Arylimidamides have potential for chemoprophylaxis against blood-transmitted Chagas disease

Chagas disease (CD) affects over 6 million people worldwide and can be transmitted iatrogenically. Crystal violet (CV) was previously used for pathogen reduction but has harmful side-effects. In the present study, three arylimidamides (AIAs) and CV were used to sterilize mice blood samples experimentally contaminated with bloodstream trypomastigotes (BT) of Trypanosoma cruzi, at non hemolytic doses. All AIAs were not toxic to mouse blood cells until the highest tested concentration (96 µM). The previous treatment of BT with the AIAs impaired the infection establishment of cardiac cell cultures. In vivo assays showed that pre-incubation of mouse blood samples with the AIAs and CV (96 µM) significantly suppressed the parasitemia peak, but only the AIA DB1831 gave ≥90% animal survival, while vehicle treated samples reached 0%. Our findings support further studies regarding the potential use of AIAs for blood bank purposes

In Vitro and In Vivo Biological Effects of Novel Arylimidamide Derivatives against Trypanosoma cruzi

ABSTRACT Chagas disease (CD), a neglected tropical disease caused by Trypanosoma cruzi , remains a serious public health problem in several Latin American countries. The available chemotherapies for CD have limited efficacy and exhibit undesirable side effects. Aromatic diamidines and arylimidamides (AIAs) have shown broad-spectrum activity against intracellular parasites, including T. cruzi . Therefore, our aim was to evaluate the biological activity of eight novel AIAs (16DAP002, 16SAB079, 18SAB075, 23SMB022, 23SMB026, 23SMB054, 26SMB070, and 27SMB009) against experimental models of T. cruzi infection in vitro and in vivo . Our data show that none of the compounds induced a loss of cellular viability up to 32 μM. Two AIAs, 18SAB075 and 16DAP002, exhibited good in vitro activity against different parasite strains (Y and Tulahuen) and against the two relevant forms of the parasite for mammalian hosts. Due to the excellent selective indexes of 18SAB075, this AIA was moved to in vivo tests for acute toxicity and parasite efficacy; nontoxic doses (no-observed-adverse-effect level [NOAEL], 50 mg/kg) were employed in the tests for parasite efficacy. In experimental models of acute T. cruzi infection, 18SAB075 reduced parasitemia levels only up to 50% and led to 40% protection against mortality (at 5 mg/kg of body weight), being less effective than the reference drug, benznidazole

Avaliação do potencial terapêutico de novos agentes tripanocidas sobre o Trypanosoma cruzi

Made available in DSpace on 2016-03-01T13:50:54Z (GMT). No. of bitstreams: 2 bruno_timm_ioc_mest_2014.pdf: 518583 bytes, checksum: 544bec01acb7c09f5e6155ee5c6a52fe (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2016-01-13Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, BrasilO tratamento etiológico disponível para a doença de Chagas, causada pelo parasito intracelular Trypanosoma cruzi, é baseado em dois nitroderivados, benzonidazol (Bz) e nifurtimox (Nif), ambos introduzidos empiricamente na prática clínica há mais de 40 anos. Estes fármacos são considerados insatisfatórios principalmente devido à (i) baixa eficácia, principalmente na fase crônica, (ii) efeitos colaterais importantes, e (iii) ocorrência de linhagens de parasitas resistentes. Um dos atuais desafios desta doença negligenciada é o desenvolvimento de tratamentos alternativos mais efetivos e seletivos, constituindo o objetivo principal da presente dissertação. Assim, ensaios in vitro e in vivo foram conduzidos para avaliar a eficácia de diamidinas aromáticas (DAs) e arilimidamidas (AIAs), sobre T. cruzi. No primeiro artigo demonstramos a atividade de dez diamidinas sobre formas tripomastigotas, na faixa micromolar, sem redução significativa da viabilidade da célula hospedeira. Três DAs com anéis externos benzimidazólicos N-metilados apresentaram diferenças na atividade tripanocida, sendo o composto DB2247, com meta-N-metilação em ambos os anéis, o mais ativo e também o de mais rápida ação Todavia, nenhum do compostos testados foi ativo sobre amastigotas intracelulares. No segundo artigo avaliamos atividade anti-T. cruzi de oito novas AIAs. Nossos dados mostram que seis destes compostos foram inativos sobre ambas formas evolutivas do parasito. As duas AIAs que apresentaram efeito sobre as formas tripomastigotas foram 18SAB075 e 16DAP005, que exibiram ainda excelente ação in vitro sobre formas intracelulares, com eficácia similar ao Bz. Neste sentido, o composto 18SAB075, que apresentou ótimo índice de seletividade para tripomastigotas sanguíneos (IS > 106), foi avaliado in vivo quanto à toxicidade aguda e eficácia. Em modelo experimental de infecção aguda com T. cruzi, o tratamento com 18SAB075 com doses não tóxicas (5 mg/kg por cinco dias consecutivos) reduziu em cerca de 50% os níveis parasitêmicos e apresentou 40% de proteção contra mortalidade, sendo menos efetivo do que o fármaco de referência (Bz 100 mg/kg/dia) Neste sentido, este trabalho apresenta informações relevantes sobre a atividade biológica de novos análogos aromáticos sobre T. cruzi, estimulando a continuidade de estudos pré-clínicos com novos agentes e derivados objetivando encontrar compostos mais seletivos para terapia da doença de ChagasThe available etiologic treatment of Chagas disease , caused by the intracellular parasite Trypanosoma cruzi , is based on two nitroderivatives, benznidazole (Bz) and Nif , both introduced empirically in the clinical practice for over 40 years ago. These drugs are considered unsatisfactory mainly due to their (i) low efficacy, mainly in the chroni c phase, (ii) severe side effects , and (iii) occurrence of resistant parasite strains. O ne of the main challenges of this neglected disease is the development of more effective and selective therapies, which is our main objective . Thus, in vitro and in vivo studies were conducted to evaluate the efficacy of aromatic amidines (DAs) and arylimidamides (AIAs) against T. cruzi . In the first paper , we demonstrated the activity of ten novel diamidines at micromolar range against against trypomastigotes , withou t significant loss in host cell viability. In this study we found that three diamidines with N - methylated benzimidazoles outer rings displayed different trypanocidal activities, being the compound DB2247 , with meta - N - methylation in both rings, the most active with also a faster trypanocidal action. However, none of the diamidines were active against intracellular amastigotes. In the second paper, we evaluated the efficacy of eight novel AIAs against T. cruzi . Our data showed that s ix out of the eight studied compounds were inactive against both evolutive forms of the parasite. The only two AIAs that were active, 18SAB075 and 16DAP005, displayed outstanding in vitro effect with efficac y similar to that of Bz against intracellular forms. In this way, the compound 18SAB075, which had an excellent selective index for bloodstream trypomasitgotes (SI > 106) , was moved to in vivo tests for acute toxicity and parasite efficacy. In experimental model of acute T. cr uzi infection, 18SAB075 treatment with non - toxic doses (5 mg/kg for five consecutive days) reduced in about 50% the parasitemia levels, leading to 40% protection against mortality, being , however, less effective than the reference drug (Bz at 100 mg/kg/day ). In this way, the present work provides useful information regarding the biological trypanocidal activity of amidine s against T. cruzi , stimulating the continuity of preclinical studies with novel related molecules aiming the finding of more selective co mpounds for Chagas disease therap

In Vitro and In Vivo Biological Effects of Novel Arylimidamide Derivatives against Trypanosoma cruzi

Made available in DSpace on 2015-04-17T17:04:28Z (GMT). No. of bitstreams: 2 license.txt: 1914 bytes, checksum: 7d48279ffeed55da8dfe2f8e81f3b81f (MD5) bruno_timmetal_IOC_2014.pdf: 984025 bytes, checksum: 9793d51f701f7a0d19ee59f53199681a (MD5) Previous issue date: 2014Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.University of North Carolina. Department of Pathology and Laboratory Medicine. Chapel Hill, North Carolina, USA.University of North Carolina. Department of Pathology and Laboratory Medicine. Chapel Hill, North Carolina, USA.University of North Carolina. Department of Pathology and Laboratory Medicine. Chapel Hill, North Carolina, USA.University of North Carolina. Department of Pathology and Laboratory Medicine. Chapel Hill, North Carolina, USA.University of North Carolina. Department of Pathology and Laboratory Medicine. Chapel Hill, North Carolina, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Chagas disease (CD), a neglected tropical disease caused by Trypanosoma cruzi, remains a serious public health problem in several Latin American countries. The available chemotherapies for CD have limited efficacy and exhibit undesirable side effects. Aromatic diamidines and arylimidamides (AIAs) have shown broad-spectrum activity against intracellular parasites, including T. cruzi. Therefore, our aim was to evaluate the biological activity of eight novel AIAs (16DAP002, 16SAB079, 18SAB075, 23SMB022, 23SMB026, 23SMB054, 26SMB070, and 27SMB009) against experimental models of T. cruzi infection in vitro and in vivo. Our data show that none of the compounds induced a loss of cellular viability up to 32 M. Two AIAs, 18SAB075 and 16DAP002, exhibited good in vitro activity against different parasite strains (Y and Tulahuen) and against the two relevant forms of the parasite for mammalian hosts. Due to the excellent selective indexes of 18SAB075, this AIA was moved to in vivo tests for acute toxicity and parasite efficacy; nontoxic doses (no-observed-adverse-effect level [NOAEL], 50 mg/kg) were employed in the tests for parasite efficacy. In experimental models of acute T. cruzi infection, 18SAB075 reduced parasitemia levels only up to 50% and led to 40% protection against mortality (at 5 mg/kg of body weight), being less effective than the reference drug, benznidazole