Binding Mode and Potency of N‑Indolyloxopyridinyl-4- aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2014 |
| Outros Autores: | , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/10768 |
Resumo: | University of California - San Francisco. Department of Pathology. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA. |
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Vieira, Debora F.Choi, Jun YongCalvet, Claudia M.Siqueira neto, Jair LageJohnston, Jonathan B.Kellar, DanielleGut, JiriCameron, Michael D.McKerrow, James H.Roush, William R.Podust, Larissa M.2015-06-10T13:55:21Z2015-06-10T13:55:21Z2014VIEIRA, 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, 2014.0022-2623https://www.arca.fiocruz.br/handle/icict/1076810.1021/jm501568bengAmerican Chemical SocietyBinding Mode and Potency of N‑Indolyloxopyridinyl-4- aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleUniversity of California - San Francisco. Department of Pathology. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA.Scripps Florida. Department of Chemistry. Florida, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultra-Estrutura Celular. Rio de Janeiro, RJ, Brasil.University of California - San Francisco. Department of Pathology. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA.University of California - San Francisco. Department of Pharmaceutical Chemistry. San Francisco, CA, USA.University of California - San Francisco. Department of Pathology. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA.University of California - San Francisco. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA.Scripps Florida. Department of Molecular Therapeutics. Florida, USA.University of California - San Francisco. Department of Pathology. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA.Scripps Florida. Department of Chemistry. Florida, USAUniversity of California - San Francisco. Department of Pathology. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA.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.Chagas DiseaseTrypanosoma cruziDoença de ChagasTrypanosoma cruziinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txttext/plain1914https://www.arca.fiocruz.br/bitstream/icict/10768/1/license.txt7d48279ffeed55da8dfe2f8e81f3b81fMD51ORIGINALclaudia_calvetetal_IOC_2014.pdfapplication/pdf5415030https://www.arca.fiocruz.br/bitstream/icict/10768/2/claudia_calvetetal_IOC_2014.pdf9a43f7d48fbc1f77f11c8b7e0ba55253MD52TEXTclaudia_calvetetal_IOC_2014.pdf.txtclaudia_calvetetal_IOC_2014.pdf.txtExtracted texttext/plain71351https://www.arca.fiocruz.br/bitstream/icict/10768/3/claudia_calvetetal_IOC_2014.pdf.txt50d590005af15fca77cdfe165648efc9MD53icict/107682023-09-05 10:26:08.549oai:www.arca.fiocruz.br:icict/10768TElDRU7Dh0EgREUgRElTVFJJQlVJw4fDg08gTsODTy1FWENMVVNJVkEKCkFvIGNvbmNvcmRhciBlIGFjZWl0YXIgZXN0YSBsaWNlbsOnYSB2b2PDqiAoYXV0b3Igb3UgZGV0ZW50b3IgZG9zIGRpcmVpdG9zIGF1dG9yYWlzKToKCmEpIERlY2xhcmEgcXVlIGNvbmhlY2UgYSBwb2zDrXRpY2EgZGUgY29weXJpZ2h0IGRhIGVkaXRvcmEgZG8gc2V1IGRvY3VtZW50by4KCmIpIERlY2xhcmEgcXVlIGNvbmhlY2UgZSBhY2VpdGEgYXMgRGlyZXRyaXplcyBwYXJhIG8gUmVwb3NpdMOzcmlvIEluc3RpdHVjaW9uYWwgZGEgRnVuZGHDp8OjbyBPc3dhbGRvIENydXogKEZJT0NSVVopLgoKYykgQ29uY2VkZSDDoCBGSU9DUlVaIG8gZGlyZWl0byBuw6NvLWV4Y2x1c2l2byBkZSBhcnF1aXZhciwgcmVwcm9kdXppciwgY29udmVydGVyIChjb21vIGRlZmluaWRvIGEgc2VndWlyKSwgY29tdW5pY2FyCiAKZS9vdSBkaXN0cmlidWlyIG5vIFJlcG9zaXTDs3JpbyBkYSBGSU9DUlVaLCBvIGRvY3VtZW50byBlbnRyZWd1ZSAoaW5jbHVpbmRvIG8gcmVzdW1vL2Fic3RyYWN0KSBlbSBmb3JtYXRvIGRpZ2l0YWwgb3UgCgpwb3IgcXVhbHF1ZXIgb3V0cm8gbWVpby4KCmQpIERlY2xhcmEgcXVlIGF1dG9yaXphIGEgRklPQ1JVWiBhIGFycXVpdmFyIG1haXMgZGUgdW1hIGPDs3BpYSBkZXN0ZSBkb2N1bWVudG8gZSBjb252ZXJ0w6otbG8sIHNlbSBhbHRlcmFyIG8gc2V1IGNvbnRlw7pkbywgCgpwYXJhIHF1YWxxdWVyIGZvcm1hdG8gZGUgYXJxdWl2bywgbWVpbyBvdSBzdXBvcnRlLCBwYXJhIGVmZWl0b3MgZGUgc2VndXJhbsOnYSwgcHJlc2VydmHDp8OjbyAoYmFja3VwKSBlIGFjZXNzby4KCmUpIERlY2xhcmEgcXVlIG8gZG9jdW1lbnRvIHN1Ym1ldGlkbyDDqSBvIHNldSB0cmFiYWxobyBvcmlnaW5hbCwgZSBxdWUgZGV0w6ltIG8gZGlyZWl0byBkZSBjb25jZWRlciBhIHRlcmNlaXJvcyBvcyBkaXJlaXRvcyAKCmNvbnRpZG9zIG5lc3RhIGxpY2Vuw6dhLiBEZWNsYXJhIHRhbWLDqW0gcXVlIGEgZW50cmVnYSBkbyBkb2N1bWVudG8gbsOjbyBpbmZyaW5nZSBvcyBkaXJlaXRvcyBkZSBxdWFscXVlciBvdXRyYSBwZXNzb2Egb3UgZW50aWRhZGUuCgpmKSBEZWNsYXJhIHF1ZSwgbm8gY2FzbyBkbyBkb2N1bWVudG8gc3VibWV0aWRvIGNvbnRlciBtYXRlcmlhbCBkbyBxdWFsIG7Do28gZGV0w6ltIG9zIGRpcmVpdG9zIGRlIGF1dG9yLCBvYnRldmUgYSBhdXRvcml6YcOnw6NvIAoKaXJyZXN0cml0YSBkbyByZXNwZWN0aXZvIGRldGVudG9yIGRlc3NlcyBkaXJlaXRvcywgcGFyYSBjZWRlciBhIEZJT0NSVVogb3MgZGlyZWl0b3MgcmVxdWVyaWRvcyBwb3IgZXN0YSBMaWNlbsOnYSBlIGF1dG9yaXphciBhIAoKdXRpbGl6w6EtbG9zIGxlZ2FsbWVudGUuIERlY2xhcmEgdGFtYsOpbSBxdWUgZXNzZSBtYXRlcmlhbCBjdWpvcyBkaXJlaXRvcyBzw6NvIGRlIHRlcmNlaXJvcyBlc3TDoSBjbGFyYW1lbnRlIGlkZW50aWZpY2FkbyBlIHJlY29uaGVjaWRvIAoKbm8gdGV4dG8gb3UgY29udGXDumRvIGRvIGRvY3VtZW50byBlbnRyZWd1ZS4KCmcpIFNFIE8gRE9DVU1FTlRPIEVOVFJFR1VFIMOJIEJBU0VBRE8gRU0gVFJBQkFMSE8gRklOQU5DSUFETyBPVSBBUE9JQURPIFBPUiBPVVRSQSBJTlNUSVRVScOHw4NPIFFVRSBOw4NPIEEgRklPQ1JVWiwgREVDTEFSQSBRVUUgQ1VNUFJJVSAKClFVQUlTUVVFUiBPQlJJR0HDh8OVRVMgRVhJR0lEQVMgUEVMTyBSRVNQRUNUSVZPIENPTlRSQVRPIE9VIEFDT1JETy4gQSBGSU9DUlVaIGlkZW50aWZpY2Fyw6EgY2xhcmFtZW50ZSBvKHMpIG5vbWUocykgZG8ocykgYXV0b3IoZXMpIGRvcyAKCmRpcmVpdG9zIGRvIGRvY3VtZW50byBlbnRyZWd1ZSBlIG7Do28gZmFyw6EgcXVhbHF1ZXIgYWx0ZXJhw6fDo28sIHBhcmEgYWzDqW0gZG8gcHJldmlzdG8gbmEgYWzDrW5lYSBjKS4KRepositório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352023-09-05T13:26:08Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)false |
| dc.title.pt_BR.fl_str_mv |
Binding Mode and Potency of N‑Indolyloxopyridinyl-4- aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51 |
| title |
Binding Mode and Potency of N‑Indolyloxopyridinyl-4- aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51 |
| spellingShingle |
Binding Mode and Potency of N‑Indolyloxopyridinyl-4- aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51 Vieira, Debora F. Chagas Disease Trypanosoma cruzi Doença de Chagas Trypanosoma cruzi |
| title_short |
Binding Mode and Potency of N‑Indolyloxopyridinyl-4- aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51 |
| title_full |
Binding Mode and Potency of N‑Indolyloxopyridinyl-4- aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51 |
| title_fullStr |
Binding Mode and Potency of N‑Indolyloxopyridinyl-4- aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51 |
| title_full_unstemmed |
Binding Mode and Potency of N‑Indolyloxopyridinyl-4- aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51 |
| title_sort |
Binding Mode and Potency of N‑Indolyloxopyridinyl-4- aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51 |
| author |
Vieira, Debora F. |
| author_facet |
Vieira, Debora F. Choi, Jun Yong Calvet, Claudia M. Siqueira neto, Jair Lage Johnston, Jonathan B. Kellar, Danielle Gut, Jiri Cameron, Michael D. McKerrow, James H. Roush, William R. Podust, Larissa M. |
| author_role |
author |
| author2 |
Choi, Jun Yong Calvet, Claudia M. Siqueira neto, Jair Lage Johnston, Jonathan B. Kellar, Danielle Gut, Jiri Cameron, Michael D. McKerrow, James H. Roush, William R. Podust, Larissa M. |
| author2_role |
author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Vieira, Debora F. Choi, Jun Yong Calvet, Claudia M. Siqueira neto, Jair Lage Johnston, Jonathan B. Kellar, Danielle Gut, Jiri Cameron, Michael D. McKerrow, James H. Roush, William R. Podust, Larissa M. |
| dc.subject.en.pt_BR.fl_str_mv |
Chagas Disease Trypanosoma cruzi |
| topic |
Chagas Disease Trypanosoma cruzi Doença de Chagas Trypanosoma cruzi |
| dc.subject.decs.pt_BR.fl_str_mv |
Doença de Chagas Trypanosoma cruzi |
| description |
University of California - San Francisco. Department of Pathology. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA. |
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2014 |
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2014 |
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2015-06-10T13:55:21Z |
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2015-06-10T13:55:21Z |
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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. |
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https://www.arca.fiocruz.br/handle/icict/10768 |
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0022-2623 |
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10.1021/jm501568b |
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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. 0022-2623 10.1021/jm501568b |
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American Chemical Society |
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