Autor(es):
Bruno de Sousa, Carolina ; Gangadhar, Katkam N. ; Morais, Thiago R. ; Conserva, Geanne A.A. ; Vizetto-Duarte, Catarina ; Pereira, Hugo ; Laurenti, Márcia D. ; Campino, Lenea ; Levy, Debora ; Uemi, Miriam ; Barreira, Luísa ; Custódio, Luísa ; Passero, Luiz Felipe D. [UNESP] ; Lago, João Henrique G. ; Varela, João
Data: 2018
Identificador Persistente: http://hdl.handle.net/11449/174159
Origem: Oasisbr
Assunto(s): Cystoseira baccata; Leishmania infantum; Macroalgae; Meroterpenoids; Tetraprenyltoluquinol; Tetraprenyltoluquinone
Descrição
Made available in DSpace on 2018-12-11T17:09:38Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-03-01
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
The development of novel drugs for the treatment of leishmaniases continues to be crucial to overcome the severe impacts of these diseases on human and animal health. Several bioactivities have been described in extracts from macroalgae belonging to the Cystoseira genus. However, none of the studies has reported the chemical compounds responsible for the antileishmanial activity observed upon incubation of the parasite with the aforementioned extracts. Thus, this work aimed to isolate and characterize the molecules present in a hexane extract of Cystoseira baccata that was found to be bioactive against Leishmania infantum in a previous screening effort. A bioactivity-guided fractionation of the C. baccata extract was carried out and the inhibitory potential of the isolated compounds was evaluated via the MTT assay against promastigotes and murine macrophages as well as direct counting against intracellular amastigotes. Moreover, the promastigote ultrastructure, DNA fragmentation and changes in the mitochondrial potential were assessed to unravel their mechanism of action. In this process, two antileishmanial meroditerpenoids, (3R)- and (3S)-tetraprenyltoluquinol (1a/1b) and (3R)- and (3S)-tetraprenyltoluquinone (2a/2b), were isolated. Compounds 1 and 2 inhibited the growth of the L. infantum promastigotes (IC50 = 44.9 ± 4.3 and 94.4 ± 10.1 μM, respectively), inducing cytoplasmic vacuolization and the presence of coiled multilamellar structures in mitochondria as well as an intense disruption of the mitochondrial membrane potential. Compound 1 decreased the intracellular infection index (IC50 = 25.0 ± 4.1 μM), while compound 2 eliminated 50% of the intracellular amastigotes at a concentration > 88.0 μM. This work identified compound 2 as a novel metabolite and compound 1 as a biochemical isolated from Cystoseira algae displaying antileishmanial activity. Compound 1 can thus be an interesting scaffold for the development of novel chemotherapeutic molecules for canine and human visceral leishmaniases studies. This work reinforces the evidence of the marine environment as source of novel molecules.
Centro de Ciências do Mar Universidade do Algarve Campus de Gambelas
Instituto de Tecnologia Química e Biológica Universidade Nova de Lisboa
Departamento de Ciências Exatas e da Terra Instituto de Ciências Ambientais Químicas e Farmacêuticas Universidade Federal de São Paulo
Laboratório de Patologia das Moléstias Infecciosas (LIM-50) Departamento de Patologia Faculdade de Medicina Universidade de São Paulo
Global Health and Tropical Medicine Centre Instituto de Higiene e Medicina Tropical Universidade Nova de Lisboa
Departamento de Ciências Biomédicas e Medicina Universidade do Algarve Campus de Gambelas
Laboratório de Genética e Hematologia Molecular (LIM-31) Departamento de Clinica Médica Faculdade de Medicina Universidade de São Paulo
São Paulo State University (UNESP) Institute of Biosciences São Vicente, Praça Infante Dom Henrique, s/n
São Paulo State University (UNESP) Institute of Biosciences São Vicente, Praça Infante Dom Henrique, s/n
FAPESP: 2013/16297-2
FAPESP: 2015/11936-2
CNPq: 470853/2012-3
