| Author | Vieira, Debora F. | |
| Author | Choi, Jun Yong | |
| Author | Calvet, Claudia M. | |
| Author | Siqueira neto, Jair Lage | |
| Author | Johnston, Jonathan B. | |
| Author | Kellar, Danielle | |
| Author | Gut, Jiri | |
| Author | Cameron, Michael D. | |
| Author | McKerrow, James H. | |
| Author | Roush, William R. | |
| Author | Podust, Larissa M. | |
| Access date | 2015-06-10T13:55:21Z | |
| Available date | 2015-06-10T13:55:21Z | |
| Document date | 2014 | |
| Citation | VIEIRA, Debora F. et al. Binding Mode and Potency of N‑Indolyloxopyridinyl-4- aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51. J. Med. Chem. v.57, n.23, p.10162−10175, 2014. | pt_BR |
| ISSN | 0022-2623 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/10768 | |
| Language | eng | pt_BR |
| Publisher | American Chemical Society | pt_BR |
| Rights | open access | |
| Title | Binding Mode and Potency of N‑Indolyloxopyridinyl-4- aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51 | pt_BR |
| Type | Article | |
| DOI | 10.1021/jm501568b | pt_BR |
| Abstract | Chagas disease is a chronic infection in humans caused by Trypanosoma cruzi and manifested in progressive
cardiomyopathy and/or gastrointestinal dysfunction. Limited therapeutic options to prevent and treat Chagas disease put 8
million people infected with T. cruzi worldwide at risk. CYP51, involved in the biosynthesis of the membrane sterol component
in eukaryotes, is a promising drug target in T. cruzi. We report the structure−activity relationships (SAR) of an N-arylpiperazine
series of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors designed to probe the impact of substituents in the terminal Nphenyl
ring on binding mode, selectivity and potency. Depending on the substituents at C-4, two distinct ring binding modes,
buried and solvent-exposed, have been observed by X-ray structure analysis (resolution of 1.95−2.48 Å). The 5-chlorosubstituted
analogs 9 and 10 with no substituent at C-4 demonstrated improved selectivity and potency, suppressing ≥99.8%
parasitemia in mice when administered orally at 25 mg/kg, b.i.d., for 4 days. | pt_BR |
| Affilliation | University of California - San Francisco. Department of Pathology. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA. | pt_BR |
| Affilliation | Scripps Florida. Department of Chemistry. Florida, USA. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultra-Estrutura Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | University of California - San Francisco. Department of Pathology. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA. | pt_BR |
| Affilliation | University of California - San Francisco. Department of Pharmaceutical Chemistry. San Francisco, CA, USA. | pt_BR |
| Affilliation | University of California - San Francisco. Department of Pathology. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA. | pt_BR |
| Affilliation | University of California - San Francisco. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA. | pt_BR |
| Affilliation | Scripps Florida. Department of Molecular Therapeutics. Florida, USA. | pt_BR |
| Affilliation | University of California - San Francisco. Department of Pathology. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA. | pt_BR |
| Affilliation | Scripps Florida. Department of Chemistry. Florida, USA | pt_BR |
| Affilliation | University of California - San Francisco. Department of Pathology. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA. | pt_BR |
| Subject | Chagas Disease | pt_BR |
| Subject | Trypanosoma cruzi | pt_BR |
| DeCS | Doença de Chagas | pt_BR |
| DeCS | Trypanosoma cruzi | pt_BR |
