The Effects ofN-Butyl-1-(4-dimethylamino)phenyl-1,2,3,4-tetrahydro-β-carboline-3-carboxamide againstLeishmania amazonensisAre Mediated by Mitochondrial Dysfunction

Volpato, Hélito; Desoti, Vânia Cristina; Cogo, Juliana; Panice, Manuela Ribeiro; Sarragiotto, María Helena; Silva, Sueli de Oliveira; Ueda-Nakamura, Tânia; Nakamura, Celso Vataru

doi:10.1155/2013/874367

Cited by 23 publications

(17 citation statements)

References 31 publications

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“…Considering that trypanosomatids have only one mitochondrion, such an organelle may be considered a potential therapeutic target (44). Several studies have reported that different classes of compounds (40,(45)(46)(47), including quinoxaline derivatives (27), cause mitochondrial dysfunction in trypanosomatids.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Activities of 2,3-Diarylsubstituted Quinoxaline Derivatives against Leishmania amazonensis

Kaplum

Cogo

Sangi

et al. 2016

Antimicrob Agents Chemother

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Leishmaniasis is endemic in 98 countries and territories worldwide. The therapies available for leishmaniasis have serious side effects, thus prompting the search for new therapies. The present study investigated the antileishmanial activities of 2,3-diarylsubstituted quinoxaline derivatives against Leishmania amazonensis. The antiproliferative activities of 6,7-dichloro-2,3-diphenylquinoxaline (LSPN329) and 2,3-di-(4-methoxyphenyl)-quinoxaline (LSPN331) against promastigotes and intracellular amastigotes were assessed, and the cytotoxicities of LSPN329 and LSPN331 were determined. Morphological and ultrastructural alterations were examined by electron microscopy, and biochemical alterations, reflected by the mitochondrial membrane potential (⌬⌿m), mitochondrial superoxide anion (O 2 · ؊ ) concentration, the intracellular ATP concentration, cell volume, the level of phosphatidylserine exposure on the cell membrane, cell membrane integrity, and lipid inclusions, were evaluated. In vivo antileishmanial activity was evaluated in a murine cutaneous leishmaniasis model. Compounds LSPN329 and LSPN331 showed significant selectivity for promastigotes and intracellular amastigotes and low cytotoxicity. In promastigotes, ultrastructural alterations were observed, including an increase in lipid inclusions, concentric membranes, and intense mitochondrial swelling, which were associated with hyperpolarization of ⌬⌿m, an increase in the O 2 · ؊ concentration, decreased intracellular ATP levels, and a decrease in cell volume. Phosphatidylserine exposure and DNA fragmentation were not observed. The cellular membrane remained intact after treatment. Thus, the multifactorial response that was responsible for the cellular collapse of promastigotes was based on intense mitochondrial alterations. BALB/c mice treated with LSPN329 or LSPN331 showed a significant decrease in lesion thickness in the infected footpad. Therefore, the antileishmanial activity and mitochondrial mechanism of action of LSPN329 and LSPN331 and the decrease in lesion thickness in vivo brought about by LSPN329 and LSPN331 make them potential candidates for new drug development for the treatment of leishmaniasis.

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Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Activities of 2,3-Diarylsubstituted Quinoxaline Derivatives against Leishmania amazonensis

Kaplum

Cogo

Sangi

et al. 2016

Antimicrob Agents Chemother

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“…In the present study, it was also active against axenic and intracel- lular amastigote forms, exhibiting high selectivity for the parasite, independent of the evolutive form assessed. Furthermore, ␤-CB presented more pronounced antileishmanial activity than another ␤-carboline compound presenting the N-butylcarboxamide group, N-butyl-1-(4-dimethylamino)phenyl-1,2,3,4-tetrahydro-␤-carboline-3-carboxamide, against the same species and evolutive form (11). However, its activity was slightly lower than a similar compound possessing an N-benzylcarboxamide in place of the N-butylcarboxamide group (12).…”

Section: Discussionmentioning

confidence: 91%

“…Several studies have sought to develop new treatment alternatives for leishmaniasis. ␤-Carboline compounds, characterized by a tricyclic pyrido [3,4-b]indole ring structure, have been evaluated as potential antileishmanial molecules (8,11,12). In the present study, we evaluated the activity of the ␤-carboline compound ␤-CB against L. amazonensis, which causes cutaneous and diffuse cutaneous forms of leishmaniasis.…”

Section: Discussionmentioning

confidence: 99%

“…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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High selective antileishmanial activity of vanadium complex with stilbene derivative

et al. 2015

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The Effects ofN-Butyl-1-(4-dimethylamino)phenyl-1,2,3,4-tetrahydro-β-carboline-3-carboxamide againstLeishmania amazonensisAre Mediated by Mitochondrial Dysfunction

Cited by 23 publications

References 31 publications

In Vitro and In Vivo Activities of 2,3-Diarylsubstituted Quinoxaline Derivatives against Leishmania amazonensis

In Vitro and In Vivo Activities of 2,3-Diarylsubstituted Quinoxaline Derivatives against Leishmania amazonensis

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

High selective antileishmanial activity of vanadium complex with stilbene derivative

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