| Author | Nefertiti, A. S. G. | |
| Author | Batista, M. M. | |
| Author | Da Silva, P. B. | |
| Author | Batista, D. G. J. | |
| Author | Silva, C. F. da | |
| Author | Peres, R. B. | |
| Author | Santos, E. C. Torres | |
| Author | Cunha Junior, E. F. | |
| Author | Holt, E. | |
| Author | Boykin, D. W. | |
| Author | Brun, R. | |
| Author | Wenzler, T. | |
| Author | Soeiro, M.. N. C. | |
| Access date | 2018-09-13T17:54:17Z | |
| Available date | 2018-09-13T17:54:17Z | |
| Document date | 2018 | |
| Citation | NEFERTITI, A. S. G. et al. In Vitro and In Vivo Studies of the Trypanocidal Effect of Novel Quinolines. Antimicrobial Agents and Chemotherapy, v. 62, n. 2, p. 1-11, Feb. 2018. | pt_BR |
| ISSN | 0066-4804 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/28754 | |
| Language | eng | pt_BR |
| Publisher | Antimicrobial Agents and Chemotherapy | pt_BR |
| Rights | open access | |
| Subject in Portuguese | Trypanosoma Cruzi | pt_BR |
| Subject in Portuguese | Trypanosoma brucei | pt_BR |
| Subject in Portuguese | Quimioterapia experimental | pt_BR |
| Subject in Portuguese | Quinolinas | pt_BR |
| Subject in Portuguese | In vitro | pt_BR |
| Subject in Portuguese | In vivo | pt_BR |
| Title | In Vitro and In Vivo Studies of the Trypanocidal Effect of Novel Quinolines | pt_BR |
| Type | Article | |
| DOI | 10.1128/AAC.01936-17 | |
| Abstract | Therapies for human African trypanosomiasis and Chagas disease, caused by Trypanosoma brucei and Trypanosoma cruzi, respectively, are limited, providing minimal therapeutic options for the millions of individuals living in very poor communities. Here the effects of 10 novel quinolines are evaluated in silico and by phenotypic studies using in vitro and in vivo models. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties revealed that most molecules did not infringe on Lipinski's rules, which is a prediction of good oral absorption. These quinolines showed high probabilities of Caco2 permeability and human intestinal absorption and low probabilities of mutagenicity and of hERG1 inhibition. In vitro screens against bloodstream forms of T. cruzi demonstrated that all quinolines were more active than the reference drug (benznidazole [Bz]), except for DB2171 and DB2192, with five (DB2187, DB2131, DB2186, DB2191, and DB2217) displaying 50% effective concentrations (EC50s) of <3 μM (4-fold lower than that of Bz). Nine quinolines were more effective than Bz (2.7 μM) against amastigotes, showing EC50s ranging from 0.6 to 0.1 μM. All quinolines were also highly active in vitro against African trypanosomes, showing EC50s of ≤0.25 μM. The most potent and highly selective candidates for each parasite species were tested in in vivo models. Results for DB2186 were promising in mice with T. cruzi and T. brucei infections, reaching a 70% reduction of the parasitemia load for T. cruzi, and it cured 2 out of 4 mice infected with T. brucei DB2217 was also active in vivo and cured all 4 mice (100% cure rate) with T. brucei infection. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanossomatídeos. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanossomatídeos. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Georgia State University. Department of Chemistry. Atlanta, Geogia, USA. | pt_BR |
| Affilliation | Georgia State University. Department of Chemistry. Atlanta, Geogia, USA. | pt_BR |
| Affilliation | Swiss Tropical and Public Health Institute. Basel, Switzerland. | pt_BR |
| Affilliation | Swiss Tropical and Public Health Institute. Basel, Switzerland. | pt_BR |
| Affilliation | Swiss Tropical and Public Health Institute. Basel, Switzerland / University of Basel. Basel, Switzerland. | pt_BR |
| Affilliation | Swiss Tropical and Public Health Institute. Basel, Switzerland / University of Basel. Basel, Switzerland. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Subject | Trypanosoma Cruzi | pt_BR |
| Subject | Trypanosoma brucei | pt_BR |
| Subject | Experimental chemotherapy | pt_BR |
| Subject | Quinolines | pt_BR |
| Subject | In vitro | pt_BR |
| Subject | In vivo | pt_BR |
| Subject | In silico | pt_BR |
| DeCS | Simulação por Computador | pt_BR |
| e-ISSN | 1098-6596 | |
