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Enantiopure Indolizinoindolones with in vitro activity against blood- and liver-stage malaria parasites

2015Journal article Restricted access
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dc.contributor.authorPereira, Nuno A. L.
dc.contributor.authorMonteiro, Ângelo
dc.contributor.authorMachado, Marta
dc.contributor.authorGut, Jiri
dc.contributor.authorMolins, Elies
dc.contributor.authorPerry, Maria Jesus
dc.contributor.authorDourado, Jorge
dc.contributor.authorMoreira, Rui
dc.contributor.authorRosenthal, Philip J.
dc.contributor.authorPrudêncio, Miguel
dc.contributor.authorSantos, Maria M. M.
dc.date.accessioned2022-02-11T16:01:53Z
dc.date.available2022-02-11T16:01:53Z
dc.date.issued2015
dc.description© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheimpt_PT
dc.description.abstractMalaria continues to be a major cause of morbidity and mortality to this day, and resistance to drugs like chloroquine has led to an urgent need to discover novel chemical entities aimed at new targets. Here, we report the discovery of a novel class of potential antimalarial compounds containing an indolizinoindolone scaffold. These novel enantiopure indolizinoindolones were synthesized, in good-to-excellent yields and excellent diastereoselectivities, by cyclocondensation reaction of (S)- or (R)-tryptophanol and 2-acyl benzoic acids, followed by intramolecular α-amidoalkylation. Interestingly, we were able to synthesize for the first time 7,13b-cis indolizinoindolones in a two-step route. The novel compounds showed promising activity against erythrocytic stages of the human malaria parasite, Plasmodium falciparum, and liver stages of the rodent parasite Plasmodium berghei. In particular, an (S)-tryptophanol-derived isoindolinone was identified as a promising starting scaffold to search for novel antimalarials, combining excellent activity against both stages of the parasite's life cycle with low cytotoxicity and excellent metabolic and chemical stability in vitro.pt_PT
dc.description.sponsorshipThis work was supported by Fundação para a Ciência e a Tecnologia (FCT) through iMed.ULisboa (UID/DTP/04138/2013) and research projects PTDC/QUI-QUI/111664/2009 and PTDC/SAU-MIC/117060/2010. M. M. M. Santos would like to acknowledge FCT, “Programa Operacional Potencial Humano” and the European Social Fund for the IF Program (IF/00732/2013).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationChemMedChem. 2015 Dec;10(12):2080-2089pt_PT
dc.identifier.doi10.1002/cmdc.201500429pt_PT
dc.identifier.eissn1860-7187
dc.identifier.issn1860-7179
dc.identifier.urihttp://hdl.handle.net/10451/51232
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWileypt_PT
dc.relationIF/00732/2013pt_PT
dc.relationEnantioselective synthesis of indole alkaloids and their application as NMDA antagonists
dc.relationUtilization of host cell resources by the malaria parasite in the liver
dc.relation.publisherversionhttps://chemistry-europe.onlinelibrary.wiley.com/journal/18607187pt_PT
dc.subjectDiastereoselectivitypt_PT
dc.subjectDrug designpt_PT
dc.subjectDual-stage antimalarialspt_PT
dc.subjectMalariapt_PT
dc.subjectNitrogen heterocyclespt_PT
dc.titleEnantiopure Indolizinoindolones with in vitro activity against blood- and liver-stage malaria parasitespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleEnantioselective synthesis of indole alkaloids and their application as NMDA antagonists
oaire.awardTitleUtilization of host cell resources by the malaria parasite in the liver
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FDTP%2F04138%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FQUI-QUI%2F111664%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-MIC%2F117060%2F2010/PT
oaire.citation.endPage2089pt_PT
oaire.citation.issue12pt_PT
oaire.citation.startPage2080pt_PT
oaire.citation.titleChemMedChempt_PT
oaire.citation.volume10pt_PT
oaire.fundingStream5876
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
person.familyNameMonteiro
person.familyNamePerry
person.familyNameMoreira
person.familyNamePrudêncio
person.familyNameSantos
person.givenNameÂngelo
person.givenNameMaria Jesus
person.givenNameRui
person.givenNameMiguel
person.givenNameMaria
person.identifierG-7485-2011
person.identifierhttps://scholar.google.pt/citations?user=zduN6wsAAAAJ&hl=pt-PT&oi=ao
person.identifier627072
person.identifier.ciencia-idA516-1A46-D715
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person.identifier.orcid0000-0002-3262-4374
person.identifier.orcid0000-0002-8110-2740
person.identifier.orcid0000-0003-0727-9852
person.identifier.orcid0000-0003-1746-6029
person.identifier.orcid0000-0002-2239-9353
person.identifier.ridE-1746-2015
person.identifier.ridI-7189-2013
person.identifier.scopus-author-id55254669000
person.identifier.scopus-author-id7102554088
person.identifier.scopus-author-id6603561872
person.identifier.scopus-author-id8634544500
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
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