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We report the discovery of marinoquinoline (3H-pyrrolo[2,3-c]quinoline) derivatives as new chemotypes with antiplasmodial activity. We evaluated their inhibitory activities against P. falciparum and conducted a structure–activity relationship study, focusing on improving their potency and maintaining low cytotoxicity. Next, we devised quantitative structure–activity relationship (QSAR) models, which we prospectively validated, to discover new analogues with enhanced potency. The most potent compound, 50 (IC503d7 = 39 nM; IC50K1 = 41 nM), is a fast-acting inhibitor with dual-stage (blood and liver) activity. The compound showed considerable selectivity (SI > 6410), an additive effect when administered in combination with artesunate, excellent tolerability in mice (all mice survived after an oral treatment with a 1000 mg/kg dose), and oral efficacy at 50 mg/kg in a mouse model of P. berghei malaria (62% reduction in parasitemia on day 5 postinfection); thus, compound 50 was considered a lead compound for th...

Despite the success achieved in the treatment of acute lymphoblastic leukemia (ALL), the search for new drugs featuring selectivity against leukemia cells and effectiveness to prevent relapsed ALL is still highly desirable. Here, we described the synthesis of several novel 3-substituted and 3,6-disubstituted-2-carboalkoxy indoles followed by the elucidation of their mechanism of action and in vivo anti-leukemia efficacy. The synthesis of 3-substituted-2-carboalkoxy indoles relied on two Heck arylations of methyl acrylate and methyl cinnamates respectively, to generate β,β-disubstituted acrylates followed by an efficient Cadogan-Sundberg reaction of these latter intermediates. The method developed led to the synthesis of twenty-one novel functionalized indoles. Of these, indole 20 showed selective cytotoxicity against leukemia cells at the nanomolar scale, and, therefore, it was selected for the investigation of its mechanism of action. Indole 20 was found to target tubulin leading to G2/M cell cycle arrest, DNA damage and apoptosis. Indole 20 decreased β-tubulin protein in leukemia cells in a time-dependent manner and induced depolymerization of the microtubule network in Hela cells, thus fully characterizing its microtubule destabilizer activity. The connectivity map analysis of HL60 promyelocytic leukemia cells treated with indole 20 revealed a transcriptional profile similar to that of cells treated with prostaglandins, apparently due to the induction of cellular differentiation as addressed by the expression of CD11 and CD14 markers. Finally, indole 20 given intraperitoneally, at 10 mg/kg, 5x/week significantly prolonged the overall survival of NOD/SCID mice transplanted with RS4; 11 B-ALL cells.

3-(Thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carboximidamides were efficiently prepared through a cyclocondensation of thiophenylchalcones with aminoguanidine hydrochloride under ultrasonic conditions in the presence of KOH and ethanol as a green solvent in short reaction times (15-35 min) and good yields (62-95%). All compounds produced were evaluated against the human Jurkat and RS4;11 acute lymphoblastic leukemia cell lines of T- and B-cell origin, respectively, and the K562 myelogenous leukemia cell line. Six compounds presented half maximal inhibitory concentration (IC50) values around 15 µmol L-1 and five compounds presented IC50 values around 40 µmol L-1 for at least one of the three cell lines analyzed. One compound was not significantly cytotoxic, presenting IC50 value > 100 µmol L-1.

Made available in DSpace on 2015-05-15T13:30:13Z (GMT). No. of bitstreams: 0 Previous issue date: 2013Bitstream added on 2015-05-15T13:56:26Z : No. of bitstreams: 1 ISSN2179-460X-2013-35-02-09-14.pdf: 302725 bytes, checksum: af24e38839e1807ca300368e3d0b0d0f (MD5) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Saccharomyces cerevisiae tem evoluído para utilizar melhor os nutrientes acessíveis e se adaptar as deficiências nutricionais de forma a maximizar sua sobrevivência. O presente trabalho avaliou o efeito das fontes de carbono e nitrogênio no desempenho fermentativo de leveduras industriais (Catanduva-1 e Pedra-2). As análises dos parâmetros fermentativos mostraram que o tipo da fonte de carbono e a complexidade estrutural da fonte nitrogenada causam efeitos diferentes sobre o metabolismo das linhagens industriais. As fontes de carbono contendo glicose e sacarose suplementadas com a fonte nitrogenada (peptona) apresentaram melhor desempenho fermentativo para as linhagens estudadas. Este estudo mostrou que a complexidade estrutural da fonte de nitrogênio, em correlação com o tipo de açúcar, tem um efeito importante no desempenho fermentativo de leveduras industriais. Saccharomyces cerevisiae has evolved to better utilize the nutrients available and to adapt nutritional deficiencies in order to maximize its survival. This study evaluated the effect of carbon and nitrogen sources in the fermentation performance of industrial yeasts (Catanduva-1 and Pedra-2). Analyses of fermentation parameters showed that the type of carbon source and structural complexity of nitrogen source cause different effects on the metabolism of industrial strains. The carbon sources containing glucose and sucrose supplemented with nitrogen source (peptone) showed better fermentation performance for the strains studied. This study showed that the structural complexity of the nitrogen source in correlation with the type of sugar has an important effect on the fermentation performance of industrial yeasts. Universidade Estadual Paulista Júlio de Mesquita Filho, Instituto de Química de Araraquara, São Paulo, R. PROF. FRANCISCO DEGNI, 55, QUITANDINHA, CEP 14800900, SP, Brasil Universidade Estadual Paulista Júlio de Mesquita Filho, Instituto de Química de Araraquara