Author | Fiuza, Ludmila Ferreira de Almeida | |
Author | Peres, Raiza Brandão | |
Author | Silva, Marianne Rocha Simões | |
Author | Silva, Patricia Bernardino da | |
Author | Batista, Denise da Gama Jaen | |
Author | Silva, Cristiane França da | |
Author | Gama, Aline Nefertiti Silva da | |
Author | Reddy, Tummala Rama Krishna | |
Author | Soeiro, Maria de Nazaré C. | |
Access date | 2019-02-14T14:03:15Z | |
Available date | 2019-02-14T14:03:15Z | |
Document date | 2018 | |
Citation | FIUZA, Ludmila Ferreira de Almeida; et al. Identification of Pyrazolo[3,4-e][1,4]thiazepin based CYP51 inhibitors as potential Chagas disease therapeutic alternative: In vitro and in vivo evaluation, binding mode prediction and SAR exploration. European Journal of Medicinal Chemistry, v.149, p.257-268, Feb. 2018. | pt_BR |
ISSN | 0223-5234 | pt_BR |
URI | https://www.arca.fiocruz.br/handle/icict/31643 | |
Language | eng | pt_BR |
Publisher | Elsevier | pt_BR |
Rights | restricted access | pt_BR |
Subject in Portuguese | Doença de Chagas | pt_BR |
Subject in Portuguese | Trypanosoma cruzi | pt_BR |
Subject in Portuguese | Inibidores de 14-alfa Desmetilase | pt_BR |
Title | Identification of Pyrazolo[3,4-e][1,4]thiazepin based CYP51 inhibitors as potential Chagas disease therapeutic alternative: In vitro and in vivo evaluation, binding mode prediction and SAR exploration | pt_BR |
Type | Article | pt_BR |
DOI | 10.1016/j.ejmech.2018.02.020 | |
Abstract | American trypanosomiasis or Chagas disease (CD) is a vector borne pathology caused by the parasite Trypanosoma cruzi (T. cruzi), which remains a serious global health problem. The current available treatment for CD is limited to two nitroderivatives with limited efficacy and several side effects. The rational design of ergosterol synthetic route inhibitors (e.g. CYP51 inhibitors) represents a promising strategy for fungi and trypanosomatids, exhibiting excellent anti-T.cruzi activity in pre-clinical assays. In the present work, we evaluate through different approaches (molecular docking, structure activity relationships, CYP51 inhibitory assay, and phenotypic screenings in vitro and in vivo) the potency and selectivity of a novel CYP51 inhibitor (compound 1) and its analogues against T.cruzi infection. Regarding anti-parasitic effect, compound 1 was active in vitro with EC50 3.86 and 4.00 μM upon intracellular (Tulahuen strain) and bloodstream forms (Y strain), respectively. In vivo assays showed that compound 1 reduced in 43% the parasitemia peak but, unfortunately failed to promote animal survival. In order to promote an enhancement at the potency and pharmacological properties, 17 new analogues were purchased and screened in vitro. Our findings demonstrated that five compounds were active against intracellular forms, highlighting compounds 1e and 1f, with EC50 2.20 and 2.70 μM, respectively, and selectivity indices (SI) = 50 and 36, respectively. Against bloodstream trypomastigotes, compound 1f reached an EC50 value of 20.62 μM, in a similar range to Benznidazole, but with low SI (3). Although improved the solubility of compound 1, the analogue 1f did not enhance the potency in vitro neither promote better in vivo efficacy against mouse model of acute T.cruzi infection arguing for the synthesis of novel pyrazolo[3,4-e][1,4]thiazepin derivatives aiming to contribute for alternative therapies for CD. | 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 Biologia Celular. Rio de Janeiro, RJ. Brasil. | pt_BR |
Affilliation | University of East London. College of Applied Health and Communities. School of Health, Sport and Bioscience. Stratford Campus, Water Lane, UK. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil. | pt_BR |
Subject | Chagas Disease | pt_BR |
Subject | Trypanosoma cruzi | pt_BR |
Subject | CYP51 inhibitors | pt_BR |
Subject | SAR studies | pt_BR |
e-ISSN | 1768-3254 | |
Embargo date | 2030-01-01 | |