Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1016/j.bmc.2017.11.030 http://hdl.handle.net/11449/170409 |
Resumo: | Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH2-imidazole or CH2-triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC = 12.5 μg/mL, 17a 50 μg/mL). Crystal structures were determined for CYP121A1 bound to series A compounds 6a and 6b that show the imidazole groups positioned directly above the haem iron with binding between the haem iron and imidazole nitrogen of both compounds at a distance of 2.2 Å. A model generated from a 1.5 Å crystal structure of CYP121A1 in complex with compound 10a showed different binding modes in agreement with the heterogeneous binding observed. Although the crystal structures of 6a and 6b would indicate binding with CYP121A1, the binding assays themselves did not allow confirmation of CYP121A1 as the target. |
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Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimicsBinding affinityCYP121A1Dicyclotyrosine derivativesMolecular modelingMycobacterium tuberculosisX-ray crystallographyThree series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH2-imidazole or CH2-triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC = 12.5 μg/mL, 17a 50 μg/mL). Crystal structures were determined for CYP121A1 bound to series A compounds 6a and 6b that show the imidazole groups positioned directly above the haem iron with binding between the haem iron and imidazole nitrogen of both compounds at a distance of 2.2 Å. A model generated from a 1.5 Å crystal structure of CYP121A1 in complex with compound 10a showed different binding modes in agreement with the heterogeneous binding observed. Although the crystal structures of 6a and 6b would indicate binding with CYP121A1, the binding assays themselves did not allow confirmation of CYP121A1 as the target.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Biotechnology and Biological Sciences Research CouncilSchool of Pharmacy and Pharmaceutical Sciences Cardiff UniversityDepartment of Medicinal Chemistry Faculty of Pharmacy Assiut UniversityDepartment of Life Sciences University of Modena and Reggio Emilia, Via G. Campi 183Faculty of Pharmaceutical Sciences UNESP – Univ Estadual Paulista, AraraquaraManchester Institute of Biotechnology School of Chemistry University of ManchesterFaculty of Pharmaceutical Sciences UNESP – Univ Estadual Paulista, AraraquaraCNPq: 140079/2013-0FAPESP: 2011/21232-1Biotechnology and Biological Sciences Research Council: BB/I019227/1Biotechnology and Biological Sciences Research Council: BB/K001884/1Cardiff UniversityAssiut UniversityUniversity of Modena and Reggio EmiliaUniversidade Estadual Paulista (Unesp)University of ManchesterEl-wahab, Hend A.A. AbdAccietto, MauroMarino, Leonardo B. [UNESP]McLean, Kirsty J.Levy, Colin W.Abdel-Rahman, Hamdy M.El-Gendy, Mahmoud A.Munro, Andrew W.Aboraia, Ahmed S.Simons, Claire2018-12-11T16:50:40Z2018-12-11T16:50:40Z2018-01-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article161-176application/pdfhttp://dx.doi.org/10.1016/j.bmc.2017.11.030Bioorganic and Medicinal Chemistry, v. 26, n. 1, p. 161-176, 2018.1464-33910968-0896http://hdl.handle.net/11449/17040910.1016/j.bmc.2017.11.0302-s2.0-850348199152-s2.0-85034819915.pdfScopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengBioorganic and Medicinal Chemistry0,8710,871info:eu-repo/semantics/openAccess2023-10-26T06:06:45Zoai:repositorio.unesp.br:11449/170409Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462023-10-26T06:06:45Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics |
title |
Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics |
spellingShingle |
Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics El-wahab, Hend A.A. Abd Binding affinity CYP121A1 Dicyclotyrosine derivatives Molecular modeling Mycobacterium tuberculosis X-ray crystallography |
title_short |
Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics |
title_full |
Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics |
title_fullStr |
Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics |
title_full_unstemmed |
Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics |
title_sort |
Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics |
author |
El-wahab, Hend A.A. Abd |
author_facet |
El-wahab, Hend A.A. Abd Accietto, Mauro Marino, Leonardo B. [UNESP] McLean, Kirsty J. Levy, Colin W. Abdel-Rahman, Hamdy M. El-Gendy, Mahmoud A. Munro, Andrew W. Aboraia, Ahmed S. Simons, Claire |
author_role |
author |
author2 |
Accietto, Mauro Marino, Leonardo B. [UNESP] McLean, Kirsty J. Levy, Colin W. Abdel-Rahman, Hamdy M. El-Gendy, Mahmoud A. Munro, Andrew W. Aboraia, Ahmed S. Simons, Claire |
author2_role |
author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Cardiff University Assiut University University of Modena and Reggio Emilia Universidade Estadual Paulista (Unesp) University of Manchester |
dc.contributor.author.fl_str_mv |
El-wahab, Hend A.A. Abd Accietto, Mauro Marino, Leonardo B. [UNESP] McLean, Kirsty J. Levy, Colin W. Abdel-Rahman, Hamdy M. El-Gendy, Mahmoud A. Munro, Andrew W. Aboraia, Ahmed S. Simons, Claire |
dc.subject.por.fl_str_mv |
Binding affinity CYP121A1 Dicyclotyrosine derivatives Molecular modeling Mycobacterium tuberculosis X-ray crystallography |
topic |
Binding affinity CYP121A1 Dicyclotyrosine derivatives Molecular modeling Mycobacterium tuberculosis X-ray crystallography |
description |
Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH2-imidazole or CH2-triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC = 12.5 μg/mL, 17a 50 μg/mL). Crystal structures were determined for CYP121A1 bound to series A compounds 6a and 6b that show the imidazole groups positioned directly above the haem iron with binding between the haem iron and imidazole nitrogen of both compounds at a distance of 2.2 Å. A model generated from a 1.5 Å crystal structure of CYP121A1 in complex with compound 10a showed different binding modes in agreement with the heterogeneous binding observed. Although the crystal structures of 6a and 6b would indicate binding with CYP121A1, the binding assays themselves did not allow confirmation of CYP121A1 as the target. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018-12-11T16:50:40Z 2018-12-11T16:50:40Z 2018-01-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1016/j.bmc.2017.11.030 Bioorganic and Medicinal Chemistry, v. 26, n. 1, p. 161-176, 2018. 1464-3391 0968-0896 http://hdl.handle.net/11449/170409 10.1016/j.bmc.2017.11.030 2-s2.0-85034819915 2-s2.0-85034819915.pdf |
url |
http://dx.doi.org/10.1016/j.bmc.2017.11.030 http://hdl.handle.net/11449/170409 |
identifier_str_mv |
Bioorganic and Medicinal Chemistry, v. 26, n. 1, p. 161-176, 2018. 1464-3391 0968-0896 10.1016/j.bmc.2017.11.030 2-s2.0-85034819915 2-s2.0-85034819915.pdf |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Bioorganic and Medicinal Chemistry 0,871 0,871 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
161-176 application/pdf |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
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1799964703853641728 |