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Discovery of spirooxadiazoline oxindoles with dual-stage antimalarial activity

2022Artigo científico Acesso aberto
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dc.contributor.authorLopes, Elizabeth A.
dc.contributor.authorMestre, Raquel
dc.contributor.authorFontinha, Diana
dc.contributor.authorLegac, Jenny
dc.contributor.authorPei, Jinxin V.
dc.contributor.authorSanches-Vaz, Margarida
dc.contributor.authorMori, Mattia
dc.contributor.authorLehane, Adele M.
dc.contributor.authorRosenthal, Philip J.
dc.contributor.authorPrudêncio, Miguel
dc.contributor.authorSantos, Maria M. M.
dc.date.accessioned2022-05-20T13:23:21Z
dc.date.available2022-05-20T13:23:21Z
dc.date.issued2022
dc.description© 2022 Published by Elsevier Masson SAS.pt_PT
dc.description.abstractMalaria remains a prevalent infectious disease in developing countries. The first-line therapeutic options are based on combinations of fast-acting artemisinin derivatives and longer-acting synthetic drugs. However, the emergence of resistance to these first-line treatments represents a serious risk, and the discovery of new effective drugs is urgently required. For this reason, new antimalarial chemotypes with new mechanisms of action, and ideally with activity against multiple parasite stages, are needed. We report a new scaffold with dual-stage (blood and liver) antiplasmodial activity. Twenty-six spirooxadiazoline oxindoles were synthesized and screened against the erythrocytic stage of the human malaria parasite P. falciparum. The most active compounds were also tested against the liver-stage of the murine parasite P. berghei. Seven compounds emerged as dual-stage antimalarials, with IC50 values in the low micromolar range. Due to structural similarity with cipargamin, which is thought to inhibit blood-stage P. falciparum growth via inhibition of the Na + efflux pump PfATP4, we tested one of the most active compounds for anti-PfATP4 activity. Our results suggest that this target is not the primary target of spirooxadiazoline oxindoles and further studies are ongoing to identify the main mechanism of action of this scaffold.pt_PT
dc.description.sponsorshipThis work was supported by FCT (Fundação para a Ciência e a Tecnologia, I.P.) through iMed.ULisboa (UID/DTP/04138/2019), project PTDC/QUI-QOR/29664/2017, and PhD fellowship SFRH/BD/137544/2018 (E. Lopes). The NMR spectrometers are part of the National NMR Network (PTNMR) and are partially supported by Infrastructure Project Nº 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC). Financial support from FCT and Portugal 2020 to the Portuguese Mass Spectrometry Network (Rede Nacional de Espectrometria de Massa – RNEM; LISBOA-01-0145-FEDER-402-022125) is also acknowledged.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationEur J Med Chem. 2022 Jun 5;236:114324pt_PT
dc.identifier.doi10.1016/j.ejmech.2022.114324pt_PT
dc.identifier.eissn1768-3254
dc.identifier.issn0223-5234
dc.identifier.urihttp://hdl.handle.net/10451/53099
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationLISBOA-01-0145-FEDER-402-022125pt_PT
dc.relationResearch Institute for Medicines
dc.relationNovo: Development of indole-based scaffolds for tackling Cancer and Malaria. Inicial: Development of spirooxindole scaffolds for tackling Cancer and Malaria
dc.relation.publisherversionhttps://www.sciencedirect.com/journal/european-journal-of-medicinal-chemistrypt_PT
dc.subjectDual-stage antiplasmodial activitypt_PT
dc.subjectMalariapt_PT
dc.subjectOxadiazolinept_PT
dc.subjectResistancept_PT
dc.subjectSpirooxindolespt_PT
dc.titleDiscovery of spirooxadiazoline oxindoles with dual-stage antimalarial activitypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberUID/DTP/04138/2019
oaire.awardNumberPTDC/QUI-QOR/29664/2017
oaire.awardNumberSFRH/BD/137544/2018
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleNovo: Development of indole-based scaffolds for tackling Cancer and Malaria. Inicial: Development of spirooxindole scaffolds for tackling Cancer and Malaria
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FDTP%2F04138%2F2019/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FQUI-QOR%2F29664%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F137544%2F2018/PT
oaire.citation.titleEuropean Journal of Medicinal Chemistrypt_PT
oaire.citation.volume236pt_PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream3599-PPCDT
person.familyNameA. Lopes
person.familyNameFontinha
person.familyNameSanches-Vaz
person.familyNamePrudêncio
person.familyNameSantos
person.givenNameElizabeth
person.givenNameDiana
person.givenNameMargarida
person.givenNameMiguel
person.givenNameMaria
person.identifierhttps://scholar.google.pt/citations?user=zduN6wsAAAAJ&hl=pt-PT&oi=ao
person.identifier627072
person.identifier.ciencia-idE61C-F1AB-4D7D
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person.identifier.orcid0000-0002-0741-6127
person.identifier.orcid0000-0003-1746-6029
person.identifier.orcid0000-0002-2239-9353
person.identifier.ridI-7189-2013
person.identifier.scopus-author-id57203321271
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.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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