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.

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 / Therapeutic potential of the evaluation of new trypanocidal agents on trypanosoma cruzi

O tratamento etiológico disponível para a doença de Chagas, causada peloparasito intracelular Trypanosoma cruzi, é baseado em dois nitroderivados,benzonidazol (Bz) e nifurtimox (Nif), ambos introduzidos empiricamente na práticaclínica há mais de 40 anos. Estes fármacos são considerados insatisfatóriosprincipalmente devido à (i) baixa eficácia, principalmente na fase crônica, (ii) efeitoscolaterais importantes, e (iii) ocorrência de linhagens de parasitas resistentes. Umdos atuais desafios desta doença negligenciada é o desenvolvimento de tratamentosalternativos mais efetivos e seletivos, constituindo o objetivo principal da presentedissertação. Assim, ensaios in vitro e in vivo foram conduzidos para avaliar aeficácia de diamidinas aromáticas (DAs) e arilimidamidas (AIAs), sobre T. cruzi. Noprimeiro artigo demonstramos a atividade de dez diamidinas sobre formastripomastigotas, na faixa micromolar, sem redução significativa da viabilidade dacélula hospedeira. Três DAs com anéis externos benzimidazólicos N-metiladosapresentaram diferenças na atividade tripanocida, sendo o composto DB2247, commeta-N-metilação em ambos os anéis, o mais ativo e também o de mais rápidaação. Todavia, nenhum do compostos testados foi ativo sobre amastigotasintracelulares. No segundo artigo avaliamos atividade anti-T. cruzi de oito novasAIAs. Nossos dados mostram que seis destes compostos foram inativos sobreambas formas evolutivas do parasito. As duas AIAs que apresentaram efeito sobreas formas tripomastigotas foram 18SAB075 e 16DAP005, que exibiram aindaexcelente ação in vitro sobre formas intracelulares, com eficácia similar ao Bz...

The available etiologic treatment of Chagas disease, caused by theintracellular parasite Trypanosoma cruzi, is based on two nitroderivatives,benznidazole (Bz) and Nif, both introduced empirically in the clinical practice for over40 years ago. These drugs are considered unsatisfactory mainly due to their (i) lowefficacy, mainly in the chronic phase, (ii) severe side effects, and (iii) occurrence ofresistant parasite strains. One of the main challenges of this neglected disease is thedevelopment 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 aromaticamidines (DAs) and arylimidamides (AIAs) against T. cruzi. In the first paper, wedemonstrated the activity of ten novel diamidines at micromolar range againstagainst trypomastigotes, without significant loss in host cell viability. In this study wefound that three diamidines with N-methylated benzimidazoles outer rings displayeddifferent trypanocidal activities, being the compound DB2247, with meta-Nmethylationin both rings, the most active with also a faster trypanocidal action.However, none of the diamidines were active against intracellular amastigotes. In thesecond paper, we evaluated the efficacy of eight novel AIAs against T. cruzi. Ourdata showed that six out of the eight studied compounds were inactive against bothevolutive forms of the parasite. The only two AIAs that were active, 18SAB075 and16DAP005, displayed outstanding in vitro effect with efficacy similar to that of Bzagainst intracellular forms. In this way, the compound 18SAB075, which had anexcellent selective index for bloodstream trypomasitgotes (SI > 106), was moved toin vivo tests for acute toxicity and parasite efficacy...