2015-06-022013-02-19ALMEIDA, Letícia. Efeito leishmanicida de derivados benzofenônicos e estudo comparativo do potencial de inibição enzimática in silico e in vitro. 2013. 157 f. Dissertação (Mestrado em Ciências Farmacêuticas) - Universidade Federal de Alfenas, Alfenas, MG, 2013.https://repositorio.unifal-mg.edu.br/handle/123456789/314Leishmaniasis are caused by protozoa of the genus Leishmania and present diverse clinical manifestations being considered a neglected tropical disease. Are currently present in 88 countries affecting 12 million people with two million new cases per year. Treatment of leishmaniasis is held today by the same chemotherapy used in the 40s, despite the persistence of side effects. In this sense, the goal of the study was to evaluate the activity of benzophenone derivatives in L. (L.) amazonensis. Besides seeking to understand possible action mechanisms by evaluating the measurement of nitric oxide and the potential of enzyme inhibition in the contexts in silico and in vitro. Were tested three benzophenone precursors (CM-A, CM-B and CM-C) commercially available and nine derivatives (LFQM-115, LFQM-116, LFQM-117, LFQM-118, LFQM-119, LFQM-120-LFQM 121, LFQM-122 and LFQM-123). Initially tests were performed in promastigotes of L. (L.) amazonensis, although all derivatives being more effective than their precursors, the best results were exhibited by LFQM-115, LFQM-118 and LFQM-123 (IC50-PRO = 4.90, 5.05 and 5.94 μg/mL, respectively). The toxicity to murine peritoneal macrophages was also evaluated, and it was found that derivatives LFQM-117, LFQM-120, LFQM-121, LFQM-122 and LFQM-123 were less cytotoxic (CC50 = 140.06, 87.10, 116.20 and > 160.00 μg/mL, respectively). The assessment of activity in amastigotes of L. (L.) amazonensis proceeded only with derivatives, being LFQM-120 the most effective in intracellular forms. The QlogP of benzophenone derivatives can be correlated with antipromastigote activity, as well as antiamastigote one. Since, derivatives that showed better activity profile in both forms of the parasite and in murine macrophages were selected (LFQM-116, LFQM-117, LFQM-119, LFQM -120 and LFQM-121) for the remaining tests. Was performed the dosage of nitric oxide (NO) in the culture supernatants of murine peritoneal macrophages infected with L. (L.) amazonensis. In this, it has been found that benzophenone derivatives LFQM-119 and LFQM-120 stimulated NO production, but only the derivative LFQM-120 induced a NO production equivalent to that produced by LPS. Some important enzymes in trypanosomatids (cruzain, oligopeptidase B, ornithine decarboxylase and trypanothione reductase) and representatives of major families of enzymes (papain and trypsin) were used in the analysis by molecular docking. Some of these were also used to assess the potential for experimental enzyme inhibition assay (papain, cruzain, trypsin and oligopeptidase B), the results exhibited by LFQM-116 were IC50 = 7.54, 8.44, 8.59 and 14.25 μg/ml, respectively. Additionally, it’s possible to check the multi-target action of the derivative LFQM-120. Therefore, this work shows the action of benzophenone derivatives in both forms of L. (L.) amazonensis, also describing the gain in biological activity with structural changes made to their precursors. Besides helping to understand possible mechanisms of action of these compounds and also allow the selection of the most effective compounds in vitro, which may then be used in future in vivo tests.application/pdfAcesso Abertohttp://creativecommons.org/licenses/by-nc-nd/4.0/LeishmaniaBenzofenonasÓxido nítricoEnzimasBiologia ComputacionalCIENCIAS BIOLOGICAS::PARASITOLOGIADissertaçãoMarques, Marcos José