Elisalva Guimarães - Academia.edu (original) (raw)
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Papers by Elisalva Guimarães
Frontiers in Pharmacology, 2020
Leishmaniasis are group of neglected diseases with worldwide distribution that affect about 12 mi... more Leishmaniasis are group of neglected diseases with worldwide distribution that affect about 12 million people. The current treatment is limited and may cause severe adverse effects, and thus, the search for new drugs more effective and less toxic is relevant. We have previously investigated the immunomodulatory effects of LASSBio-1386, an N-acylhydrazone derivative. Here we investigated the in vitro and in vivo activity of LASSBio-1386 against L. amazonensis. LASSBio-1386 inhibited the proliferation of promastigotes of L. amazonensis (EC50 = 2.4 ± 0.48 µM), while presenting low cytotoxicity to macrophages (CC50 = 74.1 ± 2.9 µM). In vitro incubation with LASSBio-1386 reduced the percentage of Leishmania-infected macrophages and the number of intracellular parasites (EC50 = 9.42 ± 0.64 µM). Also, in vivo treatment of BALB/c mice infected with L. amazonensis resulted in a decrease of lesion size, parasitic load and caused histopathological alterations, when compared to vehicle-treated ...
…, 2012
Background aims. Cirrhosis, end-stage liver disease, is caused by different mechanisms of injury,... more Background aims. Cirrhosis, end-stage liver disease, is caused by different mechanisms of injury, associated with persistent infl ammation. Galectin-3 is an important regulator of fi brosis that links chronic infl ammation to fi brogenesis. We investigated the role of bone marrow cell (BMC) transplantation in chronic infl ammation and hepatic fi brosis. Methods. Liver cirrhosis was induced by administration of carbon tetrachloride and ethanol to wild-type C57BL/6 or bone marrow chimeric mice. Bone marrow chimeras were generated by lethal irradiation and transplantation with BMC obtained from green fl uorescent protein (GFP ϩ)donors. Wild-type cirrhotic mice were transplanted with BMC without irradiation. Livers from chimeras and cirrhotic transplanted mice were obtained for evaluation of infl ammation, fi brosis and regulatory factors [galectin-3, matrix metallopeptidase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1 and transforming growth factor (TGF)-β ]. Results. The development of cirrhosis was associated with increased expression of galectin-3 by F4/80 ϩ cells and intense migration of BMC to the liver. Furthermore, when transplanted after the establishment of cirrhosis, BMC also migrated to the liver and localized within the fi brous septa. Two months after BMC therapy, cirrhotic mice had a signifi cant reduction in liver fi brosis and expression of type I collagen. We did not fi nd any difference in levels of TGF-β , TIMP-1 and MMP-9 between saline and BMC groups. However, the numbers of infl ammatory cells, phagocytes and galectin-3 ϩ cells were markedly lower in the livers of cirrhotic mice treated with BMC. Conclusions. Our results demonstrate an important role for BMC in the regulation of liver fi brosis and that transplantation of BMC can accelerate fi brosis regression through modulatory mechanisms.
Bioorganic & Medicinal Chemistry, 2012
We recently showed that oxadiazoles have anti-Trypanosoma cruzi activity at micromolar concentrat... more We recently showed that oxadiazoles have anti-Trypanosoma cruzi activity at micromolar concentrations. These compounds are easy to synthesize and show a number of clear and interpretable structure-activity relationships (SAR), features that make them attractive to pursue potency enhancement. We present here the structural design, synthesis, and anti-T. cruzi evaluation of new oxadiazoles denoted 5a-h and 6a-h. The design of these compounds was based on a previous model of computational docking of oxadiazoles on the T. cruzi protease cruzain. We tested the ability of these compounds to inhibit catalytic activity of cruzain, but we found no correlation between the enzyme inhibition and the antiparasitic activity of the compounds. However, we found reliable SAR data when we tested these compounds against the whole parasite. While none of these oxadiazoles showed toxicity for mammalian cells, oxadiazoles 6c (fluorine), 6d (chlorine), and 6e (bromine) reduced epimastigote proliferation and were cidal for trypomastigotes of T. cruzi Y strain. Oxadiazoles 6c and 6d have IC 50 of 9.5 ± 2.8 and 3.5 ± 1.8 lM for trypomastigotes, while Benznidazole, which is the currently used drug for Chagas disease treatment, showed an IC 50 of 11.3 ± 2.8 lM. Compounds 6c and 6d impair trypomastigote development and invasion in macrophages, and also induce ultrastructural alterations in trypomastigotes. Finally, compound 6d given orally at 50 mg/kg substantially reduces the parasitemia in T. cruzi-infected BALB/c mice. Our drug design resulted in potency enhancement of oxadiazoles as anti-Chagas disease agents, and culminated with the identification of oxadiazole 6d, a trypanosomicidal compound in an animal model of infection.
Acta Tropica, 2012
Inhibition of Trypanosoma brucei and Leishmania spp. sirtuins has shown promising antiparasitic a... more Inhibition of Trypanosoma brucei and Leishmania spp. sirtuins has shown promising antiparasitic activity, indicating that these enzymes may be used as targets for drug discovery against trypanosomatid infections. In the present work we carried out a virtual screening focused on the C pocket of Sir2 from Trypanosoma cruzi. Using this approach, the best ligand found was nicotinamide. In vitro tests confirmed the anti-T. cruzi activity of nicotinamide on epimastigote and trypomastigote forms. Moreover, treatment of T. cruzi-infected macrophages with nicotinamide caused a significant reduction in the number of amastigotes. In addition, alterations in the mitochondria and an increase in the vacuolization in the cytoplasm were observed in epimastigotes treated with nicotinamide. Analysis of the complex of Sir2 and nicotinamide revealed the details of the possible ligand-target interaction. Our data reveal a potential use of TcSir2 as a target for anti-T. cruzi drug discovery.
Parasitology, 2013
SUMMARYWe previously observed that physalins have immunomodulatory properties, as well as antilei... more SUMMARYWe previously observed that physalins have immunomodulatory properties, as well as antileishmanial and antiplasmodial activities. Here, we investigated the anti-Trypanosoma cruzi activity of physalins B, D, F and G. We found that physalins B and F were the most potent compounds against trypomastigote and epimastigote forms of T. cruzi. Electron microscopy of trypomastigotes incubated with physalin B showed disruption of kinetoplast, alterations in Golgi apparatus and endoplasmic reticulum, followed by the formation of myelin-like figures, which were stained with MDC to confirm their autophagic vacuole identity. Physalin B-mediated alteration in Golgi apparatus was likely due to T. cruzi protease perturbation; however physalins did not inhibit activity of the trypanosomal protease cruzain. Flow cytometry examination showed that cell death is mainly caused by necrosis. Treatment with physalins reduced the invasion process, as well as intracellular parasite development in macrop...
Antimicrobial agents and chemotherapy, 2014
cis-[RuCl(NO2)(dppb)(5,5'-mebipy)] (complex 1), cis-[Ru(NO2)2(dppb)(5,5'-mebipy)] (comple... more cis-[RuCl(NO2)(dppb)(5,5'-mebipy)] (complex 1), cis-[Ru(NO2)2(dppb)(5,5'-mebipy)] (complex 2), ct-[RuCl(NO)(dppb)(5,5'-mebipy)](PF6)2 (complex 3), and cc-[RuCl(NO)(dppb)(5,5'-mebipy)](PF6)2 (complex 4), where 5,5'-mebipy is 5,5'-dimethyl-2,2'-bipyridine and dppb is 1,4-bis(diphenylphosphino)butane, were synthesized and characterized. The structure of complex 2 was determined by X-ray crystallography. These complexes exhibited a higher anti-Trypanosoma cruzi activity than benznidazole, the current antiparasitic drug. Complex 3 was the most potent, displaying a 50% effective concentration (EC50) of 2.1 ± 0.6 μM against trypomastigotes and a 50% inhibitory concentration (IC50) of 1.3 ± 0.2 μM against amastigotes, while it displayed a 50% cytotoxic concentration (CC50) of 51.4 ± 0.2 μM in macrophages. It was observed that the nitrosyl complex 3, but not its analog lacking the nitrosyl group, releases nitric oxide into parasite cells. This release has a dimini...
Frontiers in Pharmacology, 2020
Leishmaniasis are group of neglected diseases with worldwide distribution that affect about 12 mi... more Leishmaniasis are group of neglected diseases with worldwide distribution that affect about 12 million people. The current treatment is limited and may cause severe adverse effects, and thus, the search for new drugs more effective and less toxic is relevant. We have previously investigated the immunomodulatory effects of LASSBio-1386, an N-acylhydrazone derivative. Here we investigated the in vitro and in vivo activity of LASSBio-1386 against L. amazonensis. LASSBio-1386 inhibited the proliferation of promastigotes of L. amazonensis (EC50 = 2.4 ± 0.48 µM), while presenting low cytotoxicity to macrophages (CC50 = 74.1 ± 2.9 µM). In vitro incubation with LASSBio-1386 reduced the percentage of Leishmania-infected macrophages and the number of intracellular parasites (EC50 = 9.42 ± 0.64 µM). Also, in vivo treatment of BALB/c mice infected with L. amazonensis resulted in a decrease of lesion size, parasitic load and caused histopathological alterations, when compared to vehicle-treated ...
…, 2012
Background aims. Cirrhosis, end-stage liver disease, is caused by different mechanisms of injury,... more Background aims. Cirrhosis, end-stage liver disease, is caused by different mechanisms of injury, associated with persistent infl ammation. Galectin-3 is an important regulator of fi brosis that links chronic infl ammation to fi brogenesis. We investigated the role of bone marrow cell (BMC) transplantation in chronic infl ammation and hepatic fi brosis. Methods. Liver cirrhosis was induced by administration of carbon tetrachloride and ethanol to wild-type C57BL/6 or bone marrow chimeric mice. Bone marrow chimeras were generated by lethal irradiation and transplantation with BMC obtained from green fl uorescent protein (GFP ϩ)donors. Wild-type cirrhotic mice were transplanted with BMC without irradiation. Livers from chimeras and cirrhotic transplanted mice were obtained for evaluation of infl ammation, fi brosis and regulatory factors [galectin-3, matrix metallopeptidase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1 and transforming growth factor (TGF)-β ]. Results. The development of cirrhosis was associated with increased expression of galectin-3 by F4/80 ϩ cells and intense migration of BMC to the liver. Furthermore, when transplanted after the establishment of cirrhosis, BMC also migrated to the liver and localized within the fi brous septa. Two months after BMC therapy, cirrhotic mice had a signifi cant reduction in liver fi brosis and expression of type I collagen. We did not fi nd any difference in levels of TGF-β , TIMP-1 and MMP-9 between saline and BMC groups. However, the numbers of infl ammatory cells, phagocytes and galectin-3 ϩ cells were markedly lower in the livers of cirrhotic mice treated with BMC. Conclusions. Our results demonstrate an important role for BMC in the regulation of liver fi brosis and that transplantation of BMC can accelerate fi brosis regression through modulatory mechanisms.
Bioorganic & Medicinal Chemistry, 2012
We recently showed that oxadiazoles have anti-Trypanosoma cruzi activity at micromolar concentrat... more We recently showed that oxadiazoles have anti-Trypanosoma cruzi activity at micromolar concentrations. These compounds are easy to synthesize and show a number of clear and interpretable structure-activity relationships (SAR), features that make them attractive to pursue potency enhancement. We present here the structural design, synthesis, and anti-T. cruzi evaluation of new oxadiazoles denoted 5a-h and 6a-h. The design of these compounds was based on a previous model of computational docking of oxadiazoles on the T. cruzi protease cruzain. We tested the ability of these compounds to inhibit catalytic activity of cruzain, but we found no correlation between the enzyme inhibition and the antiparasitic activity of the compounds. However, we found reliable SAR data when we tested these compounds against the whole parasite. While none of these oxadiazoles showed toxicity for mammalian cells, oxadiazoles 6c (fluorine), 6d (chlorine), and 6e (bromine) reduced epimastigote proliferation and were cidal for trypomastigotes of T. cruzi Y strain. Oxadiazoles 6c and 6d have IC 50 of 9.5 ± 2.8 and 3.5 ± 1.8 lM for trypomastigotes, while Benznidazole, which is the currently used drug for Chagas disease treatment, showed an IC 50 of 11.3 ± 2.8 lM. Compounds 6c and 6d impair trypomastigote development and invasion in macrophages, and also induce ultrastructural alterations in trypomastigotes. Finally, compound 6d given orally at 50 mg/kg substantially reduces the parasitemia in T. cruzi-infected BALB/c mice. Our drug design resulted in potency enhancement of oxadiazoles as anti-Chagas disease agents, and culminated with the identification of oxadiazole 6d, a trypanosomicidal compound in an animal model of infection.
Acta Tropica, 2012
Inhibition of Trypanosoma brucei and Leishmania spp. sirtuins has shown promising antiparasitic a... more Inhibition of Trypanosoma brucei and Leishmania spp. sirtuins has shown promising antiparasitic activity, indicating that these enzymes may be used as targets for drug discovery against trypanosomatid infections. In the present work we carried out a virtual screening focused on the C pocket of Sir2 from Trypanosoma cruzi. Using this approach, the best ligand found was nicotinamide. In vitro tests confirmed the anti-T. cruzi activity of nicotinamide on epimastigote and trypomastigote forms. Moreover, treatment of T. cruzi-infected macrophages with nicotinamide caused a significant reduction in the number of amastigotes. In addition, alterations in the mitochondria and an increase in the vacuolization in the cytoplasm were observed in epimastigotes treated with nicotinamide. Analysis of the complex of Sir2 and nicotinamide revealed the details of the possible ligand-target interaction. Our data reveal a potential use of TcSir2 as a target for anti-T. cruzi drug discovery.
Parasitology, 2013
SUMMARYWe previously observed that physalins have immunomodulatory properties, as well as antilei... more SUMMARYWe previously observed that physalins have immunomodulatory properties, as well as antileishmanial and antiplasmodial activities. Here, we investigated the anti-Trypanosoma cruzi activity of physalins B, D, F and G. We found that physalins B and F were the most potent compounds against trypomastigote and epimastigote forms of T. cruzi. Electron microscopy of trypomastigotes incubated with physalin B showed disruption of kinetoplast, alterations in Golgi apparatus and endoplasmic reticulum, followed by the formation of myelin-like figures, which were stained with MDC to confirm their autophagic vacuole identity. Physalin B-mediated alteration in Golgi apparatus was likely due to T. cruzi protease perturbation; however physalins did not inhibit activity of the trypanosomal protease cruzain. Flow cytometry examination showed that cell death is mainly caused by necrosis. Treatment with physalins reduced the invasion process, as well as intracellular parasite development in macrop...
Antimicrobial agents and chemotherapy, 2014
cis-[RuCl(NO2)(dppb)(5,5'-mebipy)] (complex 1), cis-[Ru(NO2)2(dppb)(5,5'-mebipy)] (comple... more cis-[RuCl(NO2)(dppb)(5,5'-mebipy)] (complex 1), cis-[Ru(NO2)2(dppb)(5,5'-mebipy)] (complex 2), ct-[RuCl(NO)(dppb)(5,5'-mebipy)](PF6)2 (complex 3), and cc-[RuCl(NO)(dppb)(5,5'-mebipy)](PF6)2 (complex 4), where 5,5'-mebipy is 5,5'-dimethyl-2,2'-bipyridine and dppb is 1,4-bis(diphenylphosphino)butane, were synthesized and characterized. The structure of complex 2 was determined by X-ray crystallography. These complexes exhibited a higher anti-Trypanosoma cruzi activity than benznidazole, the current antiparasitic drug. Complex 3 was the most potent, displaying a 50% effective concentration (EC50) of 2.1 ± 0.6 μM against trypomastigotes and a 50% inhibitory concentration (IC50) of 1.3 ± 0.2 μM against amastigotes, while it displayed a 50% cytotoxic concentration (CC50) of 51.4 ± 0.2 μM in macrophages. It was observed that the nitrosyl complex 3, but not its analog lacking the nitrosyl group, releases nitric oxide into parasite cells. This release has a dimini...