Synthesis and anti-Trypanosoma cruzi activity of β-lapachone analogues

Ferreira, Sabrina Baptista; Salomão, Kelly; Silva, Fernando de Carvalho da; Pinto, Antônio V.; Kaiser, Carlos R.; Pinto, Ângelo C.; Ferreira, Vı́tor F.; Castro, Solange L. de

doi:10.1016/j.ejmech.2011.03.012

Cited by 53 publications

(26 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Different protocols have been described in literature for the evaluation of T. cruzi survival, resulting in different IC 50 values. Such variations include: i) evaluation of cell lysis by light microscopy counting [37]; ii) spectrophotometric evaluation of MTT oxidation by mitochondrial dehydrogenases [38]; iii) culture-derived trypomatigotes and bloodstream trypomastigotes; iv) parasite strain; v) number parasites per well; vi) time of incubation with beznidazole, and vii) the source of the drug, which has been produced by different laboratories. Then, comparisons to other IC 50 values of benznidazole should be carefully analyzed.…”

Section: Discussionmentioning

confidence: 99%

Soulamarin Isolated from Calophyllum brasiliense (Clusiaceae) Induces Plasma Membrane Permeabilization of Trypanosoma cruzi and Mytochondrial Dysfunction

et al. 2013

View full text Add to dashboard Cite

Chagas disease is caused by the parasitic protozoan Trypanosoma cruzi. It has high mortality as well as morbidity rates and usually affects the poorer sections of the population. The development of new, less harmful and more effective drugs is a promising research target, since current standard treatments are highly toxic and administered for long periods. Fractioning of methanol (MeOH) extract of the stem bark of Calophyllum brasiliense (Clusiaceae) resulted in the isolation of the coumarin soulamarin, which was characterized by one- and two-dimensional 1H- and 13C NMR spectroscopy as well as ESI mass spectrometry. All data obtained were consistent with a structure of 6-hydroxy-4-propyl-5-(3-hydroxy-2-methyl-1-oxobutyl)-6″,6″-dimethylpyrane-[2″,3″:8,7]-benzopyran-2-one for soulamarin. Colorimetric MTT assays showed that soulamarin induces trypanocidal effects, and is also active against trypomastigotes. Hemolytic activity tests showed that soulamarin is unable to induce any observable damage to erythrocytes (cmax. = 1,300 µM). The lethal action of soulamarin against T. cruzi was investigated by using amino(4-(6-(amino(iminio)methyl)-1H-indol-2-yl)phenyl)methaniminium chloride (SYTOX Green and 1H,5H,11H,15H-Xantheno[2,3,4-ij:5,6,7-i′j′]diquinolizin-18-ium, 9-[4-(chloromethyl)phenyl]-2,3,6,7,12,13,16,17-octahydro-chloride (MitoTracker Red) as fluorimetric probes. With the former, soulamarin showed dose-dependent permeability of the plasma membrane, relative to fully permeable Triton X-100-treated parasites. Spectrofluorimetric and fluorescence microscopy with the latter revealed that soulamarin also induced a strong depolarization (ca. 97%) of the mitochondrial membrane potential. These data demonstrate that the lethal action of soulamarin towards T. cruzi involves damages to the plasma membrane of the parasite and mitochondrial dysfunction without the additional generation of reactive oxygen species, which may have also contributed to the death of the parasites. Considering the unique mitochondrion of T. cruzi, secondary metabolites of plants affecting the bioenergetic system as soulamarin may contribute as scaffolds for the design of novel and selective drug candidates for neglected diseases, mainly Chagas disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Soulamarin Isolated from Calophyllum brasiliense (Clusiaceae) Induces Plasma Membrane Permeabilization of Trypanosoma cruzi and Mytochondrial Dysfunction

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Naphtoquinones such as β–lapachone are natural products isolated from different higher plant families and shown to present antimalarial (Carvalho et al., 1988, De Andrade-Neto et al., 2004, Pérez-Sacau et al., 2005), giardicidal (Corrêa et al., 2009), leishmanicidal (Guimarães et al., 2013) and trypanocidal activity against T. brucei (De Pahn et al., 1988) and Trypanosoma cruzi (Boveris et al., 1978, Docampo et al., 1978, Goijman and Stoppani, 1985, Pinto et al., 1997, Pinto et al., 2000, Menna-Barreto et al., 2005, Menna-Barreto et al., 2007, Menna-Barreto et al., 2009a, 2014). Furthermore, lapachone derivatives/analogues may display enhanced antiparasitic activity upon T. cruzi (Pinto et al., 1997; Ferreira et al., 2011, Diogo et al., 2013). …”

Section: Introductionmentioning

confidence: 99%

Effects of a novel β–lapachone derivative on Trypanosoma cruzi : Parasite death involving apoptosis, autophagy and necrosis

Anjos

Alves

Goncalves

et al. 2016

International Journal for Parasitology: Drugs and Drug Resistan

View full text Add to dashboard Cite

Natural products comprise valuable sources for new antiparasitic drugs. Here we tested the effects of a novel β–lapachone derivative on Trypanosoma cruzi parasite survival and proliferation and used microscopy and cytometry techniques to approach the mechanism(s) underlying parasite death. The selectivity index determination indicate that the compound trypanocidal activity was over ten-fold more cytotoxic to epimastigotes than to macrophages or splenocytes. Scanning electron microscopy analysis revealed that the R72 β–lapachone derivative affected the T. cruzi morphology and surface topography. General plasma membrane waving and blebbing particularly on the cytostome region were observed in the R72-treated parasites. Transmission electron microscopy observations confirmed the surface damage at the cytostome opening vicinity. We also observed ultrastructural evidence of the autophagic mechanism termed macroautophagy. Some of the autophagosomes involved large portions of the parasite cytoplasm and their fusion/confluence may lead to necrotic parasite death. The remarkably enhanced frequency of autophagy triggering was confirmed by quantitating monodansylcadaverine labeling. Some cells displayed evidence of chromatin pycnosis and nuclear fragmentation were detected. This latter phenomenon was also indicated by DAPI staining of R72-treated cells. The apoptotis induction was suggested to take place in circa one-third of the parasites assessed by annexin V labeling measured by flow cytometry. TUNEL staining corroborated the apoptosis induction. Propidium iodide labeling indicate that at least 10% of the R72-treated parasites suffered necrosis within 24 h. The present data indicate that the β–lapachone derivative R72 selectively triggers T. cruzi cell death, involving both apoptosis and autophagy-induced necrosis.

show abstract

“…Cationic cyclic ortho-quinone methides are unstable and are reactive intermediates in organic synthesis, being involved in a large number of chemical reactions studied by our group. 18,[26][27][28][29][30][31][32] These intermediates readily react with phenyl thiol, indicating a good orbital overlap with the cationic species. The structures of the synthesized compounds were confirmed by spectroscopic techniques, such as 1 H and 13 C NMR, IR spectroscopy, and HRMS (ESI).…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and anti-Trypanosoma cruzi activity of new 3‐phenylthio-nor-β-lapachone derivatives

Cardoso

Salomão

Bombaça

et al. 2015

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

Synthesis and anti-Trypanosoma cruzi activity of β-lapachone analogues

Cited by 53 publications

References 45 publications

Soulamarin Isolated from Calophyllum brasiliense (Clusiaceae) Induces Plasma Membrane Permeabilization of Trypanosoma cruzi and Mytochondrial Dysfunction

Soulamarin Isolated from Calophyllum brasiliense (Clusiaceae) Induces Plasma Membrane Permeabilization of Trypanosoma cruzi and Mytochondrial Dysfunction

Effects of a novel β–lapachone derivative on Trypanosoma cruzi : Parasite death involving apoptosis, autophagy and necrosis

Synthesis and anti-Trypanosoma cruzi activity of new 3‐phenylthio-nor-β-lapachone derivatives

Contact Info

Product

Resources

About