Antileishmanial activity and evaluation of the mechanism of action of strychnobiflavone flavonoid isolated from Strychnos pseudoquina against Leishmania infantum

A series of new selenocyanates and diselenides bearing interesting bioactive scaffolds (quinoline, quinoxaline, acridine, chromene, furane, isosazole, etc.) was synthesized, and theirin vitroleishmanicidal activities againstLeishmania infantumamastigotes along with their cytotoxicities in human THP-1 cells were determined. Interestingly, most tested compounds were active in the low micromolar range and led us to identify four lead compounds (1h, 2d, 2e, and 2f) with 50% effective dose (ED50) values ranging from 0.45 to 1.27 μM and selectivity indexes of >25 for all of them, much higher than those observed for the reference drugs. These active derivatives were evaluated against infected macrophages, and in order to gain preliminary knowledge about their possible mechanism of action, the inhibition of trypanothione reductase (TryR) was measured. Among these novel structures, compounds 1h (3,5-dimethyl-4-isoxazolyl selenocyanate) and 2d [3,3′-(diselenodiyldimethanediyl)bis(2-bromothiophene)] exhibited good association between TryR inhibitory activity and antileishmanial potency, pointing to 1h, for its excellent theoretical ADME (absorption, distribution, metabolism, and excretion) properties, as the most promising lead molecule for leishmancidal drug design.

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The antileishmanial activity of novel oxygenated chalcones and their mechanism of action

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/43.6.793 ◽

1999 ◽

Vol 43 (6) ◽

pp. 793-803 ◽

Cited By ~ 123

Author(s):

Lin Zhai ◽

Ming Chen ◽

Jens Blom ◽

Thor G. Theander ◽

Søren Brøgger Christensen ◽

...

Keyword(s):

Mechanism Of Action ◽

Antileishmanial Activity

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In Vitro Activities of 7-Substituted 9-Chloro and 9-Amino-2-Methoxyacridines and Their Bis- and Tetra-Acridine Complexes against Leishmania infantum

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.1.174-180.2003 ◽

2003 ◽

Vol 47 (1) ◽

pp. 174-180 ◽

Cited By ~ 36

Author(s):

Carole Di Giorgio ◽

Florence Delmas ◽

Nathalie Filloux ◽

Maxime Robin ◽

Laetitia Seferian ◽

...

Keyword(s):

Lipid Metabolism ◽

Dna Synthesis ◽

Leishmania Infantum ◽

Antileishmanial Activity ◽

Human Monocytes ◽

Secondary Effects ◽

Dna Metabolism ◽

Biochemical Pathways ◽

Main Target

ABSTRACT 9-Chloro and 9-amino-2-methoxyacridines bearing different substituents in position 7, as well as their corresponding unsubstituted dimeric and tetrameric complexes, were investigated for in vitro antiproliferative properties against Leishmania infantum compared to toxicity towards human monocytes. The results clearly confirmed that several compounds of the 2-methoxyacridine series, together with their corresponding dimeric and tetrameric derivatives, had strong in vitro antiparasitic properties. Antileishmanial activity was shown to depend on the nature of both 7- and 9-substituted groups in monoacridines, while it varied according to the nature of the 9-substituted group and the length of the linker among bis- and tetra-acridines. The effects of acridine derivatives on DNA synthesis raised the hypothesis that DNA metabolism constituted their main target in Leishmania promastigotes; however, secondary effects on other biochemical pathways, including protein and lipid metabolism, were observed, suggesting that acridine compounds could be considered multitarget drugs.

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Antileishmanial activity evaluation of thiazolidine-2,4-dione against Leishmania infantum and Leishmania braziliensis

Parasitology Research ◽

10.1007/s00436-020-06706-3 ◽

2020 ◽

Vol 119 (7) ◽

pp. 2263-2274 ◽

Cited By ~ 1

Author(s):

Flávio Simas Moreira Neri ◽

David Bacelar Costa Júnior ◽

Thamires Quadros Froes ◽

Priscila Brandão Gomes da Silva ◽

Micalyne Soares do Egito ◽

...

Keyword(s):

Leishmania Infantum ◽

Antileishmanial Activity ◽

Leishmania Braziliensis ◽

Activity Evaluation

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Ultrastructural Analysis ofLeishmania infantum chagasiPromastigotes Forms TreatedIn Vitrowith Usnic Acid

The Scientific World JOURNAL ◽

10.1155/2015/617401 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 5

Author(s):

João S. B. da Luz ◽

Erwelly B. de Oliveira ◽

Monica C. B. Martins ◽

Nicácio H. da Silva ◽

Luiz C. Alves ◽

...

Keyword(s):

Leishmania Infantum ◽

Usnic Acid ◽

Public Health Problem ◽

Ultrastructural Analysis ◽

Antileishmanial Activity ◽

World Health ◽

Global Public Health ◽

Drug Induced ◽

Leishmania Infantum Chagasi

Leishmaniasis is considered by the World Health Organization as one of the infectious parasitic diseases endemic of great relevance and a global public health problem. Pentavalent antimonials used for treatment of this disease are limited and new phytochemicals emerge as an alternative to existing treatments, due to the low toxicity and cost reduction. Usnic acid is uniquely found in lichens and is especially abundant in genera such asAlectoria,Cladonia,Evernia,Lecanora,Ramalina,andUsnea. Usnic acid has been shown to exhibit antiviral, antiprotozoal, antiproliferative, anti-inflammatory, and analgesic activity. The aim of this study was to evaluate the antileishmanial activity of usnic acid onLeishmania infantum chagasipromastigotes and the occurrence of drug-induced ultrastructural damage in the parasite. Usnic acid was effective against the promastigote forms (IC50= 18.30 ± 2.00 µg/mL). Structural and ultrastructural aspects of parasite were analyzed. Morphological alterations were observed as blebs in cell membrane and shapes given off, increasing the number of cytoplasmic vacuoles, and cellular and mitochondrial swelling, with loss of cell polarity. We concluded that the usnic acid presented antileishmanial activity against promastigote forms ofLeishmania infantum chagasiand structural and ultrastructural analysis reinforces its cytotoxicity. Further,in vitrostudies are warranted to further evaluate this potential.

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