Biological activity of 1,2,3,4-tetrahydro-β-carboline-3-carboxamides against Trypanosoma cruzi

Valdez, Rodrigo Hinojosa; Tonin, Lilian Tatiani Düsman; Ueda-Nakamura, Tânia; Filho, Benedito Prado Dias; Morgado‐Díaz, José Andrés; Sarragiotto, María Helena; Nakamura, Celso Vataru

doi:10.1016/j.actatropica.2008.11.008

Cited by 64 publications

(39 citation statements)

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“…16,[48][49] Several synthetic compounds have also shown trypanocidal activity. 50,51 Acanthoic acid (1) at 3 µmol L -1 (the lowest concentration tested) displayed a growth inhibition of parasites of 13.6%, while at the highest concentration (331 µmol L -1 ), over 90% of the cells were affected. Therefore, the 50% inhibition concentration was determined at 59 µmol L -1 .…”

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confidence: 99%

Acanthoic acid and other constituents from the stem of Annona amazonica (Annonaceae)

Pinheiro

Xavier

Souza

et al. 2009

J. Braz. Chem. Soc.

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O presente trabalho descreve o isolamento, a partir do caule de Annona amazonica, do ácido acantóico, um diterpeno do tipo pimaradieno que possui várias e importantes atividades biológicas descritas na literatura. Neste estudo foi verificado que este composto apresenta significante atividade tripanocida contra as formas epimastigotas de Trypanosoma cruzi. Também foi constatado que este diterpeno é o constituinte majoritário da planta, encontrado em cerca de 65% do extrato hexânico, demonstrando que A. amazonica é uma nova fonte natural renovável desta substância. Além do ácido acantóico, a investigação química resultou no isolamento dos alcalóides liriodenina e cassiticina, entre outros compostos, tais como terpenos, esteróides e ácidos graxos. Adicionalmente, é descrita a completa e inequívoca atribuição dos deslocamentos químicos de RMN de 1 H e 13 C da cassiticina.The present work reports the isolation of acanthoic acid, a promising pimaradiene-type diterpene with several important biological activities described in the literature, from the stems of Annona amazonica. We found that acanthoic acid has significant trypanocidal activity against the epimastigote forms of Trypanosoma cruzi. This diterpene is the major constituent of the plant, comprising at least 65% of the hexane extract, demonstrating that A. amazonica is a new renewable natural source for this compound. The chemical investigation also resulted in the isolation of the alkaloids liriodenine and cassythicine, and other compounds including terpenes, sterols, and fatty acids. Additionally, the complete and unequivocal 1 H and 13 C NMR chemical shift assignments for cassythicine are provided. Keywords: Annona amazonica, Annonaceae, acanthoic acid, cassythicine, trypanocidal activity IntroductionThe family Annonaceae, comprised of tropical and subtropical species with about 135 genera and more than 2500 species and widely distributed in South and Central America, Africa, Asia, and Australia, 1 is known for its edible fruits and the medicinal properties of several species. 2 In Brazil, there are 26 genera with about 260 species, including the genus Annona, which contains approximately 120 species. 3 Chemical investigations of species of Annonaceae have revealed their high chemical diversity in terms of secondary metabolites, such as alkaloids, acetogenins, terpenoids and lactones. These compounds have shown important biological activities, including antiparasitic, in particular against Leishmania sp., Plasmodium falciparum, and Trypanosoma cruzi. [4][5][6][7][8][9][10][11][12] Annona amazonica R.E. Fries is a tropical tree that grows up to 20-25 m tall and 35-60 cm in diameter, and is found from Panama to South America. In Brazil this species commonly occurs in the Amazon, mainly in the states of Amazonas and Pará. 13 To the best of our knowledge, only one previous phytochemical study has described the isolation and identification of cyanogenic constituents from this species. 14 Here we describe the isolation and structural identification of the chemica...

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Acanthoic acid and other constituents from the stem of Annona amazonica (Annonaceae)

Pinheiro

Xavier

Souza

et al. 2009

J. Braz. Chem. Soc.

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“…Although many studies have been published on T. cruzi, T. brucei and Leishmania, few have characterized the effects of these products on the ultrastructure of the parasites. Mitochondrial swelling and the presence of concentric membrane structures in its matrix were observed after incubation of Leishmania and T. cruzi with any of the following: linalool-rich essential oil of Croton cajucara [69], usnic acid from the lichen Cladonia substellata [70], extract of the marine sponge Plakortis angulospiculatus [71], extract of the seeds of Pterodon pubescens with geranylgeraniol (GG-OH) being the most active fraction [72]), propolis [73], taxol isolated from Taxus brevifolia [74], dinitroaniline herbicides [75], -carbolines [76], chalcones from Piper aduncum [77], or neolignan from leaves of Piper regnellii [78].…”

Section: B E)mentioning

confidence: 99%

“…Sometimes, the disorganization of the kDNA network, which has mainly been observed in trypomastigotes, seems to be the result of the severe swelling of the mitochondrion and the loss of the inner membrane. In contrast, aromatic diamidines [18,[20][21][22][23], natural and synthetic -carbolines [76], topoisomerase inhibitors [80,82,83], and DAB [68] cause a drastic effect: the destruction or fragmentation of the kDNA network in promastigotes and amastigotes of Leishmania and in trypomastigotes of T. cruzi. These effects were not observed in the kinetoplasts of epimastigote forms of T. cruzi.…”

Section: Kinetoplastmentioning

confidence: 99%

Contributions of Ultrastructural Studies to the Cell Biology of Trypanosmatids: Targets for Anti-Parasitic Drugs

Almeida¹,

Souto-Padrón

2010

TOPARAJ

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Protozoan parasites cause disease in humans worldwide, and many fall into the genera Trypanosoma and Leishmania; these parasites are responsible for African trypanosomiasis, Chagas disease and the different forms of Leishmaniasis. Strategies for the development of new drugs against these protozoans have been based on their cell biology and biochemistry complemented by the use of electron microscopy. Trypanosoma and Leishmania have special organelles that are involved in metabolic pathways, which are very distinct from those in mammalian cells; these organelles are potential drug targets. Scanning and transmission electron microscopy can identify not only the target organelles but also alterations to the cell surface and ultrastructural changes that characterize distinct forms of programmed cell death.

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“…Some studies have shown that ␤-carboline compounds can induce mitochondrial dysfunction in trypanosomatids (10,11,35) , and consequently cellular damage (37,38).…”

Section: Fig 8 Cell Cycle Analysis Of Leishmania Amazonensis Promastimentioning

confidence: 99%

“…␤-Carboline alkaloids have drawn attention because of their biological activities against parasites of the Trypanosomatidae family, including antitrypanosomal activity (6)(7)(8)(9)(10) and antileishmanial activity (8,(11)(12)(13). A recent study demonstrated the antileishmanial and antitrypanosomal activity of a series of N-alkyl-(1-phenyl-substituted-tetrahydro-␤-carboline)-3-carboxamides, showing that compounds containing Nbutylcarboxamide groups were the most active, suggesting that these groups may improve the biological activity of these compounds (8).…”

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N -Butyl-[1-(4-Methoxy)Phenyl-9 H -β-Carboline]-3-Carboxamide Prevents Cytokinesis in Leishmania amazonensis

Stefanello

Panice

Ueda-Nakamura

et al. 2014

Antimicrob Agents Chemother

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dLeishmaniasis, a complex of diseases caused by protozoa of the genus Leishmania, is endemic in 98 countries, affecting approximately 12 million people worldwide. Current treatments for leishmaniasis have many disadvantages, such as toxicity, high costs, and prolonged treatment, making the development of new treatment alternatives highly relevant. Several studies have verified the antileishmanial activity of ␤-carboline compounds. In the present study, we investigated the in vitro antileishmanial activity of N-butyl-[1-(4-methoxy)phenyl-9H-␤-carboline]-3-carboxamide (␤-CB) against Leishmania amazonensis. The compound was active against promastigote, axenic amastigote, and intracellular amastigote forms of L. amazonensis, exhibiting high selectivity for the parasite. Moreover, ␤-CB did not exhibit hemolytic or mutagenic potential. Promastigotes treated with the alkaloid presented rounding of the body cell, cell membrane projections, an increase in the number of promastigotes presenting two flagella, and parasites of abnormal phenotype, with three or more flagella and/or nuclei. Furthermore, we observed an increase in the subpopulation of cells in the G 2 /M stage of the cell cycle. Altogether, these results suggest that ␤-CB likely prevents cytokinesis, although it does not interfere with the duplication of cell structures. We also verified an increase in O 2 ·؊ production and the accumulation of lipid storage bodies. Cell membrane integrity was maintained, in addition to the absence of phosphatidylserine externalization, DNA fragmentation, and autophagosomes. Although the possibility of an apoptotic process cannot be discarded, ␤-CB likely exerts its antileishmanial activity through a cytostatic effect, thus preventing cellular proliferation.

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Biological activity of 1,2,3,4-tetrahydro-β-carboline-3-carboxamides against Trypanosoma cruzi

Cited by 64 publications

References 29 publications

Acanthoic acid and other constituents from the stem of Annona amazonica (Annonaceae)

Acanthoic acid and other constituents from the stem of Annona amazonica (Annonaceae)

Contributions of Ultrastructural Studies to the Cell Biology of Trypanosmatids: Targets for Anti-Parasitic Drugs

N -Butyl-[1-(4-Methoxy)Phenyl-9 H -β-Carboline]-3-Carboxamide Prevents Cytokinesis in Leishmania amazonensis

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