title: In vitro and in vivo anthelmintic activity of (-)-6,6'-dinitrohinokinin against schistosomula and juvenile and adult worms of Schistosoma mansoni.
abstract: The chemotherapy of schistosomiasis relies on the use of praziquantel. However, concerns over drug resistance have encouraged the search for new drug leads. This paper is the first report on the in vitro and in vivo activity of (-)-6,6'-dinitrohinokinin (DNK) against Schistosoma mansoni. In vitro, the lethal concentrations for 50% of parasites (LC50) of DNK against adult worms were 103.9±3.6 and 102.5±4.8μM at 24 and 72h, respectively. Scanning electron microscopy images showed extensive tegumental alterations such as peeling and smaller numbers of tubercles in the spine of adult worms. DNK also elicited high mortality of schistosomula, with LC50 values of 57.4±2.3, 32.5±0.9, and 20.4±1.2μM at 24, 48, and 72h, respectively. DNK displayed moderate activity against the juvenile liver parasite, with an LC50 value of 179.5±2.3 μM at 72h. This compound reduced the total number of eggs by over 83%, and it affected the development of eggs produced by adult worms. The selectivity index showed that at 24h, DNK was 8.5 and 15.4 times more toxic to the adult worms and schistosomula than to Chinese hamster lung fibroblast cells, respectively. Treatment of infected mice with DNK moderately decreased worm burden (33.8-52.3%), egg production (40.7-60.0%), and spleen and liver weights. Together, our results indicated that DNK presents moderate in vitro and in vivo activities against S. mansoni, and it might therefore be interesting to explore the structure-activity relationship of the antischistosomal activity of this compound.
authors.affiliation: Universidade de Franca, Núcleo de Pesquisas em Ciências Exatas e Tecnológicas, CEP 14404-600 Franca, SP, Brazil; Universidade de São Paulo(,) Faculdade de Farmácia de Ribeirão Preto, Departamento de Ciências Farmacêuticas, CEP 14030-000, Ribeirão Preto, SP, Brazil.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Pereira
authors.affiliation: Universidade de Franca, Núcleo de Pesquisas em Ciências Exatas e Tecnológicas, CEP 14404-600 Franca, SP, Brazil.
authors.forename: Márcio L A E
authors.initials: ML
authors.lastname: Silva
authors.affiliation: Universidade de Franca, Núcleo de Pesquisas em Ciências Exatas e Tecnológicas, CEP 14404-600 Franca, SP, Brazil.
authors.forename: Julia Medeiros
authors.initials: JM
authors.lastname: Souza
authors.affiliation: Universidade Estadual Paulista, Faculdade de Engenharia de Ilha Solteira, Departamento de Física e Química, CEP 15385-000, Ilha Solteira, SP, Brazil.
authors.forename: Rosangela S de
authors.initials: RS
authors.lastname: Laurentiz
authors.affiliation: Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Bioquímica e Imunologia, CEP 14049-900, Ribeirão Preto, SP, Brazil.
authors.forename: Vanderlei
authors.initials: V
authors.lastname: Rodrigues
authors.affiliation: Universidade de Franca, Núcleo de Pesquisas em Ciências Exatas e Tecnológicas, CEP 14404-600 Franca, SP, Brazil.
authors.forename: Ana H
authors.initials: AH
authors.lastname: Januário
authors.affiliation: Universidade de Franca, Núcleo de Pesquisas em Ciências Exatas e Tecnológicas, CEP 14404-600 Franca, SP, Brazil.
authors.forename: Patrícia M
authors.initials: PM
authors.lastname: Pauletti
authors.affiliation: Universidade de Franca, Núcleo de Pesquisas em Ciências Exatas e Tecnológicas, CEP 14404-600 Franca, SP, Brazil.
authors.forename: Denise C
authors.initials: DC
authors.lastname: Tavares
authors.affiliation: Universidade Federal de Juiz de Fora, Faculdade de Farmácia de Juiz de Fora, Departamento de Ciências Farmacêuticas, CEP 36036-900, Juiz de Fora, MG, Brazil.
authors.forename: Ademar A Da Silva
authors.initials: AA
authors.lastname: Filho
authors.affiliation: Universidade de Franca, Núcleo de Pesquisas em Ciências Exatas e Tecnológicas, CEP 14404-600 Franca, SP, Brazil.
authors.forename: Wilson R
authors.initials: WR
authors.lastname: Cunha
authors.affiliation: Universidade de São Paulo(,) Faculdade de Farmácia de Ribeirão Preto, Departamento de Ciências Farmacêuticas, CEP 14030-000, Ribeirão Preto, SP, Brazil.
authors.forename: Jairo K
authors.initials: JK
authors.lastname: Bastos
authors.affiliation: Universidade de Franca, Núcleo de Pesquisas em Ciências Exatas e Tecnológicas, CEP 14404-600 Franca, SP, Brazil. Electronic address: lizandra.magalhaes@unifran.edu.br.
authors.forename: Lizandra G
authors.initials: LG
authors.lastname: Magalhães
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D066298:In Vitro Techniques; D017705:Lignans / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000469:parasitology*; D008168:Lung / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008855:Microscopy, Electron, Scanning; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D012555:Schistosomiasis mansoni
chemical_list: C000605643:6,6'-dinitrohinokinin; D000871:Anthelmintics; D052117:Benzodioxoles; D017705:Lignans; D015107:4-Butyrolactone
keywords: (−)-6,6′-Dinitrohinokinin; Lignan; Schistosoma mansoni