Estudo in vitro de derivados sintéticos da Isoniazida e da Pirazinamida sobre Leishmania (Viannia) braziliensis

• Autor(a) principal: Nery, Adriane de Lacerda
• Data de Publicação: 2015
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Biblioteca Digital de Teses e Dissertações da UERJ
• Texto Completo: http://www.bdtd.uerj.br/handle/1/14435
• topic: Leishmania (Viannia) braziliensis; Isoniazid and Pyrazinamide; In vitro activity; Leishmania (Viannia) braziliensis; Isoniazida; Pirazinamida; Atividade in vitro; Leishmania braziliensis; Isoniazida; Pirazinamida; Técnicas in vitro; CNPQ::CIENCIAS BIOLOGICAS::PARASITOLOGIA

Leishmaniasis are a group of diseases caused by protozoan of genus Leishmania spp affecting of 98 countries. In Brazil, in the year 2013 were 3.253 reported cases of visceral leishmaniasis and 18.226 cases of cutaneous leishmaniasis. The first choice of treatment is still performed with pentavalent antimonials and in cases of failures drugs of second line of treatment are pentamidine and anfotericin B. These drugs cause many adverse effects and has lately emerged resistant strains. In endemic areas it has been increasingly common the appearance of co-infection Leishmania and Mycobacterium tuberculosis. The treatment of tuberculosis with pyrazinamid and isoniazid control the leishmaniasis.The aim of this study was evaluate the anti-leishmania activity in vitro of INZ and PZA and yours derivatives compounds (serie G and serie R,respectively) on the Leishmania (Viannia) braziliensis. The molecules were tested on infected monolayers of peritoneal murine macrophages for 48h. All the molecules te inhibited the infection index in a dose-dependent manner in relation to controls. The molecules of the R series were more active than PZA, but the result was only significant for R02 (p < 0,005). Only R05 (CC50 = 76,64µM) was relatively toxic to macrophages. The most active compounds were R02, G01 and G02 whose select index were 14,31, 19 and 30, respectively. Nitrite assay was performed in supernatants of infected monolayers of peritonial macrophages treated with the substancies at 10 and 100µM. G01 and G02 stimulated NO2 prodution, however, the result was only statistically significant for G02 at 100µM (p < 0,001). All the compounds of R serie stimulated NO2 production however the results were statistically significant for the R03 and R05 at 100µM (p < 0,001). Additionally, a in silico preditive pharmacokinetic analysis was performed to active molecules using the admetSAR software the data showed that G01, G02 and R02 were similar to their original molecules as to high capacity to be absorbed by the gastrointestinal tract, low hepatotoxic and carcinogenic potencial. Together, these data demonstrate that these molecules are selectively toxic to the parasite with the potencial to be tested orally on studies in experimental infection.