Development of a focused library of triazole-linked privileged-structure-based conjugates leading to the discovery of novel phenotypic hits against protozoan parasitic infections

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dc.contributorLaboratório de Farmacologiapt_BR
dc.contributorDepartamento de Microbiologiapt_BR
dc.contributor.authorUliassi, Elisapt_BR
dc.contributor.authorPiazzi, Lornapt_BR
dc.contributor.authorMazzanti, Andreapt_BR
dc.contributor.authorKaiser, Marcelpt_BR
dc.contributor.authorBrun, Retopt_BR
dc.contributor.authorMoraes, Carolina Borsoipt_BR
dc.contributor.authorFreitas-Junior, Lucio Holanda Gondimpt_BR
dc.contributor.authorGul, Sherazpt_BR
dc.contributor.authorKuzikov, Mariapt_BR
dc.contributor.authorEllinger, Bernhardpt_BR
dc.contributor.authorBorsari, Chiarapt_BR
dc.contributor.authorCosti, Maria Paolapt_BR
dc.contributor.authorBolognesi, Maria Laurapt_BR
dc.contributor.authorBelluti, Federicapt_BR
dc.date.accessioned2020-07-09T21:20:38Z-
dc.date.available2020-07-09T21:20:38Z-
dc.date.issued2018-
dc.identifier.citationUliassi E, Piazzi L, Mazzanti A, Kaiser M, Brun R, Moraes CB, et al. Development of a focused library of triazole-linked privileged-structure-based conjugates leading to the discovery of novel phenotypic hits against protozoan parasitic infections. ChemMedChem. 2018 Apr;13(7):678-83. doi:10.1002/cmdc.201700786.pt_BR
dc.identifier.urihttps://repositorio.butantan.gov.br/handle/butantan/2507-
dc.description.abstractProtozoan infections caused by Plasmodium, Leishmania, and Trypanosoma spp. contribute significantly to the burden of infectious diseases worldwide, causing severe morbidity and mortality. The inadequacy of available treatments calls for cost- and time-effective drug discovery endeavors. To this end, we envisaged the triazole linkage of privileged structures as an effective drug design strategy to generate a focused library of high-quality compounds. The versatility of this approach was combined with the feasibility of a phenotypic assay, integrated with early ADME-tox profiling. Thus, an 18-membered library was efficiently assembled via Huisgen cycloaddition of phenothiazine, biphenyl, and phenylpiperazine scaffolds. The resulting 18 compounds were then tested against seven parasite strains, and counter-screened for selectivity against two mammalian cell lines. In parallel, hERG and cytochrome P450 (CYP) inhibition, and mitochondrial toxicity were assessed. Remarkably, 10-((1-(3-([1,1-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-5-yl)methyl)-10H-phenothiazine (7) and 10-(3-(1-(3-([1,1-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-4-yl)propyl)-10H-phenothiazine (12) showed respective IC50 values of 1.8 and 1.9gmL(-1) against T.cruzi, together with optimal selectivity. In particular, compound 7 showed a promising ADME-tox profile. Thus, hit 7 might be progressed as an antichagasic lead.pt_BR
dc.description.sponsorshipProgrammi di Finanziamento (PRIN)pt_BR
dc.description.sponsorshipUniversity of Bolognapt_BR
dc.description.sponsorshipEuropean Unionpt_BR
dc.format.extentp. 678-683pt_BR
dc.languageengpt_BR
dc.relation.ispartofChemMedChempt_BR
dc.titleDevelopment of a focused library of triazole-linked privileged-structure-based conjugates leading to the discovery of novel phenotypic hits against protozoan parasitic infectionspt_BR
dc.typeArticlept_BR
dc.identifier.doi10.1002/cmdc.201700786pt_BR
dc.identifier.urlhttp://dx.doi.org/10.1002/cmdc.201700786pt_BR
dc.contributor.externalUniversity of Bologna¦¦Itáliapt_BR
dc.contributor.externalSwiss Tropical and Public Health Institute (Swiss TPH)¦¦Suiçapt_BR
dc.contributor.externalUniversity of Basel¦¦Suiçapt_BR
dc.contributor.externalLaboratório Nacional de Biociências (LNBio)¦¦Brasilpt_BR
dc.contributor.externalFraunhofer Institute for Molecular Biology and Applied Ecology IME¦¦Alemanhapt_BR
dc.contributor.externalUniversidade de Módena e Reggio Emília¦¦Itáliapt_BR
dc.contributor.externalUniversidade de São Paulo (USP)¦¦Brasilpt_BR
dc.identifier.citationvolume13pt_BR
dc.identifier.citationissue7pt_BR
dc.subject.keywordphenotypic screeningpt_BR
dc.subject.keywordprivileged scaffoldspt_BR
dc.subject.keywordprotozoan parasitic infectionspt_BR
dc.relation.ispartofabbreviatedChemMedChempt_BR
dc.identifier.citationabntv. 13, n. 7, p. 678-683, abr. 2018pt_BR
dc.identifier.citationvancouver2018 Apr;13(7):678-83pt_BR
dc.contributor.butantanFreitas-Junior, Lucio Holanda Gondim|:Pesquisador|:|:pt_BR
dc.contributor.butantanMoraes, Carolina Borsoi|:|:Laboratório de Farmacologia:Departamento de Microbiologia|:pt_BR
dc.sponsorship.butantanEuropean Union¦¦603240pt_BR
dc.sponsorship.butantanProgrammi di Finanziamento (PRIN)¦¦201274BNKN_003pt_BR
dc.sponsorship.butantanUniversity of Bologna¦¦pt_BR
dc.identifier.bvsccBR78.1pt_BR
dc.identifier.bvsdbIBProdpt_BR
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