Aryl thiosemicarbazones for the treatment of trypanosomatidic infections

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dc.contributor.authorLinciano, Pasqualept_BR
dc.contributor.authorMoraes, Carolina Borsoipt_BR
dc.contributor.authorAlcantara, Laura M.pt_BR
dc.contributor.authorFranco, Caio Haddadpt_BR
dc.contributor.authorPascoalino, Brunopt_BR
dc.contributor.authorFreitas-Junior, Lucio Holanda Gondimpt_BR
dc.contributor.authorMacedo, Sarapt_BR
dc.contributor.authorSantarem, Nunopt_BR
dc.contributor.authorCordeiro-da-Silva, Anabelapt_BR
dc.contributor.authorGul, Sherazpt_BR
dc.contributor.authorWitt, Gesapt_BR
dc.contributor.authorKuzikov, Mariapt_BR
dc.contributor.authorEllinger, Bernhardpt_BR
dc.contributor.authorFerrari, Stefaniapt_BR
dc.contributor.authorLuciani, Rosariapt_BR
dc.contributor.authorQuotadamo, Antoniopt_BR
dc.contributor.authorCostantino, Lucapt_BR
dc.contributor.authorCosti, Maria Paolapt_BR
dc.date.accessioned2020-07-09T21:19:26Z-
dc.date.available2020-07-09T21:19:26Z-
dc.date.issued2018pt_BR
dc.identifier.citationLinciano P, Moraes CB, Alcantara LM., Franco CH, Pascoalino B, Freitas-Junior LHG, et al. Aryl thiosemicarbazones for the treatment of trypanosomatidic infections. Eur J Med Chem. 2018 Feb;146:423-34. doi:10.1016/j.ejmech.2018.01.043.pt_BR
dc.identifier.urihttps://repositorio.butantan.gov.br/handle/butantan/2419-
dc.description.abstractBasing on a library of thiadiazole derivatives showing anti-trypanosomatidic activity, we have considered the thiadiazoles opened forms and reaction intermediates, thiosemicarbazones, as compounds of interest for phenotypic screening against Trypanosoma brucei (Tb), intracellular amastigote form of Leishmania infantum (Li) and Trypanosoma cruzi (Tc). Similar compounds have already shown interesting activity against the same organisms. The compounds were particularly effective against T. brucei and T. cruzi. Among the 28 synthesized compounds, the best one was (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene) hydrazinecarbothioamide (A14) yielding a comparable anti-parasitic activity against the three parasitic species (TbEC50=231 mu M, LiEC50 = 6.14 mu M, TcEC50 = 1.31 mu M) and a Selectivity Index higher than 10 with respect to human macrophages, therefore showing a pan-anti-trypanosomatidic activity. (E)-2-((3'.4'-dimethoxy-[1.1'-biphenyl]-3-yl)methyle ne) hydrazinecarbothioamide (A12) and (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene)hydrazine carbothioamide (A14) were able to potentiate the anti parasitic activity of methotrexate (MTX) when evaluated in combination against T. brucei, yielding a 6 fold and 4-fold respectively Dose Reduction Index for MTX. The toxicity profile against four human cell lines and a panel of in vitro early-toxicity assays (comprising hERG, Aurora B, five cytochrome P450 isoforms and mitochondrial toxicity) demonstrated the low toxicity for the thosemicarbazones class in comparison with known drugs. The results confirmed thiosemicarbazones as a suitable chemical scaffold with potential for the development of properly decorated new anti-parasitic drugs.pt_BR
dc.description.sponsorshipEuropean Union’s Seventh Framework Programmept_BR
dc.description.sponsorshipEuropean Communities (EC)pt_BR
dc.description.sponsorshipMIUR-PRINpt_BR
dc.format.extentp. 423-434pt_BR
dc.language.isoEnglishpt_BR
dc.relation.ispartofEuropean Journal of Medicinal Chemistrypt_BR
dc.titleAryl thiosemicarbazones for the treatment of trypanosomatidic infectionspt_BR
dc.typeArticlept_BR
dc.identifier.doi10.1016/j.ejmech.2018.01.043pt_BR
dc.identifier.urlhttp://dx.doi.org/10.1016/j.ejmech.2018.01.043pt_BR
dc.contributor.externalUniversidade de Módena e Reggio Emília¦¦Itáliapt_BR
dc.contributor.externalLaboratório Nacional de Biociências (LNBio)¦¦Brasilpt_BR
dc.contributor.externalInstituto de Biologia Molecular e Celular (IBMC)¦¦Portugalpt_BR
dc.contributor.externalUniversidade do Porto¦¦Portugalpt_BR
dc.contributor.externalFraunhofer Institute for Molecular Biology and Applied Ecology IME¦¦Alemanhapt_BR
dc.identifier.citationvolume146pt_BR
dc.subject.keywordThiosemicarbazonept_BR
dc.subject.keywordTrypanosoma bruceipt_BR
dc.subject.keywordTrypanosoma cruzipt_BR
dc.subject.keywordLeishmania infantumpt_BR
dc.subject.keywordEarly-toxicitypt_BR
dc.subject.keywordpan-anti-trypanosomatidic activitypt_BR
dc.relation.ispartofabbreviatedEur J Med Chempt_BR
dc.identifier.citationabntv. 146, p. 423-434, fev. 2018pt_BR
dc.identifier.citationvancouver2018 Feb;146:423-34pt_BR
dc.contributor.butantanFreitas-Junior, Lucio Holanda Gondim|:Colaborador|:|:pt_BR
dc.sponsorship.butantanEuropean Communities (EC)¦¦pt_BR
dc.sponsorship.butantanEuropean Union's Seventh Framework Programme¦¦603240pt_BR
dc.sponsorship.butantanMIUR-PRIN¦¦2012 74BNKN_003pt_BR
dc.identifier.bvsccBR78.1pt_BR
dc.identifier.bvsdbIBProdpt_BR
dc.description.dbindexedYespt_BR
item.openairetypeArticle-
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item.grantfulltextembargo_29990101-
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