Leishmania sp, constitute a major challenge in public health. Our work focused first on a current state of knowledge about antiplasmodial chemotherapy. In a view to develop the study of the anti-infective properties of the 2-trichloromethylquinazoline scaffold, a second part presented antiplasmodial pharmacomodulation at position 4 using Sonogashira cross-coupling reaction, optimized with the LC/MS technology. A third part concerned other pharmacomodulation reactions, especially at positions 2 and 4, using especially SNAR reactions. A fourth part consisted in the research of the mechanism of action of the best antiplasmodial quinazolines by using the affinity chromatography on immobilized inhibitor approach. The multi-step functionalization of the most potent derivatives by a spacer side chain was followed by their anchoring onto various solid supports, so as to generate different biocompatible specific matrices. One of them, put in contact with a parasitic lysate, allowed the identification of two original plasmodial targets: the GTPase Pfrab6 and the pyruvate-kinase PfpyrK1. Finally, a fifth part presented the antileishmanial pharmacomodulation of the 8-nitroquinolin-2(1H)-one scaffold, especially at position 4 of the quinoline ring, involving SNAr reactions (with amines, phenols or thiophenols) or pallado-catalyzed coupling reactions (in particular Suzuki-Miyaura), some of them being optimized under microwave irradiation.