Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics

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dc.contributor.authorEl-wahab, Hend A.A. Abd
dc.contributor.authorAccietto, Mauro
dc.contributor.authorMarino, Leonardo B. [UNESP]
dc.contributor.authorMcLean, Kirsty J.
dc.contributor.authorLevy, Colin W.
dc.contributor.authorAbdel-Rahman, Hamdy M.
dc.contributor.authorEl-Gendy, Mahmoud A.
dc.contributor.authorMunro, Andrew W.
dc.contributor.authorAboraia, Ahmed S.
dc.contributor.authorSimons, Claire
dc.contributor.institutionCardiff University
dc.contributor.institutionAssiut University
dc.contributor.institutionUniversity of Modena and Reggio Emilia
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionUniversity of Manchester
dc.date.accessioned2018-12-11T16:50:40Z
dc.date.available2018-12-11T16:50:40Z
dc.date.issued2018-01-01
dc.description.abstractThree 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.en
dc.description.affiliationSchool of Pharmacy and Pharmaceutical Sciences Cardiff University
dc.description.affiliationDepartment of Medicinal Chemistry Faculty of Pharmacy Assiut University
dc.description.affiliationDepartment of Life Sciences University of Modena and Reggio Emilia, Via G. Campi 183
dc.description.affiliationFaculty of Pharmaceutical Sciences UNESP – Univ Estadual Paulista, Araraquara
dc.description.affiliationManchester Institute of Biotechnology School of Chemistry University of Manchester
dc.description.affiliationUnespFaculty of Pharmaceutical Sciences UNESP – Univ Estadual Paulista, Araraquara
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipBiotechnology and Biological Sciences Research Council
dc.description.sponsorshipIdCNPq: 140079/2013-0
dc.description.sponsorshipIdFAPESP: 2011/21232-1
dc.description.sponsorshipIdBiotechnology and Biological Sciences Research Council: BB/I019227/1
dc.description.sponsorshipIdBiotechnology and Biological Sciences Research Council: BB/K001884/1
dc.format.extent161-176
dc.identifierhttp://dx.doi.org/10.1016/j.bmc.2017.11.030
dc.identifier.citationBioorganic and Medicinal Chemistry, v. 26, n. 1, p. 161-176, 2018.
dc.identifier.doi10.1016/j.bmc.2017.11.030
dc.identifier.file2-s2.0-85034819915.pdf
dc.identifier.issn1464-3391
dc.identifier.issn0968-0896
dc.identifier.scopus2-s2.0-85034819915
dc.identifier.urihttp://hdl.handle.net/11449/170409
dc.language.isoeng
dc.relation.ispartofBioorganic and Medicinal Chemistry
dc.relation.ispartofsjr0,871
dc.relation.ispartofsjr0,871
dc.rights.accessRightsAcesso aberto
dc.sourceScopus
dc.subjectBinding affinity
dc.subjectCYP121A1
dc.subjectDicyclotyrosine derivatives
dc.subjectMolecular modeling
dc.subjectMycobacterium tuberculosis
dc.subjectX-ray crystallography
dc.titleDesign, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimicsen
dc.typeArtigo

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