In vitro and in vivo anthelmintic activity of (−)-6,6′-dinitrohinokinin against schistosomula and juvenile and adult worms of Schistosoma mansoni

• Published in: Acta tropica 2015-09, Vol.149, p.195-201
• Main Authors: Pereira, Ana C., Silva, Márcio L.A. e, Souza, Julia Medeiros, Laurentiz, Rosangela S. de, Rodrigues, Vanderlei, Januário, Ana H., Pauletti, Patrícia M., Tavares, Denise C., Filho, Ademar A. Da Silva, Cunha, Wilson R., Bastos, Jairo K., Magalhães, Lizandra G.
• Format: Article
• Language: English
• Subjects: (−)-6,6′-Dinitrohinokinin; 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - pharmacology; Animals; Anthelmintics - pharmacology; Benzodioxoles - pharmacology; Cricetinae; Cricetulus; Female; Fibroblasts - drug effects; In Vitro Techniques; Lignan; Lignans - pharmacology; Liver - drug effects; Liver - parasitology; Lung - cytology; Mice; Mice, Inbred BALB C; Microscopy, Electron, Scanning; Schistosoma mansoni; Schistosoma mansoni - drug effects; Schistosoma mansoni - growth & development; Schistosoma mansoni - ultrastructure; Schistosomiasis mansoni
• ISSN: 0001-706X; 1873-6254
• DOI: 10.1016/j.actatropica.2015.06.005

[Display omitted] •Effects of (−)-6,6′-dinitrohinokin (DNK) on S. mansoni were studied.•The LC50 of DNK against adult worms in vitro was 102.5±4.8μM at 72h.•DNK caused mortality of schistosomula with an LC50 of 20.4±1.2μM at 72h in vitro.•DNK reduced the total number of eggs by over 83% in vitro.•In vivo, DNK moderately decreased the worm burden and number of eggs. 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.