In vitro and in vivo activity of lignan lactones derivatives against Trypanosoma cruzi

Abstract

The trypanocidal effect of six lignan lactones, (-)-cubebin (1), (-)-O-methyl cubebin (2), (-)-O-benzyl cubebin (3), (-)-6,6'-dinitrohinokinin (4), (-)-hinokinin (5) and dimethoxymorelensin (6), previously synthesized by our research group, was evaluated in vitro and in vivo. The compounds with higher anti-epimastigote activity were screened against intracellular amastigote of Trypanosoma cruzi. Among these, compound 5 was selected to be assayed in vivo. It was observed that compounds 5, 6 and 2 showed higher trypanocidal activity against epimastigote forms of T. cruzi, displaying inhibitory concentration (IC(50)) values of 0.67, 3.89 and 31.35 muM, respectively. These compounds were also evaluated against intracellular amastigote forms of T. cruzi, with five displaying similar activity to benznidazole. In vivo assays showed significant reduction of parasitaemia after administration of five in mice infected.

Tools for Trans-Splicing Drug Interference Evaluation in Kinetoplastid

“…Furthermore, in vivo assays showed significant parasitemic reduction after administration of HQ in mice infected, and it was observed that the groups treated with HQ displayed better survival rates than that treated with benznidazole. However, DNH presented less activity than benznidazole (Saraiva et al, 2007(Saraiva et al, , 2010. It was also demonstrated that HQ and DNH were not capable to cause strong interference in the RNA processing by trans-splicing in T. cruzi, as observed by the RNase protection reaction.…”

“…(−)-Cubebin, a compound extracted from the dry seeds of the Asian pepper (Piper cubeba L.) and leaves of Zanthoxylum naranjillo, seems to provide treatments with little collateral effect as compared to benznidazole, evaluated by in vitro (cells) and in vivo (mice) tests (Bastos et al, 1999). Partial synthesis of (−)-cubebin resulted in (−)-6,6′-Dinitrohinokinin (DNH) and (−)-hinokinin (HQ) which were also tested in T. cruzi parasites and HQ showed to be a potential candidate for the development of a new drug to treat Chagas' disease (Saraiva et al, 2007(Saraiva et al, , 2010. It showed higher trypanocidal activity than benznidazole against epimastigote forms and similar activity against amastigote forms (De Souza et al, 2005;Saraiva et al, 2007).…”

“…Partial synthesis of (−)-cubebin resulted in (−)-6,6′-Dinitrohinokinin (DNH) and (−)-hinokinin (HQ) which were also tested in T. cruzi parasites and HQ showed to be a potential candidate for the development of a new drug to treat Chagas' disease (Saraiva et al, 2007(Saraiva et al, , 2010. It showed higher trypanocidal activity than benznidazole against epimastigote forms and similar activity against amastigote forms (De Souza et al, 2005;Saraiva et al, 2007). Furthermore, in vivo assays showed significant parasitemic reduction after administration of HQ in mice infected, and it was observed that the groups treated with HQ displayed better survival rates than that treated with benznidazole.…”

Biologia química: uma estratégia moderna para a pesquisa em produtos naturais

“…Somando-se a estes esforços, outras enzimas do T. cruzi também estão sendo alvo de pesquisa na procura por possíveis inibidores, como a cisteína-protease 92 e tripanotiona redutase 93 , assim como vários grupos estão empenhados na pesquisa de produtos naturais tripanocidas 94 bem como na síntese baseada em produtos naturais bioativos 95 . Alguns estudos estão sendo realizados para se averiguar atividade mutagênica 96 e testes in vivo 97 de compostos com atividade promissora.…”

Avaliação da atividade antimicobacteriana da lignana diidrocubebina extraída da Piper cubeba e de seus derivados semissintéticos

“…Em nossos estudos anteriores sobre as lignano lactonas e lactóis várias propriedades biológicas foram relatadas (Saraiva et al, 2007;2009, Silva et al, 2009, Silva et al, 2005Silva et al, 2008;Souza et al, 2005;Silva et al, 2011;Pistolozzi et al, 2013), incluindo a atividade antimicobacteriana (Silva et al, 2009 O extrato etanólico (EE) foi suspenso em solução hidrometanólica (9:1), para cada 20 g de EE foram utilizados aproximadamente 100 mL de solução hidrometanólica. Esta solução foi submetida a partição com hexano (7 x 250 mL), e em seguida separada e concentrada.…”