Submitted by Natalie Mendes (nataliermendes@gmail.com) on 2015-11-12T22:45:09Z No. of bitstreams: 1 Vers?o corrigida - vers?o final.pdf: 1423044 bytes, checksum: 6989a397b0d890ed1cb80eaaf86dcd52 (MD5) / Made available in DSpace on 2015-11-12T22:45:09Z (GMT). No. of bitstreams: 1 Vers?o corrigida - vers?o final.pdf: 1423044 bytes, checksum: 6989a397b0d890ed1cb80eaaf86dcd52 (MD5) Previous issue date: 2013-03-27 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Nifurtimox and benznidazole have been used to treat Chagas? disease since the 70s. Both drugs can induce side effects on the patients and are not effective when given during the chronic phase. Therefore, more efficient drugs with lower toxicity are needed for the treatment of this disease. The synthesis of complexes of transition metals, especially ruthenium has been increased over the years due to the interest in the biological applications of these compounds. The present study aimed to evaluate the activity of anti-Trypanosoma cruzi of nitro/nitrosyl ruthenium complexes, cis-[RuCl(NO2)(dppb)(5-mebipy)] (1), cis-[Ru(NO2)2(dppb)(5-mebipy)] (2), ct-[RuCl(NO)(dppb)(5-mebipy)](PF6)2 (3) and cc-[RuCl(NO)(dppb)(5-mebipy)](PF6)2 (4). We evaluated the cytotoxicity, anti-T. cruzi activity in vitro and in vivo, and inhibition of cruzain enzyme activity. We also evaluated the mechanism of action of compound 3, the most active among the others. All compounds showed low cytotoxicity and trypanocidal activity against the three evolutionary forms of the parasite. Only compound 1 did not inhibit the epimastigote form. Regarding the enzymatic activity, compound 2 was the only one who did not inhibit the cruzain activity. Treatment with compound 3 caused changes in the membrane and vacuoles of the parasites, correlated to positive stains for propidium iodide and monodansylcadaverine, respectively. Moreover, the treatment with compound 3 caused a reduction of parasitemia and increased survival of infected mice. Thus, the nitro/nitrosyl ruthenium complexes represent a potential class of drugs for the treatment of Chagas' disease. / Os f?rmacos nifurtimox e benzonidazol t?m sido utilizados no tratamento da doen?a de Chagas desde os anos 70. Ambos podem induzir efeitos colaterais nos pacientes e n?o possuem efic?cia na fase cr?nica. Portanto, se torna necess?ria a identifica??o de medicamentos mais eficientes e menos t?xicos para o tratamento desta doen?a. A s?ntese de complexos de metais de transi??o, especialmente o rut?nio, tem sido intensificada ao longo dos anos devido ao interesse nas aplica??es biol?gicas destes compostos. Este estudo teve, como objetivo, avaliar a atividade anti-Trypanosoma cruzi dos nitro/nitrosilo complexos de rut?nio, cis-[RuCl(NO2)(dppb)(5-me93bipy)] (1), cis-[Ru(NO2)2(dppb)(5-mebipy)] (2), ct-[RuCl(NO)(dppb)(5-mebipy)](PF6)2 (3) e cc-[RuCl(NO)(dppb)(5-mebipy)](PF6)2 (4). Foram avaliadas a citotoxicidade, a atividade anti-T. cruzi in vitro e in vivo e a inibi??o da atividade enzim?tica da cruza?na. Foi tamb?m avaliado o mecanismo de a??o do composto 3, o mais ativo dentre os demais. Os 4 compostos apresentaram baixa citotoxicidade e atividade tripanocida para as tr?s formas evolutivas do parasito. Apenas o composto 1 n?o inibiu a forma epimastigota. Em rela??o ? atividade enzim?tica, o composto 2 foi o ?nico que n?o inibiu a cruza?na. Em rela??o ao composto 3, os parasitos tratados com este composto apresentaram altera??es na membrana e presen?a de vac?olos correlacionados ?s marca??es positivas para iodeto de prop?dio e monodansilcadaverina, respectivamente. Al?m disso, o tratamento proporcionou redu??o de parasitemia e aumento de sobrevida dos camundongos infectados. Desta forma, os nitro/nitrosilo complexos de rut?nio representam uma classe de f?rmacos em potencial para o tratamento da doen?a de Chagas.

MSc (Chemistry) / Department of Chemistry / Chromones are well known naturally occurring heterocyclic compounds with oxygen as a heteroatom. Chromones are also one of the major classes of naturally occurring compounds, and the interest in their chemistry is due to their wide range of their biological activity. In this study, three classes of target compounds were synthesized through three different pathways. The first pathway, chromone-3-carbaldehyde analogues were afforded in good to excellent yield followed by the oxidation thereof to 4-oxo-4H-chromene-3-carboxylic acids. A series of chromone-3-carboxamides was obtained from corresponding 4-oxo-4H-chromene-3-carboxylic acid via the in situ generation of the corresponding acid chloride in good yield. The second class of compounds were achieved by reacting corresponding chromone-3-carbaldehyde analogues with thiazolidine-2,4-dione to afford 5-((4-oxo-4H-chromen-3-yl)methylene)thiazolidine-2,4-dione analogues. The third class of compounds followed the same reaction pathway as the second class of compounds from corresponding 8-allyl-chromone-3-carbaldehyde analogues to afford 5-((8-allyl-4-oxo-4H-chromen-3-yl)methylene)thiazolidine-2,4-dione analogues in good yield. Compounds were characterized by 1D NMR (1H, 13C and DEPT), 2D NMR (COSY, HSQC and HMBC), IR and elemental analysis (CHN analysis). Selected synthesized chromone derivatives were evaluated in vitro for two biological assays; namely trypanocidal activity and cytotoxicity. Among all tested compounds, 41A, 55B and 63D displayed promising trypanocidal activity by reducing the percentage parasite viability to 0.61, 0.15 and 0.21 respectively. These results were further substantiated by their IC50 values 4.3, 1.3 and 1.9 μg/mL respectively. Compounds 41B and 59A also showed significant trypanocidal activity, however it was below the positive control. Compounds 41A and 55B displayed cytotoxicity against the HeLa cells whilst compound 63D displayed no toxicity against the HeLa cells. / NRF