title: N-butyl-[1-(4-methoxy)phenyl-9H-β-carboline]-3-carboxamide prevents cytokinesis in Leishmania amazonensis.
abstract: Leishmaniasis, 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 β-carboline compounds. In the present study, we investigated the in vitro antileishmanial activity of N-butyl-[1-(4-methoxy)phenyl-9H-β-carboline]-3-carboxamide (β-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, β-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 G2/M stage of the cell cycle. Altogether, these results suggest that β-CB likely prevents cytokinesis, although it does not interfere with the duplication of cell structures. We also verified an increase in O2(·-) 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, β-CB likely exerts its antileishmanial activity through a cytostatic effect, thus preventing cellular proliferation.
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas: Biologia Celular e Molecular, Universidade Estadual de Maringá, Maringá, PR, Brazil.
authors.forename: T F
authors.initials: TF
authors.lastname: Stefanello
authors.affiliation: Departamento de Química, Universidade Estadual de Maringá, Maringá, PR, Brazil.
authors.forename: M R
authors.initials: MR
authors.lastname: Panice
authors.affiliation: Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brazil.
authors.forename: T
authors.initials: T
authors.lastname: Ueda-Nakamura
authors.affiliation: Departamento de Química, Universidade Estadual de Maringá, Maringá, PR, Brazil.
authors.forename: M H
authors.initials: MH
authors.lastname: Sarragiotto
authors.affiliation: Centre de Recherches sur les Macromolécules Végétales (CERMAV-CNRS), affiliated with Université Grenoble Alpes, Grenoble, France.
authors.forename: R
authors.initials: R
authors.lastname: Auzély-Velty
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas: Biologia Celular e Molecular, Universidade Estadual de Maringá, Maringá, PR, Brazil cvnakamura@uem.br.
authors.forename: C V
authors.initials: CV
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D061245:Axenic Culture; D002243:Carbolines / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D048749:Cytokinesis / Q000187:drug effects*; D054697:Cytostatic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D005407:Flagella / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007894:Leishmania mexicana / Q000187:drug effects* / Q000254:growth & development; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000382:microbiology; D008018:Life Cycle Stages / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D000981:Antiprotozoal Agents; D002243:Carbolines; D054697:Cytostatic Agents; C000599186:N-butyl-(1-(4-methoxy)phenyl-9H-beta-carboline)-3-carboxamide